These stable pharmaceutical formulations continue to increase in popularity; but new technologies require manufacturing expertise.
Although orally administered drugs are often more convenient than other dosage forms, the oral route subjects active pharmaceutical ingredients (APIs) to considerable stresses, including highly acidic and alkaline gastrointestinal environments. Thus, the stability of an API under these conditions is crucial in ensuring the correct solubility and dissolution rate for optimal bioavailability of the drug.
By keeping an API in an amorphous state, surrounded by a matrix of hydrophilic material to aid in initial wetting, pharmaceutical developers can ensure ideal stability. This type of formulation, consisting of the drug and a stabilizing polymer, is known as an amorphous solid dispersion, and is becoming increasingly popular for oral dosage forms. In addition to the benefits just mentioned, amorphous solid dispersions can sometimes be registered as unique intellectual property, giving them even greater value over traditionally formulated APIs.
As the range of cutting-edge technologies for the manufacture of amorphous solid dispersions continues to proliferate, the partnership of a contract manufacturing organization (CMO) with expertise in these formulations is essential. The following considerations are particularly key.
Recent years have seen significant advances in amorphous solid dispersion manufacturing techniques.
A wide range of technologies are used to produce amorphous solid dispersions. Two of the most common techniques are hot-melt extrusion (HME) and spray drying. Both technologies can be adapted for a variety of polymers and other excipients, and to create a water-insoluble final product at almost any scale.
Spray drying results in a fine powder, HME produces a more granular crumb texture in the final product. Although each of these types of product can be added to capsules or tablets, the differing manufacturing processes themselves involve different challenges and costs. And while many CMOs offer both spray drying and HME equipment, the choice of which process is best suited to a given drug is one that requires careful consideration and significant expertise.
For example, spray drying, requires the use of solvents, which are often flammable, and must be filtered out of the equipment’s exhaust during the manufacturing process. On the other hand, it can easily be adapted for API quantities as small as 100 milligrams, while HME typically requires enough API volume to fill the extruder. HME also utilizes heat over a longer period than spray drying, which can cause some APIs to degrade. This presents a considerable risk early-on in the development process, when the precise physical tolerances of the API may not yet be well understood.
More recently, however, new advances have expanded the capabilities of HME production lines. Some systems have been miniaturized, enabling them to work with much smaller quantities of API than their predecessors required. This enables HME to be tested earlier in the development process, when less API is on hand, risking less of the material while the manufacturing pipeline is still being fine-tuned. In addition, a wealth of new excipients have been developed specifically for use with HME equipment. New functional polymers, in particular, offer a considerably expanded range of potential tools for addressing unique formulation requirements.
The selection of a manufacturing method for an amorphous solid dispersion requires in-depth understanding of the benefits and risks of each approach.
When choosing a technology for the manufacture of an amorphous solid dispersion, the desired physiochemical traits of the resulting formulation must be taken into careful consideration. Some APIs, for example, may be less soluble, or have high melting points; both of which would suggest the use of HME technology. An API with a low glass transition temperature and/or a high thermal instability, on the other hand, would likely require spray drying instead.
One commonly used technique for determining some relevant physiochemical properties of an API is to prepare some samples via film-casting: dissolving the API and polymer in the same solvent, then evaporating the solvent away. Because this process closely approximates the stresses involved in spray drying, the results can help determine whether the API will survive that process, or if HME is necessary. An even simpler technique is simply to calculate the API’s melting point. If it’s below 180° C, spray drying is almost certainly the only viable technique.
Looking further ahead, the process of scaling up the manufacturing pipeline also involves different challenges, depending on whether spray drying or HME is used. For example, when spray driers are constructed on a larger scale, dried particles will become more likely to accumulate between the nozzle and the collection chamber, necessitating more frequent cleaning than at smaller scales. Devolatilization and filtration are also concerns with larger-scale spray drying, as hazardous gas products and water vapor will both be produced in larger quantities.
With HME, by contrast, the main challenge is to keep the temperature and shear rate of larger units consistent with those of smaller units. This requires careful calculation of changed in the number of divisions per kilogram, as well as the stress rate, within the extrusion chamber. As long as such parameters are maintained, however, scaling up an HME pipeline is typically just a matter of scaling up the amount of API fed into the equipment.
From the initial development and testing stages, all the way to full-scale manufacturing, amorphous solid dispersions must be continually evaluated to ensure that they retain critical quality attributes (CQAs) necessary for efficacy, as well as for regulatory approval; including bioavailability, solubility, particle size and crystallinity. To maintain these attributes, the manufacturing process itself must be evaluated to ensure that it falls within critical process parameters (CPPs), such as correct ranges of temperature and flow. The conditions necessary to maintain those parameters often change as the process scales up, requiring ongoing monitoring of each step in the pipeline.
In order to address challenges such as these, a growing number of pharma development firms are choosing to partner with CMOs earlier-on in the development process. Such partnerships enable developers and manufacturing experts to work together to evaluate multiple manufacturing techniques on small batches of API, creating less wastage, and shortening the time required to begin manufacturing for the clinical trial stage.
In addition to being an author and speaker, Susan Thompson serves as the Technical Director of Indianapolis based VxP Pharma.