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Smithey150x200Dan Smithey, Ph.D., is the cofounder of Agere Pharmaceuticals.

 
As has been widely documented, portfolios of compounds in discovery and development now contain a significant fraction of water-insoluble compounds. This fraction is increasing over time, at least in part due to the need for novel compounds that have specific and potent interactions with modern biological targets. It is now widely estimated that more than 40 percent of compounds in many modern discovery libraries are essentially insoluble in water.

Many of these water-insoluble and hence poorly bioavailable molecules have been advanced into development, and several have become successful marketed drugs. A major reason for their success is the use of amorphous solid dispersions (ASD). In these systems, the drug is combined with a water-soluble polymer to ideally produce a single-phase amorphous mixture of the drug and the polymer. In the last decade, broad application of ASDs as an enabling formulation technology has contributed significantly to successful clinical evaluation and commercialization of these challenging compounds. Importantly, ASD formulation technology simultaneously provides improved bioavailability, acceptable physical and chemical stability, and commercial manufacturability

The underlying mechanism of the technology, key formulation attributes, manufacturing processes and scalability, recent commercial success, and future directions are all explored in the current issue of the AAPS Newsmagazine. The cover article, developed by the Physical Pharmacy and Biopharmaceutics section, is entitled Amorphous Solid Dispersions: An Enabling Formulation Technology for Oral Delivery of Poorly Water Soluble Drugs. There are several good reviews of ASDs referenced in the cover article.

While ASD technology has advanced significantly, a key question is: “How do we determine when to dedicate resources toward solid dispersion formulation development versus more traditional formulation approaches?” This question is very common and appropriate for any formulator who is tasked with advancing a poorly soluble compound. While there is no simple answer to this question, the decision to utilize ASD technology is typically made when it is desired to maximize oral bioavailability and after other “standard” approaches have been at least explored (these “simpler” approaches include salt forms, size reduction, and liquid formulations, among others).

The use of early, comparative preclinical in vivo studies (ASD versus a “standard” formulation) are extremely valuable when deciding if/when to advance an ASD formulation, and the investment in these studies should be seriously considered. Some other typical criteria to consider when determining when to utilize ASD technology may include:

  • experience of the development team,
  • qccess to specialized equipment for prototype and clinical manufacture,
  • analytical methods and associated equipment specific to ASD formulations,
  • the specific type and number of dosage form,
  • cost and development time, and
  • regulatory issues.

 Clearly these criteria are common for standard formulations as well and thus (along with other criteria) can provide a basis for a comparison in required development resources, and thus a basic risk assessment. For those of you who have developed ASD formulations, how did you make the decision to develop ASD formulations? What were your criteria?