BIOAVAILABILITY ENHANCEMENT – Addressing Solubility Challenges: Using Effective Technology & Problem-Solving for Delivery Solutions


Oral bioavailability represents a significant challenge to the pharmaceutical industry as more than half of the compounds in early development are considered poorly soluble. Bend Research, a problem-solving drug formulation development and manufacturing company, is well known for its spray-dried dispersion (SDD) technology, which is recognized as a reliable solution to this challenge because of its proven performance, predictable long-term stability, and excellent manufacturability.

This review is a follow-up to an interview published in the May 2012 issue of Drug Development & Delivery in which the company’s background and problem-solving approach to drug delivery challenges faced by the pharmaceutical industry were discussed.


Delivery of compounds with poor aqueous solubility is a common problem as more than 50% of new chemical entities fit into Class II of the Biopharmaceutical Classification System (BCS). BCS Class II compounds are poorly soluble but highly permeable, meaning that most cannot be absorbed during normal gastrointestinal transit times without an enabling formulation.

While there are many types of enabling formulations that improve the solubility of low-solubility compounds, they are generally based on three approaches: (1) use of highenergy crystalline forms, such as salt forms, co-crystals, and crystals with reduced particle size; (2) dissolution of the drug in a lipid vehicle or lipid, solvent, and surfactant vehicle (to create a self-emulsifying dosage form); or (3) manufacture of an amorphous dispersion. Amorphous dispersions are generally manufactured by spray-drying or a hot-melt process. Each of these approaches is viable, depending on the compound’s physical and chemical properties, and all have been used for commercial pharmaceutical products.


Bend Research takes an “agnostic” approach to choosing the appropriate solubilization technology, guided by a number of factors, including the compound’s physical-chemical properties, the projected dose, the desired release profile, and the results from numerous formulation and process models that we have developed throughout the past 15 years.

The goal in choosing the optimum solubilization technology is aimed at solving the right problem for that specific compound. Bend Research is capitalized for formulation development and cGMP manufacturing for spray-drying, hot-melt extrusion, and particle-size reduction to support our agnostic approach. Additionally, we can support the formulation of self-emulsifying and lipid formulations relying on a partner to complete the cGMP manufacturing.

While we consider all possible technologies as we develop formulation approaches for poorly soluble compounds, our experience in the formulation of more than 500 low-solubility compounds is that spray-drying amorphous dispersions is the most widely applicable approach. This process involves dissolving the compound and a concentration-sustaining polymer in a volatile organic solvent that is rapidly removed in the spray dryer. This process allows for rapid drying of the formulation and isolation of the amorphous dispersion. It is widely applicable in that it avoids either melting the compound in a hot-melt process or relying on the solubility of the compound in a lipid vehicle.

An additional benefit is that the spray-drying process has been scaled down to small scales compatible with early preclinical quantities of compound and scaled up to the multi-ton scales necessary for commercial manufacture.


There are three key components to obtaining a high-performing amorphous dispersion. These are the spray-drying process conditions, the identification of the compound’s physical-chemical properties, and finally, the choice of excipients that are used in the amorphous dispersion.

The spray-drying process is conceptually quite simple. Initially, the compound and a dispersion polymer are dissolved in a volatile organic solvent (e.g., acetone or methanol). The solution is then introduced into the drying chamber of a spray dryer along with heated nitrogen. The heated gas evaporates the solvent, leaving a dried powder, which is collected in a cyclone or baghouse. Of course, the process isn’t quite that simple. If the drying capacity of the nitrogen is insufficient, product will be deposited on the walls of the spray dryer, resulting in “spray-painting” and reduction of product yield. If the drying capacity of the nitrogen is overdesigned, energy costs are increased, and the risk of degrading a thermally labile compound is increased.

However, by using best practices, spray-drying conditions can be identified that allow the product particles to be maintained at low temperatures (due to evaporative cooling as the volatile solvent evaporates), while producing high product yields (avoiding spray-painting of the walls of the dryer). These best practices for spray-drying process development were highlighted in a 2009 publication in the Journal of Pharmaceutical Innovation.


Compounds with a wide variety of physical-chemical properties can be formulated as amorphous dispersions. During our decade-and-a-half formulating amorphous dispersions, we have found fewer than 10 compounds that could not be formulated as amorphous dispersions. These fall into two categories: (1) highly reactive compounds that chemically degrade in the amorphous state and (2) compounds with very high melting points that have poor physical stability or poor solubility in suitable spray solvents. However, this small group of compounds appears to be the exception rather than the rule.

The vast majority of compounds we have worked on (out of more than 500 tested) are amenable to formulation as amorphous dispersions, although their physical-chemical properties span meltingpoint ranges from 0°C to more than 350°C and log P values from less than 0 to more than 10. However, formulation compromises must be made for compounds at the extremes of physicalchemical property ranges to ensure performance is maintained. Generally, these compromises involve decreasing the amorphous dispersion drug loading or “swamping out” the poor drug properties by diluting the drug with the dispersion polymer. Of course, diluting the drug in polymer makes obtaining higher drug doses increasingly difficult. This is especially challenging in therapeutic areas such as anti-infectives, antivirals, and oncology, in which high doses are typically needed. To address these classes of compounds, we have developed alternative technologies.

These alternatives include a nanoadsorbate technology, in which a dispersion is coated on a high surface area support to increase the dissolution rate. This technology has been used in multiple clinical trials and notably has been used in the clinic to give dose-linear absorption of a log P 10 compound with a solubility of less than 10 ng/mL. To address the other extreme”“compounds with very high melting points and a strong tendency to crystallize in both the solid state and solution”“we have developed a crystallized dispersion technology in which small, tens-of-nanometer-sized crystals are intentionally formed in the dispersion. This approach maintains a high-energy form of the compound and prevents further crystallization of the compound to a lower-energy species. This technology has also been used to advance a number of compounds to clinical evaluation.


Excipient choice is critical and depends on the specific solubilization problem being solved. Recently, BCS Class II compounds have been subcategorized into DCS IIA and DCS IIB classes by Professor Dressman and coworkers from GlaxoSmithKline. DCS Class IIA compounds have inadequate dissolution rates, whereas DCS Class IIB compounds are truly solubility limited,making bioavailability difficult to achieve without concentration enhancing polymers. An added complication is that some compounds formulated as amorphous dispersions dissolve into solution and stay at that amorphous concentration. Others, particularly those with high melting points, dissolve and then rapidly crystallize if they are not sustained by the polymer.

As an example, for a DCS Class IIA compound for which amorphous solubility is easily sustained, the critical problem to solve is getting the compound to rapidly dissolve. Often, neutral polymers, such as BASF’s Kollidon VA64 (vinyl pyrrolidonevinyl acetate copolymers), work well due to their high water solubility, ability to dissolve in gastric media, and the reduced need to sustain the drug concentration. In fact, Kollidon VA64 can be highly preferred in these cases due to its high solubility in organic solvents typically used in spray-drying. Higher spray-solvent concentrations can substantially improve throughputs, which can lead to a decrease in the cost of goods.

For compounds that have a tendency to crystallize in solution or the solid state and that require improved solubilization, enteric, cellulosic polymers, such as Dow or Shin Etsu’s hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eastman’s cellulose acetate phthalate (CAP), perform very well. This is due to a combination of factors”“one being that the high glass-transition temperature of the polymers lead to superb solid-state stability for the dispersions; the second is that both polymers form colloids in solution that combine with the drug to yield both enhanced solubility and rapid dissolution rates.

As with technology, we are not tied to the choice of specific excipients, but we do find that HPMCAS has led to superior performance for more than half of the compounds we have worked on. An added benefit of formulating with HPMCAS is that Bend Research and its clients have access to one of the most complete safety packages through the Type V drug master file (DMF) for this polymer.


With BCS Class II compounds comprising an increasing percentage of compounds in our clients’ discovery portfolios, Bend Research is positioned to continue to provide the highest-quality support and innovation for our clients’ pipelines. This proactive support is focused on two crucial areas: (1) support of the existing technology platforms and (2) development of next-generation technologies.

To support existing technologies, we are engaged in ensuring clients have seamless access to the spray-drying capacity required as their compounds advance, as well as ensuring high-quality excipient supplies. An example of ready client access to spray-drying capacity is reflected in our collaboration with Hovione. This collaboration allows for facile transfer of programs from Bend Research’s research and development facilities to Hovione commercial facilities, either during Phase III clinical trials or following product launch. We know from experience that each client has preferred timing for this transfer, and we work with them to identify the best options and to perform technology transfer against this plan.

Similarly, we are working with the leading excipient providers to ensure access to a reliable supply of solubilization excipients that meet the critical-to-quality properties that are keys to their performance. These relationships are an active piece of our technologydevelopment portfolio and continue to mature.

In addition to supporting the existing technologies, Bend Research is working to develop new solubilization technologies. These efforts include working with the excipient providers to develop new solubilization excipients that improve performance and processability as well a developing improved spray-drying processes and equipment.

Finally, in addition to our internal research and development efforts and our ongoing work with our alliance partners, we are actively forming partnerships to commercialize the best new solubilization technologies in partnership with universities and small companies. Based on our company’s successful track record in advancing numerous technologies and reducing them to practice, this work is only natural, particularly given the increasing number of poorly soluble compounds being developed by the pharmaceutical industry.

Dr. Rod Ray is Chief Executive Officer and Chairman of the Board at Bend Research, where he has worked since 1983. During his time at Bend Research, Dr. Ray has held numerous positions specializing in the development and commercialization of a wide range of products. He has been instrumental in directing the management of large-scale programs to advance pharmaceutical compounds through the development process to commercialization, serving as the primary management contact for client companies. In addition to his expertise in advancing pharmaceutical processes and products, Dr. Ray has extensive experience in commercializing diverse products for the electronics, energy, medical, agricultural, and space industries. He earned his BS in Chemical Engineering from Oregon State University, and his MS and PhD in Chemical Engineering from the University of Colorado – Boulder. He is a licensed Professional Engineer in Colorado and Oregon. Dr. Ray holds 21 US patents and has 41 scientific publications to his credit.