BIOAVAILABILITY ENHANCEMENT – Navigating a Broad Spectrum of Solubilization Technologies: Part III of III

In parts I and II of The Second Quadrant series on solubilization technologies, the conversation revolved around current uses and untapped opportunities of today’s technologies with respect to enhancing the bioavailability of poorly soluble drugs. In the final part of this series, the discussion focuses on the future. And in the spirit of the column’s goal for industry-wide collaboration, we welcome another solubilization technology company that has offered to provide their views. In Part III, 10 experts representing a broad selection of technologies (amorphous solid dispersions, co-crystallization, lipid-based solubilization, metal coordination, nano-particles, particle engineering, and particle size reduction) provide their insights. The article concludes the series with opinions on recent breakthroughs and what they could mean to all of us who are committed to overcoming poor bioavailability.


Q: In the past 5 years, what have been the most significant breakthroughs that directly involve solubilization technologies or how they’re used?

Dan Dobry: One breakthrough has been the development of a small-scale spray dryer that can produce small quantities of spray dried dispersion with high yield, but also produces particle properties that can be scaled up. This has enabled the application of spray dried dispersion technology into the preclinical setting. Companies that successfully use these dryers are able to enable rapid compound selection at the Med Chem/Development interface. Bend Research has provided these spray dryers and the training required to operate them to clients. This dryer was designed using computational fluid dynamics to ensure the process can be scaled up. An exciting area of research is the design of new excipients that are specifically designed for application to solubilization problem statements. Bend Research’s collaboration with Dow Chemical is an example of where new breakthroughs in excipient science can impact the throughput of the spray drying process. Stay tuned for future developments.

Tom Dürig:
In the past 5 years, we have seen significant improvement in understanding how different polymers work in solid dispersions, as well as in the fundamental understanding of limitations and the mechanism of how different solubilization technologies, such as amorphous dispersions, lipid, surfactant, and self-emulsifying systems, affect absorption. Additionally, we are on the cusp of a new era with several companies developing purpose-designed excipients for solubilization, for instance, new versions of AquaSolve(TM) HPMCAS with improved extrudability and solubilization power.

Dr. Joan Feixas: In the past 5 years, advances in design strategies and characterization of cocrystals have continued to increase significantly within the crystal engineering field. Crystal engineering has been improved by better understanding of known synthons (combinations of hydrogen bondings) and the discovery of new ones. Hence, the rational design approach has grown at the expense of high-throughput screening. Furthermore, cocrystal structure prediction software has also progressed, although predicting these crystal structures is still a major challenge. Single crystal X-ray diffraction (SCXRD) remains the most common method to confirm the structure of a cocrystal although other techniques like X-Ray Photoelectron Spectroscopy (XPS), 15N CP-MAS NMR and 13C CP-MAS NMR are also used.

Dr. Filipe Gaspar: More than significant breakthroughs, I believe there has been a continuum of knowledge gathering in areas such as polymer and material science, solid state characterization, formulation design, IV/IV correlations, and mechanistic understanding of processes. This, together with the existence of technology providers from early research up to commercial reality has, in my view, accelerated the use of these advanced technologies.

Dr. Robert Hoerr: Expanded uses of innovative processes and new excipients have allowed the preparation of amorphous solid dispersions or solutions. These stable amorphous forms are rapidly emerging as one of the most useful methods of enhancing the solubility and bioavailability of BCS class II/IV drugs. Electrospray technology is now being developed to achieve that goal. In particular, electrospraying offers fast processing times, scalability, and the ability to process thermally sensitive drugs.


Keith Hutchison:
The improvements in bioavailability using lipid-based formulas is impressive for many APIs throughout the past 5 years, evidenced by the significant increase in the number of compounds in development using lipid-based formulas, particularly liquid and semi-solid compositions in hard capsules. The equipment and processes used to develop, evaluate, and manufacture liquid and semi-solid hard capsules have also advanced in terms of scale-up, commercial scale, process efficiency, and versatility.

Dr. Dave Miller: The understanding of drug-polymer interactions and the identification of the most effective concentration-enhancing polymers toward maximizing and stabilizing supersaturation from amorphous solid dispersion systems has increased substantially in recent years. This has been critical to the advancement of amorphous dispersion technologies and their application for bioavailability enhancement. Also, I believe the advent of the KinetiSol technology will significantly expand the application of amorphous solid dispersion systems because it increases the space of compounds and compositions that can be viably processed into amorphous dispersions by non-solvent processing. It will relieve the current burden on commercial GMP spray drying technology and create new possibilities for advanced amorphous dispersion compositions that will yield better drug products.

Dr. Tom Piccariello: Due to poor aqueous solubility, 40% of newly approved drugs and over 60% of drugs under development have oral bioavailability issues. Ideally, a drug substance possesses both adequate aqueous solubility and hydrophobic properties. This combination remains difficult to achieve, but recent breakthroughs in solubilization technologies appear promising. These breakthroughs include advances in modeling systems to better understand bioavailability issues, as well as developments in novel excipients and new processing techniques, in innovative methods to modify drug properties, and in new reformulation techniques. Synthonics addresses the latter two areas through its application of its metal coordination chemistry. Metal coordination has the capacity to very effectively address API oral bioavailability issues of impaired drugs by enhancing both water and lipid solubility simultaneously.

Dr. Mark Mitchnick: Perhaps the biggest advance is simply the increasing acceptance that bioavailability can be impacted in a predictable way. If one really studies the currently available, scalable technologies, it’s clear there have been only incremental technical advances, but the real improvements have come from better execution.



Q: Where do you see the size and direction of the industry over the next 5 years, and the role solubilization technology innovation providers will play?

Dan Dobry: The overwhelming trend in the industry (including large pharma, mid-size, and small companies) shows high use of low-solubility compounds, especially in many specific therapeutic areas. For other targets, some researchers are steering their chemistry to more soluble compounds. Because the development timeline is lengthy, only time will tell in which philosophy enables the best new medicines. For now and the foreseeable future, low-solubility compounds will be an important part of small molecule drug development.

Tom Dürig: The industry is rapidly morphing from highly specialized niche drug-delivery applications into main stream practice. We are already seeing the second wave of solubilization demand coming from generic companies.


Dr. Joan Feixas:
More and more poorly soluble drugs emerge from contemporary drug discovery programs, and this trend may increase in the future. Development of these drugs is subject to significant risk of new products demonstrating low and erratic bioavailability with consequences for safety and efficacy. Pharmaceutical cocrystallization can certainly expand the possible solid forms available for development and should become a routine objective with relatively low cost and limited incremental risk to improve solubilization for poorly soluble APIs, especially when the formation of salts is not possible. Some drug candidates that were rejected in the past for poor solubility or poor solubility profile could certainly be reassessed using this new solubilization technology approach.

Dr. Filipe Gaspar: The vast majority of oral drugs are poorly soluble, and this will continue to foster the application of solubilization platforms not only for new entities but also in reformulations. The size of the market will certainly grow with the increased usage of current solubilization technologies and with new ones coming along. There will be specialized niche players, and contract manufacturing organizations will have a greater responsibility not only in providing a timely pathway for development and commercialization of products needing novel solubilization technologies, but also in contributing, together with academia, sponsors, and regulators, to key advances and innovations.

Dr. Robert Hoerr: Because of the new solubilization technologies, including particle engineering, the pharmaceutical companies will improve the yield of their discovery programs and have more potential compounds to develop. ENS is applicable from early screening during drug discovery for processing compounds in quantities ranging from mg to commercial scale.

Keith Hutchison: Solubilization technology providers are playing an increasing role, globally, and across all market segments, including specialty NDA 505(b)2 application. Bioenhancement is critical in both nutraceutical and pharmaceutical applications, to enhance the efficacy of existing formulations or advance new small and large molecules to market. The customer is looking to key partners to provide the scientific depth and range of technology options to address solubility, and other formulation challenges, and meet their target product profiles. Combine this with the steady flow in the number of poorly soluble compounds and the industry is set for more commercial products utilizing solubility and permeability enhancement technologies.

Dr. Dave Miller: I envision less formulations R&D and specialized formulations expertise in-house particularly in the solubilization technology space; therefore, the industry will be relying more on external providers to develop solubility-enhanced formulations. As the percentage of poorly water-soluble compounds in development pipelines continues to increase, the demand for solubilization technologies will grow. Hence, companies providing novel solubility enhancement solutions and services will be in greater demand and will become an increasingly more value-added component of the pharmaceutical development chain.

Peter Nelson: As was stated in Part II of this multi-part series, the need for solubilization technologies will continue to grow. Service providers, excipient and equipment suppliers, and the pharmaceutical companies themselves will be required to operate more efficiently and at lower cost while simultaneously reducing risk. I envision the need for further collaboration between equipment and excipient suppliers, service providers, and the pharmaceutical innovators to steadily increase. The requirements, objectives, and milestones associated with projects need to be more transparent at the onset. The more all involved parties understand, the faster the desired result is attainable.

Dr. Tom Piccariello: The role of solubilization technologies will grow as products incorporating them enter and succeed in the market. Throughout the next 5 years, we see the industry growing in size and moving in directions that are validated by success. In addition to their traditional role in drug development, these new solubility technologies could provide a rescue function for previously marketed drugs or for drug candidates that were not marketed but perhaps could be when helped by the new technology. Metal coordinated pharmaceuticals have the potential to be a significant component of this expansion.

Dr. Mark Mitchnick: We like to think of it as BA providers and solubilization being one large portion of that space. Clearly, the field will expand. Our jobs aimed at increasing BA have more than doubled in the last 12 months alone.


Q: Is there any information about
solubilization technologies, their applications, or the benefits they can deliver you believe DDD readers would find surprising?

Dan Dobry: Some readers may find it surprising how rapidly and efficiently, spray dried dispersion technology can be applied to compounds in all phases of development. Specifically, how little API is required to produce spray dried dispersions. In some cases, only tens of milligrams are necessary to produce enough dispersion to test the feasibility in vitro or in an animal model. Readers may also find that using innovative analytical methodologies, it is possible to be very fast and quite inexpensive to complete a feasibility study. Additionally, spray drying is ideally suited to compounds that may require high containment. As long as formulators partner with companies that have the experience and know-how to scale up their formulation, it can be a rewarding experience.

Tom Dürig: I believe the power of solubilization technologies and amorphous dispersions can be truly illustrated by a recent case our scientists worked on, where we developed an amorphous drug dispersion that enhanced bioavailability 15-fold and reduced the dose from 15 capsules to 1.

Dr. Joan Feixas: Pharmaceutical cocrystallization can be used not only for solubilization, but also to improve other properties of the API, such as hygroscopicity, flowability, handling (higher melting point, easier filtration…) and tabletability. Cocrystals can also be used for chiral resolution of racemates or in purification processes of APIs or intermediates.


Dr. Filipe Gaspar: It may surprise some of us to realize that solid dispersions are the fastest growing solubilization platform. Ten years ago, such approach was generally seen as a last resort, and today is for many formulators the first or second option in their tool box.

Dr. Robert Hoerr: One of the key challenges in solubilization technologies is to produce uniform nanoparticles. Electrospray is a liquid atomization method that uses electric forces to overcome surface tension during the breakup of a liquid jet. Compared with current technologies, such as ball milling, bulk mixing, high pressure homogenization, and double emulsion techniques, electrospray has many potential advantages. First, electrospray can generate monodisperse particles. The size of particles can be varied from a few nanometers to micrometers by adjusting operational parameters. More importantly, by using different nozzle designs, structured nanoparticles with complex composite structures can be produced in a controlled way, such as for high-efficiency drug particle encapsulation. Furthermore, unlike mechanical spray techniques, electrospray is a gentle method operated at ambient conditions. As a result, the particles’ chemical or biological properties are preserved without degradation due to heat or mechanical stresses. In addition, all the particles generated by electrospray carry charges with the same polarity. Particle agglomeration can be minimized using charge repulsion. Such monodisperse, non-agglomerated particles, especially particles in the nanometer range, can provide new approaches for designing high-performance drug formulations.

Keith Hutchison: Lipid, liquid, and semi-solid fill approaches are often utilized to address a range of formulation challenges in combination with bioenhancement, eg, high potency, low dosing, food effect, and API stability. And while some customers often perceive soft gel capsules as the one and only “liquid” dosage form, Capsugel has pioneered filling and sealing of liquid and semi-solid formulations in Licaps® hard capsules, and today manufactures several billion units per year commercially at US, European, and Japan-based manufacturing facilities. Combined with our SGcaps® soft gel and solid lipid pellet technology, a range of final dosage formats can be evaluated in parallel for the development of optimized bioenhanced finished dosage forms.

Dr. Dave Miller: Solubilization technologies are often thought of as being applied later in clinical development; however, these technologies are frequently employed very early in preclinical development to enable the establishment of safety and efficacy for new chemical entities. These solubilization concepts are then typically incorporated into the drug product design to support clinical studies and ultimately commercialization. In this context, solubilization technologies are enabling new molecules as they facilitate advancement at every phase of development.

Dr. Tom Piccariello: One surprising aspect of metal coordination is the degree of solubility improvement conferred upon the API relative to the low cost of synthesizing what are new compositions of matter. Once the optimized form of the drug-metal coordination complex is defined, it can be relatively simple to manufacture. The cost-effectiveness of producing patentable molecules through this approach contrasts sharply with previous efforts to accomplish similar changes with more expensive technologies. Another aspect that may be surprising is the extent to which metal coordination can be combined with other techniques to find solutions to difficult technical barriers.


Dr. Mark Mitchnick: There are several unique drug delivery approaches to enhance bioavailability by “in use” solubilization technologies, but each has different caveats. It is in the appropriate selection from the full arsenal of approaches and then excellent execution that the products with best bioavailability are developed.


This concludes our interviews of the solubilization experts from the provider side of the industry. Clearly, we are gaining significant knowledge regarding the various issues that are required to develop and commercialize “enabled” formulations. As more products progress through the development stages and are launched with nanoparticles, solid dispersions, lipids, and other vehicles, strong precedence is being set that will give those with less experience the confidence to advance more compounds that have historically been viewed as “challenging.” There were many interesting and important points made by the column contributors in 2013, and from their input, we observed much agreement on the following points, the first about our collective success, and then two key remaining challenges:

• Significant progress is being made in new and old technologies, new and repurposed excipients, and in the collaboration among providers and the clients they serve;
• There is broad recognition that we need to have a deeper understanding of the chemistry, functional relationships, and molecular interactions between insoluble APIs and excipients; and
• Even when new excipients and technologies emerge, lack of familiarity, and the cost of proving the safety and effectiveness can significantly slow their adoption.

Insights provided by excipients and technology experts have been a catalyst for additional thought about the solubilization formulation design stage. Probably one of the greatest needs is closely related to the second bullet point, the need for better predictability. For example, given a specific poorly soluble compound, it is still difficult to predict which technology and combination of excipients will result in the desired pharmacokinetic profile. In fact, to arrive at a suitable formulation, the typical process involves significant iterations between formulation and IV/IV testing. Improvements on this process will require advances in our understanding of the key factors governing bioavailability, how to manipulate those properties using materials science, and the interplay of those materials with the biological systems to which we intend to deliver these drugs. As the technologies to deliver poorly soluble molecules mature, standardization will become increasingly important. Examples of this could be algorithms for screening delivery platforms, testing methods, and the nomenclature used. Standardization of the best practices for developing, characterizing, and manufacturing solubilized formulations will become an increasingly important aspect as this segment of the industry moves forward. This will enable improvements in development cycles, reduction of risk due to false starts, and better communication amongst colleagues and regulators. These benefits of standardization could also positively impact our ability to more quickly adopt new and emerging technologies and excipients.


So where do we go from here? As it relates to the column, we plan on covering additional important topics in solubilization in 2014, including the state of the academic research environment for delivery of poorly soluble molecules and the materials science that is enabling better understanding and platforms. We want to explore the views from companies that have successfully commercialized solubilized formulations. We will see what lessons have they learned and what they believe are the unmet needs? We will take a deeper dive into the key scientific drivers behind why such a large percentage of compounds are coming from discovery with poor solubility. In conclusion, I’d like to thank again the experts who took time out of their busy schedules to contribute insights to the dialogues on excipients and solubilization technologies in the inaugural year of this column. To ensure The Second Quadrant serves as a forum for interactivity and collaboration, I invite you to send your reactions, thoughts, and suggestions so we can continue our conversation. New topic ideas are always welcome. As this is the last column of 2013, I’d like to wish all readers and colleagues success and good health in 2014.