Addressing Poor API Solubility with Comprehensive Particle Engineering Technology

With approximately three-quarters of new small molecule drug candidates considered to have poor solubility, there is a growing need for advanced solutions that manipulate the physical form of APIs without changing their molecular structures. Particle engineering has been shown to be an effective means of enhancing solubility and bioavailability. Olon is building on its experience in particle engineering, creating a center of excellence in the technology, and investing in additional large-scale equipment. These added capabilities will enable the company, in close collaboration with pharma customers, to identify optimal physical characteristics for APIs from the earliest development stages and thus accelerate the development of safe and effective medicines.

Poor Solubility and Bioavailability Drive Need for Delivery Solutions

Most pharmaceutical products developed in the last several years and currently under development today are characterized by low solubility and low absorption. In fact, it is estimated that nearly 75% of small molecule drug candidates can be classified as poorly soluble according to the Biopharmaceutical Classification System (BCS). Low solubility and permeability lead to low levels of absorption and thus low bioavailability, which directly impacts efficacy.

The increasing number of poorly soluble small molecule drugs can be attributed to the evolution of pharmacological research. The use of combinatorial chemistry and high-throughput screening has led to the identification of biologically active molecules that are highly complex and often contain hydrophobic functional groups that allow for greater specificity but result in reduced water solubility. This trend is particularly true for new anticancer therapeutics.

Focusing on the Physical Form of APIs

For APIs that suffer from poor solubility, it is not sufficient to focus all efforts on achieving highly pure drug substances free of chemical impurities. There is also a need to consider the physical forms of these APIs. Consequently, new and technologically advanced formulation and delivery solutions are needed to realize robust and reproducible bioavailability.

Focusing on the physical forms of APIs requires consideration of not only chemical quality, which remains essential, but also a broader analysis of physical characteristics. Previously, physical form analysis was generally limited to investigation of the polymorphism of small molecule APIs. Today, that has expanded to consideration of all dimensions that contribute to the ideal physical form of a drug substance, with the goal of accelerating process and formulation development for APIs with maximal solubility and absorption and the highest quality.

Particle Engineering Is Essential

One of the challenges to enhancing solubility is the need to achieve this goal without changing the molecular structure of the drug substance, as doing so can negatively impact efficacy and safety. It is well known that increasing the surface area of particles leads to increased solubility. The same is true for drug substance solubility in biofluids. Reducing the particle size and achieving reproducible, very low particle-size distributions can enhance solubility and therefore absorption. In some cases, these effects can be magnified through formulation with excipients that act as absorption enhancers. Indeed, drugs administered as solid dispersions using advanced inhalation technology require the use of nano- or microparticles with very narrow size distributions.

Such new formulations require well-defined and consistent physical quality attributes to guarantee correct API absorption profiles throughout the entire life of each product. Advanced particle-engineering technologies (milling, micronization, and nanoprecipitation) enable the manipulation of small molecule APIs so that they meet these specific physical form requirements. These technologies can be applied to APIs directly or, as mentioned above, to amorphous solid dispersions of crystalline APIs in polymeric excipients formed via spray drying or hot-melt extrusion.

Specialized Expertise Required by API Manufacturers and Formulators

A particle-engineering approach must leverage the skills and knowledge of both API producers and API formulators to avoid any misunderstandings, guarantee timelines, and ensure cost-efficient development of new drug substances and formulated drug products. Both sets of experts must communicate openly with one another and speak a common language.

To be most effective, particle-engineering technologies should be considered during the earliest phases of API development. With this approach, it is possible to ensure selection of the optimum technology and identification of critical process parameters that will reliably and reproducibly provide the target critical physical quality attributes of the API. The resulting robust processes will also be easier to scale from lab to commercial quantities. 

In the past, however, particle-engineering expertise existed among API formulators within drug companies but was generally not available within API contract development and manufacturing organizations (CDMOs). Olon is an exception to this rule. A specialist in particle engineering, the company develops highly controlled and reproducible processes that guarantee maximum precision with respect to the physical characteristics of the API, especially for poorly soluble drug substances.

Particle Engineering Investments at Olon

Olon prides itself on its leadership and innovation in particle engineering, which is clearly demonstrated through ongoing investments in research, equipment, and facilities that continue to expand the company’s internal skills and expertise. In addition, pharmaceutical clients are viewed as strategic partners, and their input is actively sought as projects move along the development cycle toward commercialization and when new technologies are investigated.

The Innovation Initiative, a wide-reaching internal program launched by Olon in 2021 to explore new particle engineering technologies in a structured manner, is a perfect example. With this initiative, Olon has established an internal path for the creation of a genuine center of excellence dedicated to particle engineering. State-of-the-art equipment and analytical instruments located at the center will enable the identification and reproducible realization of the ideal physical characteristics of API molecules with levels of definition and precision not previously attainable.

A new team focused on particle engineering will be able to monitor data generated at each drug development phase, allowing the optimization of the physical forms of new APIs during clinical development, as well as to support new applications/formulations of known drugs, including generics. When developing formulations, team members will interact directly with researchers at pharma customer organizations, and, where appropriate, other customer outsourcing partners.

Additional past and recent investments at Olon include laboratory systems for modeling the particle size of specific products — for example, different mills, micronizers, spray dryers, wet mills, and so on. These systems will allow the company to offer maximum flexibility and support for customer formulation efforts, even during the initial phase of API development.  

This flexibility will also facilitate the rapid development of candidate APIs at different particle sizes with different physical characteristics. Additionally, expanded analysis capabilities will support the investigation of the widest possible range of quality attributes. These analytical techniques will afford the ability to have greater control over the quality and physical characterization of customer products.

 Furthermore, the installation of new equipment within high-containment systems, such as glove boxes, will allow the performance of detailed studies on highly potent APIs, such as respiratory and cancer candidates. These types of compounds often require more targeted control of their physical forms, and the ability to perform particle-engineering studies in contained units ensures protection of operators and minimizes the risk of cross-contamination.

Additional investments being made at Olon in large-scale equipment, including micronizers and spray dryers, will allow implementation of the optimized solutions identified during process and formulation development at manufacturing scale.

Combined, the investments in lab- and commercial-scale production equipment and advanced analytical technologies enable Olon to provide drug developers with API particle engineering solutions that are robust, reliable, and scalable from lab to commercial manufacture.

Giorgio Bertolini, Ph.D.

Dr. Giorgio Bertolini studied chemistry at University of Milan with a thesis on stereoselective electrophilic amination and aldol condensation in the labs of Prof. Cesare Gennari. Then he moved to Polytechnic of Milan to complete his education at the Specialization School of Organic Synthetic Chemistry. He subsequently undertook postdoctoral research with Professor Barry M. Trost at Stanford University, where he worked on selective modification of steroids. In 1987, Giorgio joined the research laboratories of Zambon, where he started his industrial carrier as Medicinal Chemist in lead generation, hit identification, and optimization. After 12 years in medicinal chemistry, he became Process Chemistry Director of the Italian sites of the Clariant Life Science Molecules Business Unit. Following 20 years of experience in process chemistry in different companies, he is currently Senior Vice President Research & Development at Olon Group. Giorgio is now responsible for all the innovation activities of the group for both fermentative and chemical processes with particular focus on recombinant peptides, highly potent APIs, continuous processes, bioconversion, photo- and electrochemistry, and hazardous chemicals. Giorgio is currently vice-chair of the Innovation Committee of the European Fine Chemical Groups (EFCG) and member of the board of the Organic Chemistry Division of the Italian Chemical Society. He is the author or co-author of more than 70 patents and around 30 publications on major international Journals.