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Industry is adapting to the increasing complexity and poor solubility and bioavailability of molecules in the pipeline.
Poor solubility and low bioavailability have hindered the development pipeline for some time and are set to continue to challenge drug companies in the future. As more new chemical entities enter development with complex needs, it is becoming more pressing for the industry to employ innovative and effective solutions to overcome solubility and bioavailability challenges.
To find out more about the issue of poor solubility and bioavailability, current approaches aimed at helping advance poorly-soluble drugs through the clinical pipeline, and best formulation practices for poorly-soluble drugs in development, Pharmaceutical Technology Europe spoke with Michael Morgen, R&D director, Lonza Small Molecules, and Craig Grant, global director, solid form and particle engineering, Veranova.
PTE: Could you explain why solubility/bioavailability is still such a big issue in bio/pharmaceutical drug formulation?
Morgen (Lonza Small Molecules): Compounds with low solubility or low bioavailability fall into Biopharmaceutical Classification System (BCS) II (high solubility–low permeability) and IV (low solubility–low permeability) regions. Over time, the industry has observed that these types of molecules are becoming the rule rather than the norm, as around 90% of preclinical compounds are now estimated to have bioavailability challenges (1).
There are several market factors that contribute to this continuing trend. For example, disease targets and associated API chemistry are being driven towards low solubility drug candidates. Many targets have pushed discovery chemists to molecules that are very hydrophobic, have high melting points, and/or high molecular weights—trends that have been clearly seen in Lonza’s portfolio of client compounds. The first two issues lead to low water solubility, while the third can limit solubility but also permeability, and therefore put a premium on solubilization. As examples, kinases have become important targets for oncology, and the kinase inhibitors often have rigid planar structures with high melting points. Many recent antivirals, however, tend to be larger, hydrophobic molecules having molecular weights >500 Da. High molecular weights are also typical of the newer classes of protein degraders being developed for a range of therapeutic areas.
Another market factor having an impact is that patients prefer the convenience, non-invasiveness, and lower cost of oral tablets or capsules. This is because orally-administered drugs are much easier to adhere to compared to those delivered parenterally. This is critical, as patient compliance is a paramount priority in drug development. The challenge, however, is the low intrinsic permeability of the API in the gastrointestinal (GI) tract, which results in poor bioavailability.
Grant (Veranova): The biotech and pharmaceutical industries are continually looking for novel and efficacious APIs to meet the needs of the growing and aging global population. During early-stage development, innovators often focus on potency or efficacy for candidate selection, meaning that downstream solubility/bioavailability considerations are often overlooked. This oversight can lead to time and effort being spent on overcoming developability deficiencies of a compound that can increase time to market. Despite that, there have been many technological advances in recent years making the development of poorly soluble drug moieties more attainable.
PTE: Is the issue of poor solubility/low bioavailability getting increasingly difficult?
Grant (Veranova): The issue has been growing for a number of years now. As of 2018, it was estimated that around 90% of APIs in the development pipeline are poorly soluble (1). This is fuelled by drug discovery turning towards candidates derived from more complex core molecular scaffolds, with increased molecular weight and often an increased number of chiral centres. Here, the introduced chirality provides developers with a tool to improve stereoselectivity, target specificity, and increase drug activity—as such, it’s likely this trend will continue.
However, many larger molecules typically don’t want to crystallize at all, and chiral drug molecules can present potential challenges from a chemical synthesis perspective.
Fortunately, solid form screening approaches with complex chiral APIs can aid syntheses via resolution methods, and once chirally-pure entities are in hand, absolute stereochemical assignments can be made using single crystal X-ray diffraction.
Looking ahead, the industry has become more accustomed to working with complex molecules; so, it’s likely that further advancements in technology and solid form methods will continue to evolve. Perhaps one day it will be possible to screen these larger, more complex molecules to understand—through predictive techniques—if they are likely to crystallize and determine the most thermodynamically stable form as well as the number of potential polymorphs, to speed up analysis.
Morgen (Lonza Small Molecules): While we anticipate that oral bioavailability will continue to be a common challenge, there are a number of bioavailability-enhancing technologies that can be leveraged to deliver small molecules orally. The key is to have a solid scientific understanding of the target drug product profile to be able to
select and utilize the appropriate enabling technology to address this challenge and create the most efficacious small molecule drug. Even as compounds entering the pipeline are becoming more complex over time, proven scientific methods and understanding will continue to be at the heart of solutions.
PTE: Are there ‘conventional’ and ‘non-conventional’ approaches to overcome solubility/bioavailability issues during formulation?
Morgen (Lonza Small Molecules): There are several technologies that have been developed to improve bioavailability. However, two of the most commonly used for commercially-viable compounds are particle size reduction (jet milling) and amorphous solid dispersions (ASDs).
Micronization, often performed using a jet mill, reduces the particle size of APIs (typically to <10 µm) to enhance bioavailability by increasing the surface area, and therefore the dissolution rate. ASD formulations are typically manufactured using either spray drying or hot-melt extrusion, depending on physical-chemical properties. ASD prevalence is driven by its broad applicability across a diverse drug compound property space and its scalability, offering the flexibility and control needed for an optimized drug product.
In terms of unconventional approaches, there are several opportunities for formulation and process innovation to extend the applicability of ‘conventional’ ASDs technologies to a broader range of APIs. One approach is the use of solvent technologies to enable spray drying of ‘brick dust’ compounds that have poor solubility in typical process solvents, as well as process improvements to thermal-based methods to reduce the thermal exposure while achieving a homogeneous system. On the formulation side, there is an opportunity to use existing excipient materials in novel engineered architectures to increase drug loading and to aid in the dissolution and sustainment of high drug concentrations.
Highly impermeable compounds—for example, high molecular weight ‘small molecules’ or biologics—continue to be a difficult challenge to deliver orally. A number of academic labs and start-up companies, especially, are working on innovative technologies to address these molecules. The specific challenges are to find ‘permeation enhancing’ approaches that are safe and that are broadly useful, as opposed to very specific to a particular active molecule.
Grant (Veranova): Fundamentally, the formation of an optimal solid form is the most important step in creating a drug product that has good solubility and bioavailability. For crystalline materials, optimal refers to the best salt, cocrystal, or parent-free form of an API that is developable. However, when it comes to the most ‘conventional’ or ‘non-conventional’ methods, these are wholly dependent on individual attitudes towards solid form techniques. Beyond selecting the ‘optimal’ solid form, we routinely overcome solubility issues using particle engineering approaches as well as enabling formulation techniques. These include excipient screening, the use of surfactants, and other related methods.
About 20 years ago, cocrystals were seen as a novel approach to overcoming poor solubility and bioavailability. Although they are more widely accepted today, there is still some hesitancy in the industry towards their use. This hesitancy is mostly due to a lack of understanding or experience in developing cocrystals. Hopefully, with increasing regulatory approvals of novel cocrystal products, they will become more conventionally accepted, as they are a valuable solution when no ionizable groups are present. As such, it is preferred, at Veranova, to run salt and cocrystal studies in parallel.
PTE: What technological advances have there been in terms of aiding solubility/bioavailability in drug formulation? Are there any advances in the pipeline that will be impactful in your opinion?
Grant (Veranova): As the industry has been forced to adapt to the increasing complexity of novel APIs and new chemical entities, technology to characterize and evaluate these compounds has also evolved.
Oral dosage forms continue to be the most preferable delivery route—due to self-administrative convenience and ease of manufacture. Therefore, advancements in the methods used to monitor their dissolution in the GI tract have been invaluable. Small-scale in situ dissolution is one such technology that has helped improve understanding of the solubility and bioavailability of BCS Class II compounds, those which are highly permeable in the GI tract but have poor solubility. When issues with the dissolution of APIs are highlighted earlier in development, it’s much easier for innovators to identify the potential developability issues and look to understand if the optimal solid form of a drug moiety will solve solubility and bioavailability issues. There have also been some advancements in the use of porous excipients, such as mesoporous silica, and metal-organic frameworks. Although there are still no FDA [US Food and Drug Administration]‑approved drugs utilizing these technologies, it’s likely the research in this area will advance in the coming years.
Morgen (Lonza Small Molecules): Improved in-silico prediction of formulation performance will be a significant opportunity going forward. There have been recent advances in using physiologically-based pharmacokinetic modelling in conjunction with more targeted in-vitro tests to select formulation technologies and compositions that will help aid bioavailability-enhancement strategies.
In addition, artificial intelligence approaches will likely play an increasingly important role in pharmaceutical development going forward. Machine learning approaches that have been broadly applied to drug discovery and clinical trial design are beginning to find applications in formulation selection and optimization.
PTE: Could you provide some best practices for formulators when dealing with poor solubility/bioavailability?
Morgen (Lonza Small Molecules): Addressing poor solubility and low bioavailability is often a critical need in commercializing a small-molecule drug.
Characterize the target product profile well. This information, along with extensive institutional knowledge of molecules with similar properties and target product profiles, can be used to develop a formulation strategy and choose which enabling technology to use.
Strategically choose drug delivery technologies early in the development process, based on preclinical, and then verified by first-in-human clinical success. Making this choice can be time- and resource-intensive; so, it is critical to base this decision on science and data. Depending on the target drug product profile, this will determine which bioavailability enhancing technology is needed to effectively formulate your compound.
Keep commercialization in the line of sight. As the product is moved through the development pipeline, it is important to demonstrate the ability to scale that formulation to the next phase. Early clinical trials can require significant quantities of drug products that may be challenging to provide under accelerated timelines without a well-planned scale-up strategy.
Minimize company-to-company transfers. Working with multiple outsourcing partners can result in duplicated efforts, longer timelines, and increased costs. This can be addressed with a single outsourcing model, where the right partner can optimize a formulation, progress a compound through clinical trials, and rapidly scale the drug product to launch.
Grant (Veranova): Optimizing the properties and performance of the drug substance is one of the most important things for formulators to consider when dealing with poorly soluble APIs. It’s vital to get as much information about the end goals of a novel drug product; things like the route of administration, drug target, and so on can impact the type of experimental design and yield the best value-added data. At Veranova, a hierarchical approach is employed, following the molecule through every stage of development to gather as much data as possible.
However, it’s unlikely that a single partner will be a ‘one-stop-shop’ expert; so, it’s important that developers consider their needs, requirements, and the complexity of their molecule when outsourcing. This consideration ensures the selection of the right expertise for a particular drug candidate.
With modern technology being able to work on a smaller scale without compromising quality, pertinent data can be captured earlier in development so that leading candidates pose fewer solubility and/or bioavailability issues that need to be overcome through formulation.
1. S. Kalepu and V. Nekkanti, Acta Pharm. Sin. B., 5 (5) 442–453 (2015).
Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.
Pharmaceutical Technology Europe
Vol. 34, No. 8
When referring to this article, please cite it as F. Thomas, “Adapting to Solubility/Bioavailability Challenges” Pharmaceutical Technology Europe 34 (7) 2022.