Dr. Robert W. Lee- President, Lubrizol Life Science Health – CDMO Division.
Water solubility is a key factor in determining the extent of a drug molecule’s therapeutic effect. There is a clear relationship between poor water solubility and bioavailability, as drug uptake may be variable and insufficient to provide the desired therapeutic effect.1
However, the molecular targets that exhibit physiological responses are often receptive to hydrophobic molecules, as they can cross membranes and fit into target active sites – leading to the development of active pharmaceutical ingredients (APIs) with poor water solubility. It is estimated that approximately 40% of existing market drugs and 90% of newly developed APIs suffer from poor water solubility.2
Historically, potential drug candidates were discarded in the early stages of drug development if they exhibited poor water solubility, giving rise to an increase in water soluble APIs with poor pharmacokinetic properties. But today, there exist a variety of techniques to enhance molecules with poor water solubility, allowing developers to create more efficacious medicines with improved delivery routes. This ultimately brings substantial benefits to patients, not only by accelerating the development of new treatments, but also enabling patient-centric dose forms including less invasive delivery routes such as oral and topical delivery, as well as benefits like smaller tablet size. These solutions are however not without challenge, and developers must navigate the complexity faced in their design, implementation and scale up.
Solubility Enhancement Techniques – A Breakdown
Drug developers and formulators can employ several techniques to increase the uptake of APIs with poor water solubility. These can be specific drug delivery systems, excipients, or size reduction techniques, to help increase the bioavailability of the API.
Size reduction techniques, such as nanomilling, can increase the drug particles rate of dissolution. By reducing particle size using mechanical energy to form nanosuspensions, the exposed surface area of the API is increased, allowing greater interaction with water. These suspensions ultimately result in the drug particles dissolving more quickly. Nanomilling is widely used as a method of solubility enhancement for APIs as it is a highly scalable and reproducible process with a proven track record, which is highly compatible with most dosage forms.
In amorphous solid dispersions (ASDs), the solubility of the drug substance is improved by disarranging its crystalline lattice to produce a higher energy state in amorphous form. ASDs require less energy for dissolution, therefore overcoming solubility barriers and providing increased uptake at the target site via a higher concentration gradient compared to its crystalline counterpart.
Inclusion complexes and novel excipients can also be used to enhance the uptake of a low-solubility API. In an aqueous environment, the drug and matrix or excipient form a complex that not only improves the dissolution and bioavailability of poorly soluble APIs through a low association constant, but also enhances the stability of the drug product. With inclusion complexes, stability is improved as the API is either partially or fully encapsulated within a hydrophobic cavity or segment of the host molecule.
Recent Developments in Solubilization Techniques
As the water insolubility of drug molecules has increased, the need for effective solubilization techniques has increased too. With traditional additives struggling to keep pace with the demand for improved solubility, novel excipients offer great potential for solubilization as well as offering additional formulatory and commercial benefits.
Recently, novel excipients have been shown to increase the solubility of water insoluble APIs 50,000-fold where commonly used excipients have previously failed.3 These formulants provide additional solubilization routes as one size does not fit all, increasing the overall chance of achieving the target product profile. Additionally, there is plenty of patent life remaining for novel excipients, resulting in more exclusivity in future drug design projects.
Over recent years, the sterile pharmaceutical market has expanded significantly, mainly driven by the COVID-19 pandemic. With this growth expected to continue, formulators are presented with not only the challenge of solubilizing poorly soluble APIs, but also producing sterile dosage forms for parenteral, ophthalmic, optic, and inhaled routes, as per FDA requirements.
Sterile medicines must have careful control over the levels of microorganisms, which can cause life-threatening conditions, such as sepsis, if released into the bloodstream.3 However, the common approach of terminal sterilization is often incompatible with solubilization techniques. For example, very few nanosuspensions are amenable to terminal sterilization. An important development has been the aseptic nanomilling process, where contamination is controlled throughout the manufacturing process. The sterile API is combined with sterile excipients and milled in a fully closed sterile equipment train. The sterile drug product intermediate is then aseptically filled and finished, affording sterile products that are safe for injectables and other sterile dosage forms.
Key Challenges in Solubilization
With a plethora of techniques available for increasing drug solubility, the first challenge is knowing where to start in the development and formulation process. Having several options – ideally orthogonal approaches that can be run in parallel – will enable the highest chance of success, as some techniques are more likely to work with certain routes of administration. For example, ASDs are ideal for oral dosage forms, but not so for other routes of administration.4
By identifying the physicochemical characteristics of the API and the target product profile, formulators can decide which solubilization methods are most likely to yield success. However, this requires experience and expertise, and may also call for specialized equipment not currently available in-house.
Reproducibility and reliability are key pillars in pharmaceutical development, and this is especially true when formulating APIs with poor solubility. To ensure the drug product is consistent throughout, suitable analytical methods must be used to adequately characterize the drug product, as well as to identify and correlate relevant critical quality attributes (CQAs) to biological performance and drug product stability. Pharmaceutical manufacturing that incorporates solubility enhancement often involves complex processes, which can make it difficult to ensure that operations are progressing as intended. As a result, maintenance and calibration may need to be more frequent to ensure the equipment is working as intended, leading to increased costs.
Another important consideration is the scalability of the process. Some systems, such as microfluidics processing, are very effective but struggle when the time comes to scale up for commercial manufacture. Traditionally, the solution would be to run the technique in parallel to afford larger quantities – but this can lead to an engineering headache when trying to scale up processes that are not designed for large throughput.
When new equipment is brought into the process, additional time and cost must be expended not only for design, installation, and qualification, but also to train staff to GMP standards on the new technologies. Additionally, the inclusion of automation adds further complexity and, given that the system will need to be compliant with the FDA’s 21 CFR Part 11 data expectations, more resources will be required during the set-up process, potentially setting back the project and further increasing the costs.
In summary, where solubilization techniques are required, drug developers may see extended timelines and increased overall development costs of a drug product, due to the need for specialized equipment, as well as the appropriate expertise.
Leveraging CDMOs to Reduce Cost and Accelerate Time to Market
Many of the challenges associated with developing and manufacturing drug products with poorly soluble APIs can be mitigated by leveraging external resources. Outsourcing to a CDMO has many advantages – ultimately saving time and expense, with the bonus of working with a team that is experienced in multiple techniques. This allows for a better evaluation of compatible drug delivery systems and helps to sidestep potential roadblocks in development and scale up.
Qualified contract developers will work in close collaboration with their clients to fully understand the API and the desired drug product, including communicating efficiently to define the target product profile. Using a wealth of knowledge and experience, potential drug delivery systems and bioavailability enhancement techniques can be evaluated through feasibility studies. These are inexpensive and rapid programs designed to evaluate a specific technology and identify whether it would be suitable for a given API. Following successful screening, clients can then decide whether to invest in the equipment needed to carry out this technique in-house or to proceed with using the CDMO’s facilities. Even with the capabilities to perform a feasibility study in-house, there may be additional challenges in taking the API from R&D to a larger scale while complying with GMP protocols. As an alternative, CDMOs can offer large scale up based on their feasibility studies – enabling the manufacture of GLP test articles and GMP clinical trial materials, which can save months of work and reduce financial costs. Outsourcing also affords flexibility during periods of reduced activity on a project. For example, during lengthy toxicology studies, engagement with a CDMO can be paused – whereas in-house costs would remain fixed, despite the lower demand on resources.
Choosing a CDMO with wide-ranging technical capabilities opens further possibilities for developing drugs with poorly soluble APIs. With a better stocked toolbox at their disposal as well as the relevant expertise, such CDMOs have the scope to successfully combine solubilizing techniques and alternative dosage forms for an optimal outcome. For example, nanosuspensions could be paired with techniques such as spray drying or incorporated into a drug-eluting device or dissolvable film strips. In most cases, cost and lack of expertise are prohibitive to this holistic approach in-house.
Key Takeaways
There are many effective methods to enhance solubility, which can in theory allow a growing number of poorly soluble APIs to reach their full therapeutic potential. But without the relevant expertise and resources, projects can easily stall, fail, or see costs spiral.
Outsourcing to an expert CDMO can help reduce the impact on timescales and budget compared to performing solubility enhancement in-house, as well as providing peace of mind to developers that operations are compliant with GXP standards. However, it’s of paramount importance to select the right partner to work with. One solubilization technique will not fit all poorly soluble APIs, so a CDMO with a broad range of technical expertise and facilities will allow more shots at goal, increasing the chance of delivering the target product profile.
References
- Savjani KT, Gajjar AK, Savjani JK. Drug Solubility: Importance and Enhancement Techniques, ISRN Pharm 2012; 2012:195727
- Key Considerations for Ocular Drug Development & Solubility Enhancement Techniques. Available at https://lubrizolcdmo.com/resource-center/guides/premium-thank-you solving-solubility-challenges-for-a-novel-oncology-drug/. Accessed July 7, 2023
- Reich J, Weyer FA, Tamura H, Nagaoka I, Motschmann H. Low Endotoxin Recovery— Masking of Naturally Occurring Endotoxin, Int. J. Mol. Sci. 2019, 20(4), 838
- Schittny A, Huwyler J, Puchkov M. Mechanisms of Increased Bioavailability through Amorphous Solid Dispersions: a Review, Drug Deliv. 2020, 27(7), 110-127
Dr. Robert W. Lee is President at Lubrizol Life Science Health – CDMO Division. He holds BSs in Biology and Chemistry from the University of Washington and a PhD in Physical Bioorganic Chemistry from the University of California, Santa Barbara. Rob has published more than three dozen articles and five book chapters plus holds 11 issued patents and 15 provisional or PCT patent applications. He has over 30 years’ experience in pharmaceutical research and development.
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