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Chemical choreography: orchestrating complex API syntheses

Small molecules are essential for developing effective medicines, but their structural complexity and material behaviour present difficulties. In this article, Chris Brown, Senior Chemist, Onyx Scientific Ltd, discusses how the right technologies and approaches can enhance drug development and mitigate risk from initial phase to commercial launch.

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Strategies for the synthesis and development of complex active pharmaceutical ingredients

While the prevalence of biologics has grown within the pharmaceutical sector over recent decades, small molecules remain important and can offer significant advantages. Most are taken orally by patients and are bioavailable to target both extracellular components, such as surface receptors, and intracellular proteins by easily permeating the cell membrane. They can also be synthesised by chemical means alone and are often cheaper to produce.

Small molecules with increased molecular complexity can impart greater potency and selectivity in vivo,1 as evidenced by the prevalence of drugs derived from or closely related to natural products.2 Structural complexity can be hard to define, with several metrics available such as the fraction of sp3-hybridised (Fsp3) and stereogenic (FCstereo) atoms or, more recently, the spacial score (SPS).3 Analysis of existing drug libraries using these metrics identifies an optimal range of complexity for achieving high binding efficiencies and target selectivity without negatively impacting the manufacturing and developability of the molecule.

Alongside structural complexity and the associated synthetic challenges, complexity also presents with respect to physiochemical properties, materials handling and the developability of candidate molecules. This is especially true given the trend for molecules to become larger, more highly functionalised, lipophilic and less soluble.4

Molecular complexity and manufacturability

Considerations regarding a complex synthesis must start at the route selection stage and are multifaceted by nature. A synthetic pathway should be designed around readily available and cost-effective raw materials, make use of robust, selective and high-yielding chemistry and strive to minimise the total number of chemical steps performed.

The use of asymmetric transformations can be vital to the success of any process where a chiral centre is formed, as is often the case in more complex active pharmaceutical ingredients (APIs). This is an area where recent advances in (bio)catalysis can deliver big returns. The use of novel catalytic systems or enzymatic alternatives is far superior to classical chiral resolution or separation in terms of both economics and green credentials. Similarly, advances in catalysis can enable new transformations that have the potential to streamline synthetic pathways and should be considered as part of any development effort.

Scrutinising the green credentials of the process at an early stage enables the integration of improvements in atom efficiency and reaction mass intensity by design. This can be achieved by favouring efficient transformations such as rearrangements, additions, cycloadditions and concerted reactions where the formation of high mass, toxic or environmentally sensitive by-products is minimised. In many ways this approach aligns naturally with the goals of good process development and all efficiency gains contribute to a more sustainable and commercially viable process, which is especially important for longer routes.

Safety and hazard assessment

Process and operator safety will also influence route selection and highly energetic processes, intermediates (eg, low molecular weight azides or other explosives) and toxic reagents should always be avoided where safer alternatives exist. Where this is not possible, further investigations of reaction thermodynamics may be warranted. Often, a simple differential scanning calorimetry assessment (showing exotherms not exceeding 500 J/g) combined with careful step-wise scale up is sufficient for safe production of preclinical and early-phase API at a limited scale. If activities are to be extended into and above 100-200L vessels, further safety assessments are typically needed. This is particularly true for less efficient processes or when early-phase study requirements warrant production of > 10 kilos. In these cases, techniques such as reaction calorimetry and adiabatic calorimetry would be employed.

Efficient scouting, better by design

Often, a proposed synthetic route hinges on the success of a potentially challenging key chemical transformation. Evaluating these key stages of the synthesis in the lab first facilitates rapid decision making regarding which synthetic route offers the best chance of success. This avoids unproductive work on unsuitable pathways and generates valuable advanced intermediates and API samples to supply ancillary activities such as analytical development and solid-state profiling.

The success of early reactions with respect to literature examples may often depend on subtle changes in solubility, electronics or pKa associated with the target molecule. Therefore, it is important to initially screen a wide range of possible reagents and conditions. This work can be greatly accelerated by adopting carefully considered experimental design combined with efficient use of parallel synthesis equipment. Of perhaps even greater importance is the iterative process by which experimental data is clearly tabulated, interrogated and discussed within the project team so that important trends can be identified and conclusions made to inform future experiments.

Once starting conditions are identified, some reaction optimisation is typically performed looking to further refine basic parameters such as stoichiometry, solvent choice, temperature, reaction time and addition regime. Success is usually judged based on increased yield and reaction throughput or, often more importantly, a cleaner reaction profile, which gives fewer impurities that are difficult to purge. Often suitable conditions are identified early on, that with only minor changes, can form the basis of a successful process. A pragmatic approach should be taken to avoid over-development of a particular step during early phase work and should a molecule progress in the clinic, further optimisation can be scheduled to refine the chemistry.

Control of impurities

Impurity identification and tracking during development activities is readily achieved by liquid chromatography-mass spectrometry without significant additional burden on the development chemist. The resulting dataset is invaluable when assessing the purge and fate of key impurities and, in combination with a representative toxicology batch, setting specifications in line with ICH Q3A guidance. It is also important to consider composition in terms of potency of assay versus a highly purified standard even during early phase development. This can help avoid unexpected failures during critical process steps such as recrystallisation where inorganic impurities or oligomer/polymer content can fundamentally alter the physical behaviour of a batch during processing.

An assessment of potential mutagenic impurities (PMIs) and a nitrosamine risk assessment should also be performed to allow time for any associated analytical activities ahead of clinical studies. Where risks are identified, suitable control strategies must be developed in line with ICH M7 guidance, either based on a purge argument, analytical testing or often a combined approach. The core principles of the Quality by Design (QbD) approach should be applied where process knowledge is used to further understand and better define the relationship between the manufacturing process, the final product quality and any risks associated with manufacture so they can be effectively mitigated.

To support Phase II/III studies and move towards commercial manufacture the synthesis and full characterisation of impurity species is required. This allows formal fate and purge studies to be conducted which, in combination with Design of Experiments (DOE), can be utilised as an efficient means to identify and define the critical process parameters (CPPs) and critical quality attributes (CQAs).

Developability and performance of complex APIs

When developing complex APIs, a useful reference to consider during early phase assessment is that of Butler and Dressman who derived a Developability Classification System (DCS).5 This system, designed for oral immediate-release compounds, helps identify what aspects of a molecule’s performance characteristics, such as solubility, would limit oral absorption.5 The DCS can help derive strategies for formulation and identify the CQAs of the drug substance. These CQAs should be the target deliverables of an integrated solid form and chemical development process.

The incorporation of solid form characteristics and ‘performance’ of the final molecule (including key intermediates) plays a pivotal role in delivering a pro-active and risk-averse development strategy. Even compounds that reside within DCS class II and IV that display complex polymorphism can be appropriately controlled. This is achieved through a well-designed recrystallisation protocol that aims to control not only the crystal form but also purity and morphology. A phase-appropriate and iterative design approach is essential, avoiding over-engineering the presentation of a complex molecule until sufficient data is available to justify further process refinement.

Overcoming challenges in small molecule drug development

Small molecules continue to play a pivotal role in the supply of effective medicines. Their complexity, either in terms of structure or material behaviour, makes synthesis and development a continual challenge for those involved in deriving strategies that will deliver an effective drug product. Those molecules that are classified or predicted to sit within DCS class II and IV are of particular significance due to their low solubility, which is often compounded by poor physicochemical characteristics, a propensity toward polymorphism, or both. However, realising the benefits of integrating development teams from an early phase, plus making use of appropriate technology, can provide a streamlined and risk-mitigating journey from the early phase to commercial launch. Partnering with industry experts who possess specialised knowledge in areas such as solid form screening and regulatory guidance can significantly enhance the efficiency and success of drug development programmes.

References

[1] Clemons et al. Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles, PNAS, 2010, 107 (44), 18787–18792, https://doi.org/10.1073/pnas.1012741107

2 Newman J, Cragg GM. Natural Products as Sources of New Drugs over the 30 Years from 1981 to 2010, J. Nat. Prod., 2012, 75, 311–335, https://doi.org/10.1021/np200906s

3 Krzyzanowski A, Pahl A, Grigalunas M, Waldmann H. Spacial Score─A Comprehensive Topological Indicator for Small-Molecule Complexity, Journal of Medicinal Chemistry, 2023, 66 (18), 12739-12750, https://doi.org/10.1021/acs.jmedchem.3c00689

4 Agarwal A, Huckle J, Newman J, Reid DL. Trends in small molecule drug properties: A developability molecule assessment perspective, Drug Discov. Today, 2022, 27 (12), 103366, https://doi.org/10.1016/j.drudis.2022.103366

5 Butler JM, Dressman JB. The developability classification system: application of biopharmaceutics concepts to formulation development, J. Pharm. Sci.; 2010, 99 (12), 4940-54, https://doi.org/10.1002/jps.22217

About the author

Chris Brown, Senior Chemist, Onyx Scientific Ltd

Chris BrownChris Brown has gained 11 years of process development experience at Onyx Scientific Ltd, Sunderland. After graduating with a master’s degree in chemistry from the University of St Andrews, he moved into industry gaining experience in a GMP-compliant environment. Subsequently transitioning to process development, he has worked to deliver scalable processes suitable for the production of complex drug substance. Knowledgeable in IMPD-supporting activities, and in particular CMC, he has supported progression of molecules through all clinical phases.

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