Phase Appropriate Solid Form Development – Considerations Ahead of Phase 1

Introduction

Solid form optimisation and screening is a critical part of the development pathway for a new chemical entity. While historically most drugs have been produced as solids for oral delivery, the physicochemical properties of modern small molecules have led to an expansion in the technologies and complexity applied to the delivery of candidate drugs. Phase-appropriate screening addresses such issues as early as possible, beginning the iterative process of designing a development pathway that reduces risk and mitigates late-stage shortcomings. Identifying a suitable crystalline form, whether it is a salt or the parent molecule, is a typical benchmark. Other approaches that require consideration are cocrystal and amorphous solid dispersion, both with the potential to improve solubility and bioavailability. For newer modalities such as proteolysis targeting chimeras (PROTACs) whose physicochemical properties are often poor and complex, the latter is particularly relevant.

Development must strike a balance between cost, due to the high attrition rate of lead candidates, and the need for rapid progression. To achieve this, a phased approach to development is essential, with each phase tailored to the specific needs and challenges of the drug development process.

Physicochemical & biopharmaceutical considerations

The solid form of a drug product significantly influences properties such as melting point, hygroscopicity, solubility and powder flow. Before a form can be selected, candidates should be profiled in terms of predicted solubility and permeability, often accomplished in silico by medicinal chemistry teams as part of the lead selection process. This process often overlooks considerations such as morphology, material handling and manufacturing behaviour. This is not surprising, but does highlight the need to bear in mind such attributes or desirable critical quality attributes (CQAs) as development progresses and consideration of dose and dosage form are put in place.

Critical preformulation activities should include pH solubility measurement, stability over a range of pH and conditions and biorelevant solubility. Combined with pKA determination, this reveals whether a stable salt can form and if it is needed. Salt formulations typically address solubility/bioavailability issues, but can also improve manufacturability or remove impurities (although this is typically identified later in development when more material is available).

This can be accomplished at low cost to the material with the use of mini screens that aim to confirm the ability to form a stable salt and/or obtain a crystalline form. Mini screens requiring less than 1g of material can be used to differentiate lead candidates or simply profile a single lead before focused optimisation.

More than 90% of emerging small molecules demonstrate poor solubility, falling into (Developability Classification System) DCS class 2 (2a and 2b) or 4 (Figure 1)¹, often requiring bioavailability-enhancing formulations to achieve the desired toxicological coverage or exposure in different species. Therefore, it is critical to perform an appropriate series of profiling experiments to determine the development path for these candidates.

Figure 1 – The Developability Classification System (DCS) proposed by Butler and Dressman

Integrated solid form screening and chemical development

With data established, development that considers the desirable and molecule-specific CQAs can be initiated.

Understanding material behaviour is crucial, and access to both purified and processed typical solids becomes more significant as screening and chemical development progress. Therefore, an integrated scheme for development is optimal.

Appropriate solid form screening and stability studies facilitate chemical development, which in turn delivers early gram and multi-gram scale batches that fuel further solid form development.

A phased approach to pharmaceutical development

There is no one-size-fits-all when it comes to development. Compounds should be developed on a material basis, as solid form screening and selection should never be formulaic. The entire process must be both iterative and pragmatic when required, ideally integrating various aspects of pharmaceutical development, especially in the early phases. A schematic of a phased approach is provided below (Figure 2).

Figure 2- Schematic of the development work-flow for chemistry overlaid with solid form development and available amounts of material. 

The typical development pathway involves:

• Early phase lead differentiation and profiling screens (1-2 weeks, 0.5-1.0 g).
  • Crystallinity, salt potential, pH solubility are assessed, and parent vs salt forms are compared.
• Salt screening/cocrystal screening (4 weeks/6 weeks, 5-10 g).
  • A range of 12-20 salt formers and 2-3 solvents are employed in a cascade approach to screening and testing. Throughout the process, factors like processability and morphology are considered.
• Biorelevant performance and stability leading to salt selection including manufacturability assessment. Additional preformulation studies are often included (2-3 weeks, 1-2g).
  • Kinetic and thermodynamic solubility profiling are assessed in a range of pH values. Solubility is also tested in biorelevant media and buffer solutions at 25 and 37 °C. The recovered solids are then analysed to determine form and stability.
• Polymorphism screening (parent molecule or salt) (4 weeks, 5-7g).
  • Multiple modes of crystallisation are assessed, amorphous forms are profiled and thermal studies are performed to gain insight into the properties of the material, and determine the relationship between different forms (monotropic/enantiotropic) and identify the most stable form.
• Crystallisation development (4-6 weeks, 50-250g).
  • The production of the chosen crystal form is scaled up to meet the quantity needed for clinical trials. Crystallisation conditions are optimised by assessing temperature and solubility profile, experimenting with seeding techniques (adding crystals to control growth), evaluating the final crystal morphology and assessing the ability to remove impurities during the process.

Salt versus parent?

If early physicochemical profiling work is in place, the choice of salt vs parent is more obvious. As it is expensive and time-consuming to change salt versions in later development phases, it is crucial to make a robust choice based on reliable data.

Phase-appropriate screening necessitates thorough investigation, but not exhaustive screening typical of Phase 3 candidates. For these candidates, the route of synthesis is well established, impurity profiles are defined and the need to provide a comprehensive form landscape for intellectual property purposes is justified and imperative.

The choice of salt vs parent is a critical early step and involves more than solubility considerations. Creating a salt involves an extra chemical step, impacting overall yield, sustainability and production costs, which become more significant as batch sizes increase. The potency of the compound must also be considered in terms of relative molecular weight. For example, dosing a 200MV parent molecule as a tosylate salt means that for a given dose just over 53%wt of a simple drug in capsule formulation would be the active ingredient.

Overlapping solid form and chemical development can provide real efficiencies throughout the lifetime of the project. As a significant number of synthetic routes terminate with a functional group deprotection, understanding the optimal salt form enables a strategy that deprotects and delivers the salt directly. Classic examples of this are hydrochloride, sulfate and mesylate salts following BOC-deprotection.

Value in collaboration

Collaboration is crucial throughout development activities. Timely and effective communication of learnings from initial solid form development to chemistry, formulation development and toxicology teams can reduce development times and optimise the planning of later phase activities based on real data. This is an iterative process where the growing knowledge base generated by all teams forms a critical feedback loop.

Polymorphism and design of crystallisation

This type of collaboration is routinely demonstrated in-house, as data relating to chemical and form stability and purge of impurity guides what should be considered as ‘process typical’ for feeding into solid form activities such as crystallisation development.

Polymorphism studies typically rely on a supply of high-purity API where impurities do not impede the discovery of relevant crystalline forms. This input should form the basis of early screening activities. However, as development moves forward, a smaller-scale solvent screen should be performed using ‘process typical’ materials to confirm earlier findings. The impact of impurities on crystallisation performance and polymorphic form is significant and well documented (the case of Ritonavir)².

Access to well-profiled material enables choice for the production of pre-clinical solids destined for toxicological evaluation. It is likely that a robust crystallisation that purges the majority of impurities is not necessary initially, but it becomes crucial for entry into Phase 1 clinical campaigns. Solvent choice, impurity purge/ retention and isolation of the correct form should all be feasible to satisfy these requirements.

Solubility drives these activities, and a well-understood form map over a process applicable temperature range allows a skilled crystallisation scientist to design a form-specific recrystallisation for the parent molecule or a salt form. For the latter, a salt-forming crystallisation as a single step is preferred.

Final thoughts

Efficiently solving the challenges faced during API development can be a difficult feat for any drug development team. Teams should focus on minimising complexity through in-depth knowledge, ideally reducing timelines. This should be considered in a phase-appropriate manner with the depth of study increasing along the development pipeline. A thorough understanding of a candidate’s solid state chemistry and astute process optimisation is crucial for rapidly gaining comprehensive molecular insight. Adopting a proactive and pragmatic approach, with multidisciplinary input ahead of Phase 1 studies is recommended, and will reduce the number of hurdles encountered resulting in a smooth pathway to market.

 

References

1 JM Butler, JB Dressman, J. Pharm. Sci.; Dec. 99, (12), 4940-54 (2010), DOI: 10.1002/jps.22217  

2 J Bauer ,S Spanton, R Henry, J Quick, W Dziki, W Porter, J Morris; Pharm Res. 2001, Jun;18(6):859-66. doi: 10.1023/a:1011052932607