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Early phase preformulation and physicochemical property optimisation

Preformulation studies and physicochemical property optimisation are critical to the successful development of a modern drug candidate. Historically, the majority of drugs have been produced as solids for oral delivery. However the physicochemical properties of modern small molecules have led to an expansion in the technologies and complexity applied to the delivery of novel drugs. Phase appropriate screening is an accepted and cost effective strategy that looks to address such issues as early as possible, initiating the iterative process of designing a development pathway that reduces risk and mitigates late stage shortcomings. 

Physicochemical & biopharmaceutical considerations

It is well known that solid form will have a significant impact on 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, pKa/Log D and permeability, often accomplished in silico as part of the lead selection process. This often overlooks considerations such as morphology, material handling and behaviour during manufacture. While this is not surprising, it highlights the need to consider such attributes, or desirable critical quality attributes (CQAs), as development progresses and dose and dosage form are determined.

Effective preformulation studies form the foundation from which CQAs are derived, initially for the drug substance, but also with a forward-looking approach to effective drug product design. This is particularly relevant given that more than 90% of emerging small molecules demonstrate poor solubility and belong to Developability Classification System (DCS) 2 (2a and 2b) or 4 (DCS, Figure 1).1 

Compounds within these classes often require bioavailability-enhancing formulations to achieve the desired exposure. Therefore, performing an appropriate series of profiling experiments is critical to designing the route forward for these candidates.

Figure 1. The DCS proposed by Butler and Dressman

The basis for robust preformulation requires a strategy and investigation that should consider a number of the critical elements listed in the table below. This process is iterative, and well-integrated development is preferred, with the understanding that all parts will not be in place until key decisions, such as version selection, have been made. 

For this reason there is often value in aiding lead candidate differentiation by performing early phase mini screens to verify the capacity to form stable salts, their performance and to gauge propensity toward polymorphism. This CMC biassed data does not trump in vivo efficacy or other critical ADME properties but is useful where it is difficult to discriminate between candidates with this data.

There is no single roadmap that fits every drug and studies must be constructed based on data rather than opinion. The pivotal data that forms the basis of such a design is robust physicochemical characterisation, which should incorporate:

  • Melting point
  • Morphology (microscopy)
  • Log P
  • pKa
  • Chemical stability
  • Solubility (pH 1/7.4)
  • Permeability

Polymorphism and bioavailability

Beyond this the importance of understanding polymorphic form and the impact this has on the molecule is critical. This is especially true as the compound moves into the clinical phases of development where a change can result in significant changes in performance.

Solubility is also a key determining factor for bioavailability (BA), but high solubility does not always correlate with high exposure. Understanding the factors that influence bioavailability early can help guide later development. Testing whether a solution vs a suspension provides a significant variance in BA can be informative in conjunction with permeability data, to determine whether BA is dissolution rate or solubility limited.

Simple decision trees are favoured to guide development. Similarly, the approach to preformulation studies and techniques to improve performance can be generalised relative to the BCS (Biopharmaceutics classification system) and DCS listed previously. An example of the strategies often utilised is shown below.

Figure 2. Example of early pre-formulation considerations to optimize APIs within the separate BCS classes

 

Figure 3. Simple example of a preclinical preformulation decision tree to identify a strategy for development 

Key preformulation objectives     

From the discussion above it is clear that to enable a robust development plan, several critical attributes or material properties must be studied and reported as part of an ongoing risk assessment. The outcome should be a planned route of formulation or formulations that account for the behaviour of the material. The objectives should be phase appropriate with the progressive aim of delivering a drug that is fit for delivery to the patient. Some of the fundamental studies are listed below and briefly elaborated upon.

Optimising solubility

  • A critical factor to measure and understand as it directly affects the efficacy of a drug and must be considered alongside permeability data
  • Solubility should be discussed and understood in relation to BA within an in vivo setting
  • Dissolution rate is important to measure as this will impact upon how much drug dissolves and where. An example would be dissolution rate limited absorption
  • Solvents effects – the impact solvent has upon solubility is important for many formulations. Studying the type and loading required to elevate aqueous or lipidic solubility is important (also see stability)
  • Understanding the impact of pH upon solubility is equally important, the environment in vivo has a well-understood pH gradient and this can impact upon solubility significantly for ionisable molecules. Some disease states also demand attention as they can alter physiological conditions that in turn may impact upon absorption.

Understanding polymorphism

  • Polymorphism is a fundamental aspect of material behaviour to benchmark during physicochemical characterisation
  • Many drugs exhibit multiple forms and unless they are exposed to varying conditions and solvents, change that is not understood is inevitable
  • Identification, characterisation and selection of the thermodynamically favoured form is a fundamental requirement of drug development. Adapting to utilise a metastable form is an option, but must be risk assessed against a significant body of work that demonstrates the kinetics of transformation to the thermodynamic form are manageable and provide an acceptable shelf-life
  • An unwanted change of form not only impacts solubility; a change of morphology is also a risk that may impact effective drug product development
  • Ultimately, appropriate form selection minimises risk to drug performance during manufacture, storage and distribution

Defining excipient compatibility

  • The selection of a suitable combination of excipients is an integral part of drug product development that has a direct impact upon performance
  • Drug-excipient interactions are common and can lead to an unacceptable level of impurities within the drug product or an inability to formulate the molecule into the intended presentation
  • Understanding any incompatibility is critical to selecting a simple, effective formulation
  • Both active and inactive ingredients require consideration, separately and in combination
  • A phase appropriate study of excipients prevents adverse effects such as reduced potency, increased degradation and potential for toxic impurity generation

Executing appropriate stability studies

  • These studies are intrinsically linked to compatibility studies and are designed with the phase of study in mind
  • Adherence to the regulatory guidelines is critical for a successful and accepted drug substance and product
  • Consideration of the current formulation route, intended storage, packaging and length of studies for early phase work are a starting point
  • Forced degradation that adheres to regulatory guidelines is essential
  • They should be expansive and include:
    • Temperature
    • Humidity
    • Oxidative stress
    • pH variation
    • Concentration (in combination with the above)
    • Including liquid and solid presentations of the drug substance
  • Benchmarking drug product and substance shelf-life is an important outcome. This supports transfer and storage to the different geographical locations where trials or distribution will take place.

Defining an appropriate particle size distribution (PSD)

  • PSD is a critical element of development that may impact efficacy and developability
  • The impact PSD has on solubility requires understanding. The kinetics of dissolution and intrinsic dissolution rate within different environments is important. As mentioned, this can impact BA in particular if absorption is limiting
  • The morphology of the crystallised product is important and can have an adverse impact on the ability to modify size via milling. It also impacts on the ability the effectively blend with excipients
  • Crystallisation development with these attributes in mind plays an important role in delivering a drug substance that is fit for downstream processing
  • Robustness toward the mechanical stress of milling is a stability study in addition to those listed previously. Control of amorphous content, fines and unwanted agglomeration are just a few of the more obvious risks to consider.
  • Investigating whether conditioning of milled solids is required to avoid unwanted agglomeration is a common requirement
  • Communication during early development is important so that PSD becomes a critical quality attribute as part of the development pathway. As with some of the other attributes, requirements may change throughout development and the impact of change should be well documented

In summary

The importance of preformulation studies in drug development is clear, as they form the basis for ensuring that a drug is safe and effective. As with any potentially complex problem or feat of engineering, the best approach is to break down the problem into its simplest constituent parts and design from these foundations. This is the principle that should be applied during drug development to deliver a phase appropriate and robust product as it transitions from early phase optimisation to clinical study and eventually regulatory approval.

 

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