Issue:May 2024

FORMULATION DEVELOPMENT - The Rising Need for an Integrated Approach to Small Molecules Drug Development


Small molecules as therapeutic agents have played a significant role in the improvement of human health and well-being since the discovery and commercial­ization of molecules, such as Aspirin and Salvarsan over a century ago.1 They can broadly be defined as any organic com­pound with a low molecular weight (<1000 Daltons) and often have advan­tageous properties. These include the abil­ity to be administered orally or to permeate via cell membranes to reach their intracellular targets, or not in the case of the blood-brain barrier where ingress may not be wanted.

Since the early days of drug develop­ment, the needs of the population have changed with regard to the medicines pro­duced by the pharmaceutical industry. As the population ages, human behaviors shift and lifestyles change, so do the de­mands for effective treatments.

These changes pose a number of challenges. In living longer, we find that neurodegenerative conditions now pose an increased burden that requires effective treatment.2 As the demands of a changing society evolve and continue to act as a driver for the identification of novel small molecules, the roles and diversity of the available medicines will also change.


Historically, it has been estimated that approximately 90% of all marketed drugs are represented by small molecules, demonstrating the opportunities that these candidates have provided.3 Advances in the technologies available to scientists have seen a rise in the application of bio­logics, such as antibody, cellular, and gene-based therapies.

The generation of new leads in the small molecule field remains a highly at­tractive challenge and one that is being met by the combined use of in silico screening tools and artificial intelligence (AI). These machine learning algorithms aim to significantly reduce the risk of fail­ure and streamline the development process to provide structures of stable, druggable target molecules that are sen­sible from both a synthetic and a toxico­logical perspective.4 Although this is an exciting advancement in the complex process of developing new medicines, the need for the integration of more traditional “medicinal chemistry expertise” remains.

Throughout the past 20 years, there has been a shift in the demographic of those companies taking small molecules into later-stage clinical development. There has been growth in the number of small-to medium-size companies that hold on to their assets after Phase 1. Whilst the risk of possible failure remains high, the rewards are also more significant.

Another trend has been a growth in the number of products that are on an ac­celerated development pathway, due to the needs of a particular patient group being unmet by current therapeutics. This accelerated trajectory toward the clinic poses a burden on those planning for suc­cess as a significant amount of data is re­quired early in the development timeline to support safe and rapid progression.


Despite the integration of in silico modelling and AI approaches to design, there are an increasing number of small molecules entering development that ex­hibit challenges to their progression. These most commonly manifest as sub-optimal physicochemical characteristics, particu­larly inadequate or very low solubility, poor permeability, and unacceptable powder handling properties.

A rather succinct representation of this trend was provided over a decade ago by Amidon, who presented a graphic of im­mediate-release oral drugs by region as a percentage set against solubility.5 Most drugs for each region were those listed as practically insoluble (Figure 1).

Percentage of immediate-release oral drugs by region vs. solubility.

Another graphic depicting the land­scape for new chemical entities (NCEs) utilized by the biopharmaceutical classifi­cation system (BCS) to define the chal­lenges being faced with at least 70% of those NCE’s falling within the BCS Class II category (Figure 2).6

BSC schematic of solubility vs. permeability relationships for Classes I-IV.


Medicinal chemists may utilize in silico screening and AI to aid in the design of new structures. The pharmaceutical chemist has access to AI and screening tools to help with the prediction of solvate formation, propensity toward polymor­phism and the likelihood of forming salt or cocrystal versions.7 AI and screening tools represent a growing part of the develop­ment toolbox and function to supplement the more traditional screening and manu­facturing activities.

From a preformulation perspective, challenging molecules require a suitable strategy to be in place early in the drug substance’s life cycle. A simplified example of a training tool used in-house that de­scribes this approach (a schematic relative to the BCS) is illustrated in Figure 3.

Example of early preformulation considerations to optimize APIs within the separate BCS classes.

Thorough characterization and per­formance evaluation of a molecule with the route of administration in mind should answer the question: “What are the critical quality attributes (CQAs) that the selected solid form should provide?”

This question is continually chal­lenged during development. For example, the acceptable and desirable attributes for a parenteral application may well differ significantly from that required for a respi­ratory indication.

A review of the approaches used to manipulate BCS Class II and IV candidates in Figure 3 illustrates that salt formation is a common route traditionally employed to improve many fundamental properties of a molecule. The well-cited reference – the Handbook of Pharmaceutical Salts – neatly defines that the selection of an op­timal salt form for a novel drug candidate.9 Such studies are common­place and can be extended to consider the benefits relative to:

  • Polymorphism footprint (salt vs free API polymorphism)
  • Morphology and powder flow (impact on size reduction/capsule filling/blend uniformity)
  • Crystallinity/thermal stability
  • Excipient compatibility and stability
  • Recrystallization – further potential to control CQAs


There is no one size fits all when it comes to development. Compounds should be developed on a material basis, as screening and selection should never be formulaic. The entire process must be both iterative and pragmatic when required, and the ability to integrate the various as­pects of pharmaceutical development, es­pecially in the early phases, is ideal. A schematic of a phased approach is pro­vided in Figure 4.

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

Given the pace of early phase devel­opment and the challenging nature of many NCEs, having a team of synthetic chemists integrated and coordinating with solid state experts enables rapid and suc­cessful progression. Taking the time to un­derstand what is important from the beginning allows the construction of tai­lored programs.

One of the critical benefits of integra­tion is easy access to material. As a syn­thetic process is optimized the impurity profile changes, and not always subtly. If the composition of the final product is brought to the forefront of the initial inter­actions between the chemist and the solid state scientist, early batches can be pro­filed with only a few mg cost in terms of spent API.

Ideally, this work starts to build a data set correlating solubility characteristics with form and impurity profiles. Solubility is typically gathered in water and processes ap­plicable solvents during early phase chemical development. Solid form characterization normally includes (but is not lim­ited to) crystallographic profile by XRPD and thermal properties.

For BCS class II and IV candidates, this solubility correlation can be of partic­ular significance if an early amorphous batch was positioned toward the lower end of acceptable. Form change to a crys­talline or to a more stable crystalline poly­morph would likely reduce efficacy and require a more complex formulation strat­egy.

Another benefit of integration is the opportunity to profile each stage of the synthetic process. For highly insoluble mol­ecules, it is likely that as you progress to­ward the final structure, solubility will drop, with work-up and isolation becoming more challenging. If this is combined with a propensity to polymorphism, control of the CQAs of intermediates, as well as the final product can be more than problem­atic.

Understanding form change through­out reduces the risk of failure at a later stage when more is at stake from a pro­duction perspective. Inorganic impurities that may become entrapped within the API and oligomers can be particularly trouble­some. This is particularly evident during early phase batch isolation in which well-designed crystallizations are less common and precipitative methods are more often innocently applied before sufficient data is in hand.

This pragmatic approach to develop­ment should enable choices from an early stage and answer the question: “Will a salt be required, or is size reduction the initial option ahead of more complex strate­gies?” These decisions are critical and the integration of solid form with chemistry and early preformulation activities is a sig­nificant benefit to a risk-mitigating pro­gram.

Preformulation evaluations in partic­ular are vital and more so in which a mol­ecule has a pKa profile that makes salt formation likely but not without challenge. Having a well-characterized batch, solubility data can make the choice of salt or parent less of a challenge and for very little material cost.

A very useful reference to consider is that of Butler and Dressman who derived a Developability Classification Sys­tem (DCS). Figure 5 illustrates this system in a schematic for oral immediate-release compounds and addresses the question of whether dose/solubility ratio, dissolution rate, and/or permeability would limit oral absorption of a drug. It can be used to help derive strategies for formulation and in turn the identification of the CQAs of the drug substance that should be the target deliverables.10 From the CDMO perspective, partnerships between internal working groups and the customer are essential.

Re-defining the BCS for developability, DCS put forth by Butler and Dressman.


Small molecules continue to play a pivotal role in the supply of effective medicines to an ageing population and as tools to better understand the mechanism of interaction with their biological targets. Their complexity in terms of structure and material behavior makes 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 BCS class II and IV are of particular significance. However, realizing the bene­fits of integrating solid form and chemical development teams from an early phase, plus making use in silico and AI technology can provide a streamlined and risk-mitigating journey from the early phase to the clinic.


  1. Hartmut, B.; Harter, M.; Hab, B.; Schmeck, C.; Baerfacker, L.; Drug Discovery Today, v27, No6, 2022, 1560-1574.
  2. Abbott, A.; Dementia: A problem for our age; Nature, 475, 2021, 52-54.
  3. Ngo, H.X.; Garneau-Tsodikan, S.; Med.Chem. Comm., v9(5), 2018, 757-758.
  4. Mullard, A.; Nature, v549, 2017, 445-447 / Gonzalez, M.G. et al.; Drug Discovery Today, v27, No6, 2022, 1661-1670
  5. G.L.Amidon et al; Mol Pharm 2006 Nov-Dec;3(6):631-43
  6. L.Benet, Pharm Res; 2005 Jan; 22(1):11-23
  7. Heng, T. et al; ACS Omega, 6, 2021, 15543-15550.
  8. Pharmaceutical Preformulation and Formulation, M.Gibson, Ed. Chapters 1-2; ISBN 1-57491-120-1.
  9. C.G. Wermuth and P.H. Stahl, “Introduction,” in Handbook of Pharmaceutical Salts: Properties, Selec­tion and Use, P.H. Stahl and C.G. Wermuth, Eds. (Wiley–VCH, Weinheim, Germany, 2002).
  10. Butler, J.M; Dressman, J.B, J. Pharm. Sci.; Vol 99, 12, 2010.

Julian Northen graduated from the University of Newcastle upon Tyne with a 1st Class Honours degree and subsequently a PhD in Medicinal Chemistry and Anti-cancer Drug Design. This was followed by two post-doctoral positions, before a move from academia to Onyx. He has over 20 years of industrial experience in PR and D and is currently Solid State Manager at Onyx and is responsible for all solid form development, crystallization development, and preformulation activities.