The rise and rise of cocrystals

Poor solubility remains a major challenge in drug development, limiting bioavailability and constraining formulation strategies. As modern drug discovery produces increasingly complex and lipophilic molecules, traditional approaches such as salt formation are not always viable.

Cocrystals offer a flexible and increasingly proven alternative. When applied strategically, they can convert a difficult-to-manufacture active pharmaceutical ingredient (API) into a viable, manufacturable drug substance.

Pharmaceutical cocrystals are crystalline materials composed of an API and a neutral coformer in a defined stoichiometric ratio within a single crystal lattice. These components interact through non-covalent forces, such as hydrogen bonding, π-stacking and van der Waals interactions, to form a stable solid phase.

Unlike salts, cocrystals do not rely on ionisation. This makes them particularly useful when ΔpKa is insufficient, ionisable groups are absent or the salt forms are unstable. Their formation is governed by supramolecular chemistry, where functional groups such as carboxylic acids, amides, phenols and heterocycles drive predictable intermolecular interactions.

Why cocrystals matter

Many modern APIs fall into BCS Class II and IV, where poor aqueous solubility limits performance. Cocrystals allow modification of solid-state properties without altering the chemical structure, an important advantage when structural modification is not feasible.

Since the approval of Entresto in 2015, cocrystals have become a validated development strategy. Their strength lies in their ability to optimise multiple properties simultaneously, particularly where a balance is required. Key benefits include:

• Improved solubility and dissolution behaviour
• Enhanced stability and photostability
• Better mechanical properties, such as flow and compressibility
• Conversion of oils into stable crystalline solids
• Opportunities for impurity control, morphology management and lifecycle strategy

Designing and screening cocrystals

Cocrystal design begins with coformer selection, typically from compounds recognised as safe by regulatory authorities. This is guided by both the desired property and structural compatibility with the API.

While supramolecular synthons provide a useful framework, predicting crystal packing remains complex. Computational tools, including in silico screening, can support this process, but are most effective when combined with experimental screening.

A strong understanding of the solubility of both API and coformer is essential, as it governs crystallisation pathways. Equally important is mapping the solid-form landscape, including polymorphs, solvates and hydrates, which may compete with cocrystal formation.

Screening typically combines solution-based and solid-state techniques, supported by analytical methods such as XRPD to identify and confirm new crystalline phases.

When to use cocrystals and key challenges

Cocrystals should be considered alongside salts rather than as a replacement. They are particularly valuable when traditional approaches fail or when multiple properties must be optimised.

They are often advantageous:

• When salt formation is not feasible
• When salt forms are unstable or hygroscopic
• When fine-tuning of properties is required
• When multiple solid-state risks must be managed

However, challenges remain. Misidentification of phases during screening is common, and over-reliance on computational prediction can limit success. Competing solid forms and late-stage scale-up issues can also impact development. Careful coformer selection is essential to avoid regulatory or supply constraints.

From screening to strategy

Once identified, cocrystals must be evaluated against key criteria, including solubility, stability and manufacturability. They should be considered within a broader solid-form strategy, alongside salts and polymorphs, to ensure the most appropriate development pathway.

Cocrystals are most effective when integrated early, rather than introduced as a late-stage solution.

Final thoughts

Cocrystals are now a practical and proven tool in modern drug development. As APIs become more complex, they offer a flexible and often underutilised route to improving performance.

When applied strategically, cocrystal development can de-risk programmes and enable the progression of compounds that might otherwise fail.

Looking to evaluate cocrystals in your programme?

If you are assessing solid-form strategies for a challenging API, we can help determine whether a cocrystal approach is appropriate and how best to integrate it into your development plan.

Contact the Onyx expert team.