Two Strategies for the Same Problem
Poor aqueous solubility is one of the most common challenges in small molecule drug development. A molecule that does not dissolve adequately in the gastrointestinal fluid cannot be absorbed at a rate sufficient to achieve the intended therapeutic effect, regardless of how potent it is in a biochemical assay. Two of the most widely used solid form strategies for addressing this problem are pharmaceutical salts and co-crystals. Both involve creating a multicomponent solid that modifies the physical properties of the API, but they do so through different mechanisms, and each has a different regulatory footprint.
What Is a Pharmaceutical Salt?
A pharmaceutical salt is formed when an ionisable API reacts with a pharmaceutically acceptable acid or base to form an ionic compound. The positive and negative charges of the salt components are held together by electrostatic interactions. Salt formation is only possible when the API has an ionisable group with a suitable pKa, and where the difference in pKa between the API and the counterion is sufficient to drive proton transfer. As a general rule, a pKa difference of at least two units is required for reliable salt formation.
Salts are regulatory well-established. They are classified as the same active ingredient as the free form in most jurisdictions, which simplifies the regulatory pathway. The FDA has published guidance on the pharmaceutical salts framework, and the EMA’s ICH Q6A guideline addresses solid state characterisation requirements.
What Is a Pharmaceutical Co-Crystal?
A co-crystal is a multicomponent crystalline solid in which the API and a coformer are held together in the crystal lattice by non-covalent interactions, typically hydrogen bonds, rather than ionic bonds. Because no proton transfer occurs, co-crystal formation is not limited to ionisable molecules. This makes co-crystals particularly valuable for neutral or weakly ionisable APIs where salt formation is not feasible.
The regulatory status of co-crystals has evolved significantly over the past decade. The FDA’s 2018 guidance on co-crystals classifies them as drug products containing a drug substance, meaning they follow a standard NDA or ANDA regulatory pathway rather than being treated as new chemical entities. The EMA has taken a broadly similar position.
Salt vs. Co-Crystal: A Practical Comparison
| Factor | Salt | Co-Crystal |
| Applicable molecules | Ionisable APIs (pKa difference > 2 units) | Ionisable and non-ionisable APIs |
| Interaction type | Ionic (electrostatic) | Non-ionic (hydrogen bonds, pi-pi stacking) |
| Regulatory classification | Same active ingredient as free form | Drug product containing drug substance (FDA) |
| IP potential | Well-established, many precedents | Growing body of co-crystal patents |
| Solubility improvement | Can be significant; dependent on counterion | Variable; coformer selection is critical |
| Physical stability | Generally robust if polymorph is stable | Can be hygroscopic; humidity sensitivity must be assessed |
| Coformer options | Pharmaceutically acceptable acids/bases | GRAS substances, excipients, or other APIs |
Choosing the Right Approach for Your Molecule
Start with Ionisability
The first question is whether the API is ionisable. If it has a basic nitrogen or an acidic group with a pKa in the right range, salt screening is typically the first strategy to evaluate. If the molecule is neutral or weakly ionisable, co-crystal screening becomes the primary option alongside other solubility-enhancing technologies.
Consider the Stability Requirements
Some salts are hygroscopic or unstable at elevated humidity, which creates challenges during manufacturing and storage. Co-crystals can also show humidity sensitivity depending on the coformer. Understanding the stability profile of candidate forms under conditions relevant to your intended market, using ICH storage conditions as a minimum, is essential before committing to a development form.
Factor in the IP Landscape
If the free form and common salts of your API are already in the prior art, a novel co-crystal form with demonstrated physicochemical advantages may offer a patentable differentiation. A solid state research team with experience in the IP dimensions of form screening can help structure the work to generate data that supports a patent filing.
Ardena’s Approach to Salt and Co-Crystal Screening
Ardena’s solid state research team in Ghent conducts both salt and co-crystal screening as part of pre-formulation development programmes. The screening process uses a design-of-experiments approach to evaluate a broad range of counterions and coformers, with XRPD, DSC, and solution NMR used to characterise and confirm the nature of each candidate form.
Screening results are evaluated against the full development context, including target dose, intended manufacturing process, and the regulatory and IP strategy, so that the form recommendation reflects not just the best physical chemistry but the best outcome for the programme as a whole.
