Technical Insight

Exploring the key questions in formulation strategies

Polymorphs sit at the intersection of chemistry, formulation, and long-term risk. Traditional solid-form screening gives real, valuable data, but it is never exhaustive. By combining those experimental efforts with in-silico predictions, teams can see where they are on the solid-form energy landscape, estimate the impact of unseen forms, and make clearer decisions on screening, formulation, and backup plans.

Key questions

• Have I found the most stable polymorph?

• Can I safely stop the experimental screening?

• What would be the impact of a new, more stable form turning up later?

No screen can guarantee you've found the global minimum. The real goal is to understand how risky the unknown space is.

• Crystal structure prediction (CSP) maps a set of low-energy crystal structures that are thermodynamically plausible for the API.

• Experimental hits can then be overlaid on this map, showing which predicted structures have already been observed and which remain purely theoretical.

• If the working form sits at or near the bottom of the predicted landscape, and other low-lying structures are very similar, the residual risk is small.

• If CSP identifies several significantly lower-energy candidates that have not been seen experimentally, the risk of a problematic late-appearing polymorph is higher.

The question shifts from "Did we find the most stable polymorph?" to

| "Given this landscape, how much do unseen structures matter for our program?"

Stopping a solid-form screen is a risk management decision.

A combined experimental + in-silico approach supports that decision:

• Experimental work identifies actual forms and gives key data on solubility, stability, and manufacturability.

• In-silico predictions highlight regions of the solid-form landscape that have not yet been sampled experimentally, including structures that are energetically feasible but remain unobserved.

• By comparing the predicted lattice energies and simulated solubilities to what is already known, teams can estimate whether potential new forms would be benign or disruptive.

If all plausible lower-energy structures would have minimal impact on solubility and pharmacokinetics, teams can justify pausing broad screening and reallocating resources. If not, it may be worth extending the screen, refining crystallization conditions, or exploring salts, co-crystals, or amorphous options.

| "What would be the impact of a new, more stable form turning up later?"

When a lower-lying polymorph shows up in late preclinical or even clinical phases, the default reaction is often panic. A structured risk assessment replaces that with scenario planning.

1. From lattice energy to solubility

• More stable forms typically show lower solubility, but the magnitude of the change matters.

• A small energy difference may translate into a modest solubility drop; a larger gap can significantly reduce exposure.

2. From solubility to pharmacokinetics

• Using solubility estimates for the hypothetical new form, one can simulate fraction absorbed and exposure.

• If the drug is far from solubility-limited, even a new, more stable form may have little clinical impact.

• If the program is already close to the solubility boundary, the same change could compromise efficacy.

3. From impact to action

Depending on these simulations, possible responses include:

• Continuing with the existing form while tightening monitoring and controls.

• Adjusting the formulation strategy (e.g., enabling formulations) to offset lower solubility.

• Activating a Plan B: alternative polymorph, salt/co-crystal, amorphous dispersion, or even a backup compound.

Implications for CMC and Formulation Strategy

• Shift from polymorph “paranoia” to quantified, scenario-based risk across the solid-form landscape.

• Link solid-form selection directly to formulation design and PK performance, rather than lattice energies alone.

• Use computational screening to define when experimental screening is sufficient and to pre-plan realistic contingency options (e.g., alternative polymorphs, salts, amorphous routes, or backup APIs).

Project-specific support

Project-specific assessments of solid-form risk and formulation strategy are available from Crystal Pharmatech. To discuss a particular molecule or program, please contact our BD team at bd_global@crystalpharmatech.com or visit www.crystalpharmatech.com.