Problems we were asked to solve

The situation

The client had a crystallization process running reliably at pilot scale and a stability programme under way. Late in the programme a batch produced material with a different X-ray powder diffraction pattern and a markedly lower dissolution rate. The new form appeared intermittently and could not be traced to any deliberate process change.

What was at stake

An unidentified second form late in development puts the stability data, the dissolution specification and the regulatory submission in question at once. The practical question was not only which form had appeared, but whether the original form could still be manufactured with confidence.

What we did

We characterized both the original and the anomalous material by diffraction, thermal analysis, microscopy and moisture sorption, and established the relationship between the two forms. A broad screening followed, covering solvent set, cooling and evaporation regimes, anti-solvent addition, slurry maturation and mechanochemical routes, to determine whether further forms existed and under what conditions each appeared.

Competitive slurry experiments then established which form was thermodynamically stable across the relevant temperature range — the question that determines whether a form is a manufacturing risk or a manufacturing target.

The outcome

The anomalous material proved to be the thermodynamically stable form, and the original form metastable: it had been produced consistently only because the process happened to stay in a kinetic window. The screening also identified the conditions under which the transformation occurred, which explained the intermittency.

On that basis the client moved development onto the stable form, with a seeded crystallization designed to deliver it reproducibly. The comparative data and the screening record went into the regulatory dossier as the justification for the form change.

The situation

A neutral, poorly soluble candidate was giving exposure too low and too variable to support the target dose. Salt formation was not available: the molecule has no suitable acidic or basic site. Micronisation had been tried and had not resolved the variability.

What was at stake

Without a solid-state route to higher apparent solubility, the programme faced either a formulation approach with its own stability burden or a dose the safety profile would not support.

What we did

We ran a co-crystal screening in parallel with an amorphous dispersion feasibility study, so the two enabling routes could be compared on the same molecule rather than sequentially.

The coformer set was selected on hydrogen-bonding complementarity and restricted to pharmaceutically accepted compounds. Liquid-assisted grinding served as the first pass, because it consumes very little API; hits were then reproduced by solution and slurry crystallization, which is what separates a laboratory artefact from a manufacturable co-crystal. Diffraction, thermal analysis and vibrational spectroscopy together confirmed that new crystalline phases had formed rather than mixtures or eutectics.

The outcome

Two co-crystals were confirmed and characterized. Both improved apparent solubility and dissolution rate against the parent; one of the two also held its form under temperature and humidity stress, while the other dissociated. Comparative dissolution in biorelevant media showed that the stable co-crystal sustained supersaturation long enough to be useful, whereas the amorphous dispersion reached a higher peak concentration but precipitated earlier.

The client progressed the stable co-crystal, with the amorphous route documented as a fallback. Because the co-crystal is a new solid form, it also supported a patent filing.