Devoting early-phase resources to finding the lead solid form of an active pharmaceutical ingredient (API) can save you time and resources down the road. The webinar titled "Solid Form Screening of Active Pharmaceutical Ingredients" highlighted the benefits of solid form understanding and screening on a drug’s development cycle. Throughout the presentation, Abhijeet S. Sinha, Manager of Solid Form Services (SFS), provided a breakdown of different solid forms, the workflow of solid form screenings, and a Lonza SFS client case study focused on polymorphs of a late-stage API.

The scope of solid form screening is dependent on the phase of drug development. In early development, SFS can conduct several screens, including polymorph, salt, and cocrystal screens, as well as characterization and risk assessments, to nominate the lead crystalline form. In later phases, SFS can conduct additional risk assessment screens and troubleshoot your crystallization process development. Below, Abhijeet addresses webinar attendees’ questions on how to nominate a lead form, when to utilize a salt screen, and other solid form strategies.

How do you determine which is the preferred solid form: manufacturability, stability, or something else?

Sinha: It depends on whether you’re doing a polymorph screen or a salt screen. For a polymorph screen, ideally, you’d want your preferred form to be the thermodynamically stable one. You would determine that by doing the standard polymorph screen followed by building the polymorphic landscape. For salts and cocrystals, lead form selection is dependent on manufacturability, solubility enhancement, and stability.

How do you know if a salt screen is applicable?

Sinha: If the API has ionizable functional groups, then depending on the pKa value of the acidic/basic site, appropriate counterions can be shortlisted for the salt screen. For example, carboxylic acids, amines, and pyridines are all ionizable functional groups commonly found in drugs.

Would there be a reason to nominate the lead form to be amorphous rather than crystalline after screening?

Sinha: Yes. If the lead crystalline form of the API does not meet the target solubility profile, then an enabled form such as salt/ cocrystal can be considered. If a lead salt/cocrystal cannot be nominated, then alternative enabled forms such as amorphous forms can be the lead form for formulation.

Do I need specific equipment for wet cake powder X-ray diffraction (PXRD)?

Sinha: No, you can do the PXRD on semi-wet samples on your standard PXRD equipment. You just have to spread out the paste on the sample plate. It usually dries up by the time you might mount it on the instrument, anyway. In short, no special equipment is needed.

In the case study, 5% of Form 1 can be detected in Form 2 and vice versa. Is 5% the regulatory limit?

Sinha: No, in this case study, 5% was the limit of detection for one form in the other for the PXRD equipment that we used. We did prepare blends at even lower percent mixtures of one form in the other, but then we could not detect that.

How have you determined the transition temperature? Is it by differential scanning calorimetry (DSC) or experimentally by competitive slurries?

Sinha: We determined it experimentally by competitive slurries at different temperatures and then analyzed the obtained solids by PXRD to determine the form present.

Have you ever observed a change in the polymorphic form upon micronization?

Sinha: Yes, that’s common. I haven’t personally encountered it, but I’ve heard horror stories where, upon micronization, the form changes. Selecting the thermodynamically stable form at an early stage may help mitigate such issues.

Want to stay up-to-date in the small molecule space?

Join our community to receive regular updates, content and insights

You may also be interested in:
Latest content
Latest briefing from the Knowledge Center