Case Study

Solid-State Characterization Of A Small Molecule API

GettyImages-1087219020 Scientists wearing protective coveralls working in manufacturing laboratory

Client Profile

The client needed a routine hygroscopicity assessment to complete the solid-state characterization of their small molecule API for inclusion in the IND application. The development of a formulation to support animal PK studies was already underway and involved the only known crystalline anhydrous form (i.e. Form 1).

Partnering with Alcami:

Alcami’s Solid-State Characterization team used gravimetric sorption analysis (DVS Intrinsic Plus – Surface Measurement Systems) to obtain the water sorption-desorption profile of Form 1. The DVS data indicated a complex solid-state nature of the API and likely a new hydrated form. The new form was stable above 50% relative humidity (RH), which overlaps with ambient humidities in laboratory and manufacturing sites. Powder X-ray diffraction (PXRD; Bruker D8 Advance) and hyphenated thermogravimetric analysis with IR detection (TGA-IR; TA Instruments 5500- Thermofisher iS50) were immediately collected on the post-DVS solid and confirmed a formation of a new dihydrate (Form 2). Alcami collected and reported these data to the client within 72 hours, with a recommendation to incorporate drier conditions during relevant unit operations to prevent the formation of Form 2. Low-humidity conditions (<40%RH) were immediately applied during API handling, formulation, and packaging unit operations at Alcami and client sites.

In order to understand any risks to the formulation and crystallization processes of Form 1 that could be posed by the new Form 2 and other, potentially undiscovered solid forms, Alcami assessed the API’s polymorphic landscape. A polymorph screen was conducted and included 100 experiments, capturing diverse crystallization conditions (solvents, temperatures, etc.). Using an automated sample processing platform and high-throughput analytical tools, a new anhydrous form was identified (Form 3) within one week. Thermodynamic stability studies were conducted and showed that Form 3 was stable at elevated temperatures (enantiotropic form) that are utilized in the current cooling crystallization process of Form 1. Alcami’s team recommended the adjustment of seeding, isolation, and drying temperatures in the crystallization process to ensure a reliable production of phase-pure Form 1.

Alcami worked alongside the client to incorporate the changes to the ongoing formulation and crystallization process activities, supporting the quick progression of this program.

Challenges and Solutions:

The program faced various challenges:

  • Tight timelines imposed by the IND filing deadline were mitigated by flexible and efficient workflows leveraging the team’s deep experience and expertise
  • Extremely high solubility of API in water and organic solvents were mitigated by customization of solid and solvent dosing strategies and temperatures at the various stages of the polymorph screen
  • Interconversion of Form 1 and 2 at ambient humidity affecting analytical readouts were mitigated by use of a low humidity room and proper testing schedules
  • High potency of the API (1-10 µm/m³) requiring additional safety measures and sample containment during testing were mitigated by the existing safety-focused workflows.

Where Are They Now?

The work was completed on time and the content of the produced technical reports was directly utilized in the IND application, as well as in the patent application to secure the IP around the newly identified crystalline forms. Alcami is progressing the program toward the manufacture of GMP oral solid dose product to support a Phase I clinical trial.