Approximately 40% of marketed drugs and up to 90% of pipeline compounds are poorly water-soluble. Choosing and controlling the right solid form early—through screening, characterization, and process-ready crystallization—secures exposure and manufacturability while mitigating risks from phase changes and storage-related instability, preventing costly reformulations and keeping CMC timelines on track.
At Solitek, we reduce this risk through solid form screening and selection, rigorous solid-state characterisation, and crystallization process development, aligning the chosen form with your clinical and manufacturing needs.
Key Concepts That Govern Stability
Solid forms are not interchangeable labels; they are different states with real consequences for performance and processing. Polymorphs—distinct crystal packings of the same API—can differ in melting point, solubility, compressibility, and flow, which directly influences dose delivery and tableting. Salts leverage ionizable APIs and appropriate counter-ions to improve solubility, stability, or processability when the free base/acid falls short. When salt formation isn’t suitable, cocrystals pair the API with a neutral coformer to tune dissolution, mechanical behavior, and sometimes moisture sensitivity without altering the API’s covalent structure.
Thermodynamic vs. Kinetic Stability
Two types of stability matter and they don’t always agree. Thermodynamic stability favors the lowest-energy form under given temperature and humidity—often the form you want for long-term control. Kinetic stability, however, explains why a higher-energy (metastable) form can persist if the transformation pathway is slow. That metastable form can be strategically useful early (for exposure in tox/PK), but it demands tight controls and a clear exit plan before pivotal phases.
Water, Solvents, and Disorder
Moisture and residual solvents reshape the landscape. Hydrates and solvates can form—or desolvate—across common processing and storage conditions, shifting mass, density, and dissolution. Amorphous or partially disordered solids often dissolve faster, which is attractive for bioavailability, yet they tend to relax or crystallize over time. Without a control strategy, that “free” performance gain can vanish mid-development.
Why Solid Forms Become Unstable
Instability rarely comes from a single culprit. Small humidity excursions can tip a system into hydrate formation or trigger a polymorphic switch; temperature cycles in transport amplify these transitions. Mechanical energy—from milling, wet granulation, or tableting—introduces lattice defects and localized heating that push a metastable phase toward conversion.
Residual solvents sometimes hide in the lattice and drift out slowly, subtly altering form or particle properties if they’re not monitored with orthogonal methods. And when the project finally leaves the lab, scale-up changes supersaturation, mixing, cooling rates, and impurity profiles; the pathway that produced your target form on grams might favor a different outcome on kilos. The root cause is often upstream: narrow early screening misses robust alternatives and creates downstream rework in preclinical formulation and tech transfer.
How Solitek Reduces Stability Risk
Form discovery designed for real processes
Our solid form screening and selection explores polymorphs, salts, and cocrystals under the stresses you’ll actually see—humidity, heat, mechanical energy, and the solvents you plan to use. The goal is not just to find a form that works in the lab, but one that survives scale-up.
Decision-grade analytics
With solid-state characterisation we combine PXRD, DSC/TGA, DVS, Raman/IR, and hot-stage microscopy to confirm identity, detect low-level transformations, and define control strategies (e.g., acceptable RH windows and packaging needs).
From stable form to stable process
In crystallization process development we translate form knowledge into seeded, reproducible protocols. We specify supersaturation control, isolation/drying windows, and engineer particle size and habit to support flow and compression—so the target form is the form you keep.
Bridge to in vivo without breaking the form
For animal studies, our early enabling formulation development creates fit-for-purpose tox/PK formulations that respect the chosen form’s stability and dissolution profile, improving exposure consistency and de-risking interpretation.
Practical Guidance You Can Apply Now
Think of stability as a set of habits rather than a checklist. Screen broadly and stress early—if wet granulation will appear later, simulate it during screening to surface conversion risks when they’re still cheap to fix. Define water management with DVS: map hydrate stability, set explicit RH limits for processing, storage, and packaging, and—if a hydrate proves most robust—adopt it while controlling stoichiometry.
Use orthogonal analytics so no signal is missed: pair phase identification (XRPD) with thermal events (DSC/TGA) and moisture-triggered changes (DVS). Engineer the pathway through seeding, mixing, and solvent exchange to favor nuclei and habits that lead to the target form, verifying with in-process sampling. And align the form with clinical intent: metastable can be useful early under tight governance; for pivotal and commercial phases, thermodynamic and processing robustness should take precedence.
Conclusion
Solid-form stability is a primary lever for reliable performance, manufacturability, and regulatory confidence. By combining targeted form screening, orthogonal characterisation, robust crystallization processes, and fit-for-purpose preclinical formulations, Solitek helps you choose the right form—and keep it right—through scale-up and into clinic.
