Every solid form tells a story, one of stability gained or lost, solubility improved or compromised, and formulations that succeed or struggle. But sometimes, perhaps too often, the story begins too late. In many drug development programs, solid-state considerations are only addressed once a compound shows promise in formulation, by which point, key opportunities for optimization may have already passed.
Integrating solid-state chemistry early in the CMC strategy helps anticipate and control how an API behaves under later development, manufacturing and storage conditions. Polymorphs, salts, and cocrystals can profoundly influence stability, bioavailability, and even intellectual property positioning.
Understanding Solid-State Chemistry and Its Role in CMC
Solid-state chemistry examines how molecules pack together in the solid form, which determines a material’s physical and chemical properties. Different arrangements of the same molecule (i.e. different polymorphs) can exhibit significant differences in solubility, stability, and processability. Similarly, forming a salt or cocrystal can fine-tune these properties by modifying the crystal lattice without altering the pharmacologically active component.
These differences are not merely academic. Selecting the optimal solid form early in development ensures consistent drug performance, simplifies manufacturing, and supports intellectual property strategies. On the contrary, failing to understand the solid-state landscape can lead to unexpected polymorphic transitions, stability problems, or formulation delays, issues that often emerge too late, when changes are costly and time-consuming.
Challenges in Implementing Solid-State Strategies
Despite its importance, solid-state chemistry is frequently underutilized in CMC planning. Time pressures in early development and limited material availability often push solid form studies to later phases, when decisions have already been made about formulation or process routes. This reactive approach can increase the risk of encountering instability during scale-up or clinical manufacturing.
Another common challenge comes from the complex interplay between solid form and process conditions. A polymorph that appears stable in the lab may convert during drying, milling, or granulation. Even subtle variations in temperature, humidity, or solvent composition can trigger unwanted transformations. Without detailed characterization and process understanding, controlling these factors becomes difficult, leading to variability in product quality.
Moreover, as molecules become more complex and lipophilic, solubility limitations are increasingly severe. In such cases, identifying alternative solid forms, such as cocrystals with pharmaceutically acceptable coformers, can dramatically improve dissolution and bioavailability, but requires expertise in both experimental and computational solid-state analysis.
Solitek’s Integrated Approach to Solid-State in CMC
At Solitek, we believe solid-state chemistry should be an integral part of your CMC strategy, not an afterthought. Our comprehensive approach combines advanced solid-state characterization with predictive and experimental screening technologies to identify the most suitable form of your API early in development.
Our polymorph, salt, and cocrystal screening services systematically explore the solid form landscape to ensure no viable options are overlooked. Using a combination of solvent-based and dry techniques, we assess stability, solubility, and manufacturability under relevant conditions. When needed, we complement experimental screening with computational modeling powered by our collaboration with XtalPi, enabling in silico prediction of crystal structures and potential cocrystal formers even before extensive lab work begins.
Beyond identifying the optimal solid form, we support crystallization process development to ensure reproducibility and scalability. This includes evaluating parameters that affect particle size, morphology, and habit, all of which influence downstream processing and formulation performance. For preclinical programs, our expertise extends to formulation development for animal studies, ensuring the selected solid form translates effectively into a dosage form suitable for pharmacokinetic and toxicology assessments.
From Insight to Implementation: Practical Considerations
Integrating solid-state insights into your CMC workflow brings tangible benefits when done early and strategically. The best results come from a continuous dialogue between solid-state scientists, formulators, and process engineers. Early polymorph and salt screening helps define a stable, manufacturable form before formulation optimization begins. Characterization data such as XRPD, DSC, TGA, and microscopy, guide the selection of appropriate process parameters and control strategies, ensuring the chosen form remains consistent throughout development.
One illustrative case involved an early-stage API that initially crystallized as a metastable form with excellent apparent solubility, but which repeatedly converted to a more stable, less soluble polymorph during drying and milling. This conversion threatened formulation performance and introduced significant scale-up risk. Working with the client, Solitek conducted parallel polymorph and salt/cocrystal screens and combined those results with particle-engineering experiments. We identified a salt form that delivered a pragmatic balance: improved physical stability under manufacturing stresses while maintaining clinically relevant dissolution, and we defined crystallization and drying conditions that avoided the transformation pathway. By integrating these findings into the CMC package early, the team avoided late-stage reformulation, reducing development time and uncertainty.
This example highlights how a proactive, science-driven solid-state approach can transform development outcomes by reducing risk, improving performance, and enhancing regulatory confidence.
Solid-state chemistry is not just an analytical exercise, it’s a strategic element of successful pharmaceutical development. By integrating polymorph, salt, and cocrystal screening, solid-state characterization, and crystallization process development into your CMC plan, you can make informed decisions that minimize risk and maximize performance.
At Solitek, our solid-state experts combine deep experimental insight with advanced computational tools to help you build robust, scalable, and compliant drug development programs.
Need robust solid-state solutions for your next project? Contact our team to learn more about our solid form screening and CMC support services.
