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21 Feb 2024
CATUG and Crystal Bio Establish Strategic Partnership, Launching “CATUG-Crystal” Joint Lab Dedicated to Advanced Nucleic Acid Analytical Services
21 Feb 2024
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From early developability to late-stage specifications—polymorph/salt-cocrystal strategy, SCXRD/MicroED solutions, solvent & pathway design, drug-product form control, ASD crystalline-form limits, PROTAC readiness, and crystal-form IP support.
Solid-State Characterization: Techniques, Standards, and Verified Data—An Integrated Lens for CMC Development
Solid-state characterization is foundational to API development because crystal form—and its evolution under stress—governs solubility/dissolution (exposure), stability (chemical and phase), and manufacturability (flow, compression, electrostatics). Defensible phase identification and boundaries (e.g., XRPD, DSC/TGA, PLM, DVS, PSD) provide the evidence base for CMC specifications and control strategy under ICH expectations. Done proactively, solid-state work de-risks scale-up and storage, strengthens filings and IP, and prevents costly late-stage surprises.
XRPD is a primary, “gold standard” technique for crystal-form analysis in pharmaceuticals. Owing to its speed, specificity, low material demand, and broad applicability, XRPD supports qualitative phase identification, quantitative phase analysis, and crystallinity assessment. It is deployed throughout drug development—from API solid-form research to drug product studies—and underpins quality control across stages of CMC.
| XRPD Modes and Key Features | Key Features |
| Reflection geometry | Short run time, low sample demand, and low cost Meets most of the polymorph-testing needs |
| Transmission geometry | Suited to temperature-/humidity-sensitive samples Tablets can be tested by direct sectioning, minimizing sample prep artifacts Reduces/assesses preferred-orientation effects |
| Variable temperature / variable humidity (VT/VH) | Controlled T/RH during measurement to track phase changes under different environmental conditions |
| Qualitative / quantitative analysis | Form identification in drug products Qualitative and quantitative phase analysis for APIs and finished dosage forms |
Valsartan exhibits polymorphism, while the marketed product contains valsartan in an amorphous state within the formulation. XRPD cleanly separates the two: amorphous material shows a broad, diffuse halo with no discrete Bragg peaks, whereas crystalline valsartan displays multiple sharp reflections at defined 2θ positions. This contrast enables unambiguous phase identification in both API and drug product.
XRPD patterns of distinct polymorphs differ in the number of peaks, their 2θ positions, relative intensities, and even line shapes. Consequently, an XRPD diffractogram serves as a “fingerprint” for polymorph identification.
For assigning a specific polymorph, peak positions are the primary criterion. Relative intensities are informative but less reliable because they are sensitive to test geometry and sample factors—e.g., preparation method, crystal habit, particle size, crystallinity, residual solvent, and preferred orientation. Therefore, in early-phase work, qualitative polymorph identification should rely chiefly on peak positions, with intensities used as supportive evidence.
Dynamic Vapor Sorption (DVS)
DVS quantifies how a sample gains or loses mass as a function of controlled temperature and relative humidity using a microbalance with microgram sensitivity. By programming sorption–desorption steps, it rapidly generates isotherms and kinetics with minimal material and high automation.
These data inform solid-form decisions across development: selecting the preferred form, defining storage/handling conditions, identifying critical RH and deliquescence, and mapping stability windows and interconversion risks for anhydrates, hydrates/solvates, and amorphous states.
Polarized Light Microscopy (PLM)
PLM provides direct visualization of particle morphology, size, and agglomeration, while birefringence reveals crystallinity and crystal habit. With a hot-stage microscope, crystals can be observed in real time across temperature ramps to detect melting, desolvation/hydration, and polymorphic transitions. Correlating PLM observations with DSC/TGA strengthens interpretation of thermal events and phase changes, using only minute sample amounts.
Particle size distribution (PSD)
Particle size distribution (PSD) is the percentage of particles falling within specified size ranges as determined by a given method. Owing to its speed, convenience, and low sample consumption, the laser diffraction method has become a commonly used technique for measuring PSD.
According to the dispersion medium, PSD testing can be divided into wet testing (liquid medium) and dry testing (gas medium). The appropriate PSD method should be selected based on the sample’s physicochemical properties.
PSD, as a particle size characterization method, can be combined with other techniques to jointly describe particle properties. For example, when combined with PLM, PLM visually shows approximate morphology, particle size, and whether agglomeration is present, assisting PSD. As shown in the figure, PLM indicates obvious agglomeration; together with the PSD results, the reduced particle size after ultrasonication is due to weakened agglomeration. The post-ultrasonication PSD result more closely reflects the sample’s true state.
For humidity-sensitive polymorphs, transferring a sample to ambient conditions for XRPD may induce form changes, making potential metastable forms difficult to capture. In such cases, variable-humidity XRPD can be used to collect in-situ diffractograms at different relative humidities to capture potential forms.
Together with DVS data (see Fig. b), clear mass increases are observed when RH rises from 50% to 60% and from 90% to 95%, indicating a likelihood of phase transformation. In this project, variable-humidity XRPD was applied to collect patterns at each RH condition and a new polymorph was identified.
