Why Solid Form Characterisation Starts with XRPD
X-ray powder diffraction (XRPD) is the most widely used technique for characterising the crystalline structure of pharmaceutical solids. Every crystalline form of a drug substance produces a unique diffraction pattern, a fingerprint determined by the arrangement of molecules in the crystal lattice. This fingerprint allows scientists to identify which polymorph, salt, hydrate, or solvate is present in a sample, and to detect the presence of multiple forms in a mixture.
For drug development, this capability is critical at almost every stage. In pre-formulation, XRPD maps the solid state landscape of the API. During formulation development, it monitors whether an amorphous dispersion has begun to recrystallise. In GMP manufacturing, it confirms batch-to-batch consistency of the crystalline form. And in regulatory submissions, the XRPD pattern of the intended commercial form is a required element of the Module 3 CTD.
How XRPD Works
When a beam of X-rays strikes a crystalline material, the periodic arrangement of atoms in the lattice causes the X-rays to diffract at specific angles. The resulting diffraction pattern, a series of peaks at characteristic 2-theta angles with characteristic relative intensities, is determined by the geometry of the crystal lattice and the identity of the atoms within it. Different polymorphs of the same molecule have different lattice geometries and therefore produce different XRPD patterns.
Variable temperature XRPD allows the solid state behaviour of a compound to be monitored in real time as it is heated or cooled, revealing polymorphic transitions, melting events, and recrystallisation phenomena that cannot be captured by measurements at a single temperature.
XRPD Applications Across the Drug Development Lifecycle
| Development Stage | XRPD Application | What It Answers |
| Pre-formulation | Polymorph screening characterisation | Which crystalline forms exist? Which is the thermodynamic stable form? |
| Salt and co-crystal screening | Form identification and confirmation | Is the screen hit a salt, co-crystal, or solvate? Is it a new crystalline form? |
| ASD development | Amorphous state confirmation and recrystallisation monitoring | Is the API fully amorphous after processing? Has any recrystallisation occurred? |
| Formulation development | Drug-excipient compatibility | Have any crystalline interactions or form conversions occurred in the blend? |
| GMP manufacturing | In-process and release testing | Does the batch contain the correct crystalline form? Are there unexpected peaks? |
| Stability testing | Physical stability monitoring | Has the solid form changed under ICH storage conditions? |
| Regulatory submission | Reference pattern for Module 3 | What is the defining XRPD fingerprint of the approved solid form? |
XRPD vs. Other Solid State Characterisation Techniques
XRPD is the primary tool for solid form identification, but it works best alongside complementary techniques. Differential scanning calorimetry (DSC) provides thermal event data, including melting points, polymorphic transitions, and glass transition temperatures, that complement the structural information from XRPD. Thermogravimetric analysis (TGA) measures mass loss as a function of temperature, confirming solvate and hydrate stoichiometry. Raman spectroscopy and solid-state NMR provide molecular-level information about bonding and environment that can resolve ambiguities in XRPD data.
A complete solid state characterisation programme uses all of these techniques in combination, with XRPD as the reference method for form identification and batch control.
Regulatory Expectations for XRPD Data
The ICH Q6A guideline on specifications for new drug substances requires that the solid state form of the drug substance is defined and included in the specification when it affects drug performance or manufacturability. The reference XRPD pattern of the intended commercial form must be included in Module 3.2.S of the CTD, and the specification must include a test for solid form identity using XRPD or an equivalent technique.
For amorphous drug substances and amorphous solid dispersions, the regulatory expectation is that the absence of crystallinity is demonstrated by XRPD, and that stability studies monitor for crystalline conversion over the proposed shelf life.
XRPD Capability at Ardena Ghent
Ardena’s solid state research facility in Ghent operates transmission and reflection XRPD instruments capable of routine form identification, high-sensitivity amorphous detection, and variable temperature measurements. The analytical team has extensive experience interpreting XRPD data in the context of pharmaceutical development, including for complex mixtures, amorphous materials, and novel salt and co-crystal forms.
XRPD data generated in Ghent is directly connected to the development programme, ensuring that form-related findings are interpreted in context and feed immediately into formulation and regulatory strategy decisions.
