Thermal Analysis — DSC and TGA
Molecular spectroscopy named this family in passing: the API is the same molecule in every crystal form, and a separate family of techniques reads how it’s packed rather than what bonds it has. Thermal analysis is the simplest member of that family — heat the sample at a controlled rate and watch what happens — and it is usually the first thing run on a new polymorph, salt, or hydrate.
The one idea
DSC and TGA run the same experiment — a controlled temperature ramp — and read two different physical quantities off it: DSC reads heat flow (something absorbing or releasing energy), TGA reads mass. An event that looks identical on a DSC trace alone can mean two completely different things depending on whether TGA shows mass loss at the same temperature — and calling it the wrong one gets a specification wrong.
What each technique reads
| Technique | Measures | Typical thermal events |
|---|---|---|
| DSC (differential scanning calorimetry) | Heat flow into or out of the sample versus a reference, as a function of temperature | Glass transition (Tg) — a step, not a peak, in an amorphous fraction; melting — a sharp endotherm; polymorphic transition / recrystallization — an exotherm as a metastable form converts; desolvation / dehydration — an endotherm as bound solvent or water leaves |
| TGA (thermogravimetric analysis) | Sample mass versus temperature | Free water loss (low temperature, gradual); bound/hydrate water or solvent loss (a defined step, often stoichiometric); decomposition (a sharp mass loss, usually well above any pharmaceutically relevant processing temperature) |
Reading the pair together
A DSC endotherm at 150 °C could be a true melt, or it could be desolvation — a hydrate or solvate losing bound water or solvent, which also absorbs heat. Run alongside a TGA trace on the same sample: if the DSC endotherm coincides with a mass loss step, it’s desolvation, not melting; if there’s no corresponding mass change, it’s a genuine phase transition. Neither trace alone answers the question — this is the same “orthogonal method” logic as DAD peak purity plus mass balance catching a co-eluting degradant: one measurement’s blind spot is the other’s core signal.
This pairing is also how a hydrate stoichiometry gets confirmed quantitatively — a TGA mass-loss step of, say, 4.5% against a molecular weight lets you calculate whether the sample is a mono-, di-, or hemihydrate, a number a DSC endotherm alone can’t give you.
The amorphous-content connection
An amorphous fraction shows up on DSC as a glass transition — a step in baseline heat flow, not a peak, and it is easy to miss if you aren’t looking for it. This matters because XRPD — the next section — typically can’t see amorphous content below about 5%: DSC (and dynamic vapour sorption) are often what actually catches it, which is why a polymorph or amorphous-content investigation runs both techniques together rather than picking one.
Where the analyst sits
Sample preparation is not incidental to the result: pan type (crimped, hermetic, pinhole) and heating rate both shift the apparent onset temperature of a melt or transition, so a “melting point” reported without its method conditions is not fully specified. A single instrument run is a screening result, not a validated method result — a genuinely unexpected thermal event (an extra endotherm, a shifted Tm) gets confirmed by a second technique before it changes a conclusion about polymorphic form.
On the job
- Confirming an incoming lot’s polymorphic form by DSC melting point is a common early task when XRPD access or turnaround is limited — know the reference melting point and its accepted range, not just “does it melt somewhere reasonable.”
- A hydrate’s TGA mass-loss step is one of the more reliable numbers in solid-state characterization precisely because it’s stoichiometric — learn to convert a percent mass loss into a hydrate ratio before you’re asked to.
- “The DSC looks different from the reference” is a triage problem, not an automatic OOS: check heating rate and pan type against the reference method before treating it as a genuine form change.
For discussion
- The same batch run at 5 °C/min and at 20 °C/min gives melting onsets 3 °C apart. Which is “right,” and what does that tell you about reporting a melting point without its method?
- A DSC trace shows a single sharp endotherm; TGA on the same sample shows a two-step mass loss ending well before that endotherm. What does that combination imply about the sample’s solid form?
- A generic manufacturer’s DSC trace shows a small glass-transition-like step that XRPD doesn’t flag as unusual. Is this worth investigating, and what would you run next?
Source note. Compendial basis: USP ⟨891⟩ (Thermal Analysis), Ph. Eur. 2.2.34 (differential scanning calorimetry), 2.2.35 (thermogravimetry, where adopted). General reference: Giron, Thermal Analysis and Calorimetric Methods in the Characterisation of Polymorphs and Solvates.