Why polymorph control matters in API manufacturing

Many drug substances can pack into more than one crystal structure. These structures are called polymorphs. They are chemically identical and physically different, and the difference reaches all the way to the patient.

What changes between forms

Polymorphs of the same API can differ in solubility, dissolution rate, melting point, stability and how the powder flows and compresses. A formulation developed on one form may not perform the same way if the API arrives as another.

Where the form is decided

Crystal form is set in the last steps of the process. Solvent, temperature, cooling rate, seeding and drying conditions all influence which form appears. That makes the final crystallisation one of the most tightly controlled operations in API manufacture.

How it is checked

• X-ray powder diffraction gives each crystal form a characteristic pattern and is the reference technique for identifying it.
• Differential scanning calorimetry shows melting and transition events that differ between forms.
• FTIR can distinguish forms where the crystal packing changes the spectrum.
• Particle size analysis does not identify the form but tracks a property that often moves with it.

Why it is also a regulatory matter

Regulators expect the polymorphic form to be identified and, where it affects performance, controlled in the specification. Stability studies also need to show the form does not convert during storage.

What to ask an API supplier

• Which form do you supply, and how do you confirm it batch to batch?
• Is the form part of the release specification?
• Has form stability been followed through the stability programme?

Polymorph development is one of Nivika's stated research focus areas, alongside impurity profiling and process development. See the quality section for the laboratory capability behind it.