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Polymorph Screens
Polymorphs are examples of single compounds which, although chemically identical,
exist in two or more different crystalline structures. The presence of single or
multiple polymorphs can present both drug substance and drug product issues. Differences
in physical and chemical properties of drug substance can impact bioavailability,
dissolution rate, oral absorption, pharmacokinetics, ease of manufacturing and dosage
form stability.
Strategy: Conduct a polymorph screen of a drug substance using a selection of possible
solvents that have come into contact with or may come into contact with the drug
substance during synthesis, purification, process, cleaning, and/or salt formation.
Method: A typical polymorph screen consists of a selection of solvents to evaluate
for possible chemical and physical interactions. The procedure consists of dissolving
the drug substance individually into the chosen solvents or a slurry creation at
room temperature and/or elevated temperatures (example: 50°C). The available material
is then isolated from the solvent or slurry in various procedures; precipitation,
evaporation (rapid or slow), cooling, etc. All material isolated is then evaluated
in comparison to the initial unaltered material (i.e. a baseline) by use of XRPD,
thermal evaluation by Differential Scanning Calorimetry (DSC) and Thermogravimetric
Analysis (TGA), polarized microscope (for morphology and birefringence observations)
and FT-IR. Additional tests can be conducted if deemed necessary which might include
the following; solubility and pH properties, vapor sorption and/or particle size
evaluation.
Result: The identification of polymorphs generally differ in their morphology, chemical
and physical stability, melting point, density, solubility, heat of fusion and dissolution
rate to list a few. DSC evaluation is used as a tool to verify differences in onset
temperatures, melting temperatures and heat of fusion of the isolated materials.
This evaluation is to determine the most suitable form, or the thermodynamically
most stable form.
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