Melting point analysis

Why is Melting point analysis used?

•Easy (cheap) check on purity of a crystalline drug substance

What do impurties do to the melting point ? and why?

•Impurities lower melting point

•How? Only one of these is correct!

oOption 1: weaken crystal lattice and lower melting point

oOption 2: do nothing to crystal but stabilise the (liquid) melt

What is melting point T_m ?

solid and liquid are in equilibrium

How do impurties effect solids and liquids?

Impurities can't affect solid (close-packed) but can mix with liquid

Liquid (melt) stabilised by entropy of mixing

Liquid more stable than solid so equilibrium shifts and melting point drops

How to calculate Tm?

T_m is measured melting point of sample of interest, T₀ is melting point of pure substance, ΔH is molar enthalpy of melting, R is ideal gas constant, x is the mole fraction of substance (x=1 is pure material, x=0.9 is 10 % impurity etc)

Summary

•SvL assumes no interactions between different types of molecule, purely entropy of mixing

•Melting point is given on most drug substance bottles

•Can’t use melting point if a drug decomposes near melting point (e.g. aspirin, most proteins, etc)

•If the question is "is my drug substance pure" melting point often the analysis of choice

Questions

•Explain how the SvL equation can be used to determine the purity of a drug substance. How do impurities affect the melting point?

•A drug is reported to have a melting point of 150 °C and a melting enthalpy of 35 kJ/mol. A sample of the drug is found to melt at 145-147 °C. Estimate the percentage by mole purity of the sample. What might the root cause of the lower melting point and how might you confirm this?