Polymorphic transitions by DSC and MDCS

Leonard C Thomas talks on polymorphic transitions in drugs

Pharmaceutical companies prefer crystalline compounds for the development of new drug formulations because crystalline drugs generally have better storage stability. However, a frequently encountered problem is the ability of a drug to exist in multiple crystal forms called polymorphs. Since polymorphs can have significantly different physical properties, such as dissolution rate and therefore bioavailability, it is important to control both concentration and crystal form.

Details

The two methods that are generally used to detect polymorphic forms are Differential Scanning Calorimetry (DSC) and Modulated DSC (MDSC). They are preferred because they have different melting points and heats of fusion. Heating rate has no significant effect on the melting peaks except for the width of the largest peak near 165ºC. This shows that the sample is quite stable and there is little tendency for a polymorph to transform into another.

The use of multiple heating rates is an excellent way to detect kinetic events like decomposition or transformation of one crystalline form into another. At high heating rates (20°C per minute), the melting peak of phenacetin broadens, but is essentially unchanged from the melt observed at 1°C per minute. This small difference indicates that the sample is truly melting and there are no observed kinetic events.

Cipro behaves quite differently when the heating rate is increased from 1°C to 20°C per minute. According to its Material Safety Data Sheet, Cipro is reported to decompose on melting. If a single heating rate is used, such as seen in the 5°C per minute data, it could easily be interpreted as melting at 319°C followed by decomposition. However, this would be wrong. The difference of 29°C between the observed "melting" endotherms for the one and 20°C per minute data shows that the endotherm is really a part of the decomposition process and not due to melting.

Summing it up!

DSC is an excellent tool for characterising crystalline drugs. However, just as with any other analytical technique, it should not be used without much thought to experimental conditions. Use of multiple heating rates is a good approach for detecting transitions in materials, as well as, their tendency to undergo kinetic processes as the sample is heated.

(The writer is currently working with TA Instruments, New Castle in USA)