“Diamonds are a girl´s best friend” is a famous musical and film song (tracing back to the film “Gentlemen Prefer Blondes” with Marilyn Monroe) which targets at the preciousness of diamonds – although, from the chemical point of view, diamonds are just made of carbon. The phenomenon that chemical elements can occur in different forms within the same phase, i.e., in different structural modifications, is called allotropy.
A more general term for chemical compounds is polymorphism. It means the ability of a solid material to exist in more than one form or crystal structure. Directly related to the crystalline form is a multitude of material properties such as (1)
- Stability (e.g., shelf life, precipitation from solution)
- Solubility and bioavailability
- Mechanical behavior (e.g., for tablet compression) or
- Physico-chemical characteristics (e.g., hygroscopicity, dissolution rate, density, melting point)
Due to the relationship between crystal modification and melting point, differential scanning calorimetry (DSC) is ideally suited to discriminate between different polymorphic forms.
Monotropy and Enantiotropy
By changing temperature, it can happen that polymorphic forms (or modifications) are converted into one another. If this transformation occurs in one direction only, we speak of monotropy. However, if the transformation is reversibly, the term is enantiotropy. Such phase transformations can often be investigated by DSC as well.
The Ritonavir Story – Or Why is it Important to Perform Polymorph Screening
The possible serious consequence of such modification change shows the example of ritonavir very vividly (based on the literature sources (2) to (4)).
Ritonavir (an antiretroviral medication) came into medical use in 1996 and was originally sold as an ordinary capsule for oral intake. At that time, the only existing modification was the one which is nowadays called form I. However, in 1998, another modification, form II, appeared which was exhibiting worse solubility and therefore had much lower therapeutic effect. Unfortunately, this form II was thermodynamically more stable and so even traces of form II catalyzed the transformation from the biological active from I into form II with much lower bioavailability.
The end of the story was that the capsule formulation had to be withdrawn from the market. The solution was a revised formulation (tablet) which got approval by the FDA in 2000.
More information about polymorphism can be found here.
(1) F. Bauer, Polymorphism – A Critical Consideration in Pharmaceutical Development, Manufacturing, and Stability, Journal of Validation Technology, 2008
(3) F. Bauer et al. (2001), “Ritonavir: An Extraordinary Example of Conformational Polymorphism”. Pharmaceutical Research. 18 (6): 859–866