Detection of Previously Unknown Menthol Polymorphs by Flash DSC

Knowledge of the polymorphic forms of an active substance is very important, especially in the pharmaceutical industry. In this article, we show how previously unknown polymorphs of menthol can be identified and characterized by Flash DSC.

Introduction

Both the stability of a chemical compound and its solubility in a medium depend on the structure of the compound. For example, in the development of a pharmaceutical substance it is important to identify different polymorphs and assess their stability. DSC is often used for the rapid detection of polymorphs.

Here the choice of the heating and cooling rate has a large influence on whether polymorphs are found and if so which ones. The formation of a structure in a liquid is strongly influenced by the cooling conditions. Depending on the cooling rate, different polymorphs or mixtures of different polymorphs are formed. During heating, reorganization processes occur which indicate the presence of other polymorphs.

Conventional DSC instruments provide heating and cooling rates of up to a maximum of about 300 K/min. In this article, we show how the high heating and cooling rates possible in the Flash DSC allow polymorphs to be identified that cannot be detected by conventional DSC. The substance chosen for this work was menthol. Previously unknown polymorphs were found both in levorotatory levomenthol as well as in the racemate (a 1:1 mixture of levorotatory and dextrorotatory enantiomers).

Experimental details

Levomenthol or (1R,2S,5R)-5-methyl-2 propan-2-yl) cyclohexanol) was obtained from the Acros Organics company and the racemate from Alfa Aesar in the form stable at room temperature and normal pressure (the α-form). The measurements were performed using a METTLER TOLEDO Flash DSC 1. Heating and cooling rates of 1000 K/s were used. A single crystallite was positioned on the sensor for the measurements

The mass of the crystallite used for the Flash DSC measurement mFDSC cannot be directly determined. It can however be estimated by comparing the enthalpy of fusion of the α-form, ΔHFDSC (in μJ) measured in the Flash DSC measurement with the enthalpy of fusion of the stable form normalized with respect to mass measured by conventional DSC (Δhα in J/g), according to eq 1:

mFDSC[ug]= Δ H_FDSC / Δ h_α

Conclusions

Experiments are usually performed at different heating and cooling rates in order to investigate polymorphic behavior. Whether a particular form occurs depends greatly on the heating and cooling conditions. Using levomenthol and a racemic sample of menthol, we showed that unknown polymorphs could be found with the aid of the Flash DSC and its high heating and cooling rates.

_{Detection of previously unknown menthol polymorphs by Flash DSC | Thermal Analysis Application No. UC 466 | Application published in METTLER TOLEDO Thermal Analysis UserCom 46}