The increasing number of product recalls in recent months has again made us aware how important the purity of drug ingredients is. The presence of unwanted chemicals, even in small amounts, may have an influence on the efficacy and safety of pharmaceutical products. Various analytical techniques are employed for purity checks. Among these, differential scanning calorimetry (DSC) is able to quickly analyze the absolute purity of chemical compounds within a single run, without the need for a reference standard.
What is an Impurity and Where Does it Come From?
According to the ICH guidelines (ICH = International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), an impurity is “any component … which is not the chemical entity defined as the active substance or an excipient in the product”. Impurities are classified as:
- Organic impurities
- Inorganic impurities
- Residual solvents
Organic impurities may originate from starting materials, synthetic intermediates, by-products or decomposition products. Inorganic impurities may arise from the manufacturing process and include catalysts, filter aids, inorganic salts, reagents, etc. Residual solvents are – as the name implies – residues of applied inorganic or organic liquids. Out of this list, the number of inorganic impurities and residual solvents is usually limited. And, they are normally known and can easily be identified. However, the situation is different for organic impurities. Their number is almost unlimited and their nature strongly depends on the reaction conditions of the synthesis, the properties of the raw materials, etc. (1)
Purity Determination According to USP <891> and Ph. Eur. 2.2.34
Chapter <891> of the US pharmacopeia as well as chapter 2.2.34 of the European Pharmacopeia are dealing with thermal analysis. The total amount of impurities which are melting together with the main component (also called eutectic impurities) can be investigated by analyzing the profile of the corresponding melting peak. The calculation is based on the fact that an increasing impurity content leads to broadening of the melting effect. Additionally, the peak is shifted to lower temperature values (Van´t Hoff law of Melting Temperatures and EnthalpiesThe enthalpy of fusion of a substance, also known as latent heat, is a measure of the energy input, typically heat, which is necessary to convert a substance from solid to liquid state. The melting point of a substance is the temperature at which it changes state from solid (crystalline) to liquid (isotropic melt).melting point depression of eutectic systems, see fig. 1).
Fig. 1: Comparison of the melting effects of pure phenacetin (green), phenacetin + 2 mol% p-aminobenzoic acid (blue) and phenacetin + 5 mol% p-aminobenzoic acid; Sample masses: 1 to 1.3 mg, heating rate: 1 K/min, Al crucibles, N2 atmosphere More about the Van´t Hoff equation and the way how to determine purity can be found here. Precondition for applying this method is that no solid solution is formed, i.e., that the impurities are only soluble in the liquid phase, but not in the solid phase. Furthermore, for reliable results, the following aspects should be considered:
- Substances should have a purity of more than 98.5% (USP <891>) or 98% (Ph. Eur. 2.2.34)
- Materials should be crystalline (not amorphous or partially amorphous)
- Materials should not decompose during melting
- Compounds that exist in polymorphic form should be completely converted to one form
- Impurities which originate from the synthesis can have a similar shape or size than the major component and thus fit into its matrix without disruption of the lattice. Such impurities are not detectable by DSC.
Besides the description in the mentioned pharmacopeias there is also an ASTM standard existing (ASTM E928) which describes in detail how to determine the purity of thermally stable compounds with well-defined melting temperatures using DSC. Read also my article on purity determination in the upcoming blog! Literature: (1) ICH Topic Q 3 A (R2), Impurities in new Drug Substances, EMEA, October 2006