What is physical characterisation?

Physical characterisation is determination of all the physical properties of a pharmaceutical drug (API) such as stability, melting point, water uptake etc. The main purpose of performing physical characterisation is to understand and control the drug: When developing a new drug product you want to make sure that it is stable during storage for a certain period (usually some years). Thus, it is very relevant to know what happens when it is exposed to, for instance, higher temperature or humidity. Further, the API should be bioavailable when given to a patient, i.e. it is necessary to know the behaviour with regard to solubility and dissolution.  Some of the methods used in physical characterisation are described briefly in the following section.

Physical characterisation with regard to temperature:  If an API melts at a relative low temperature (i.e. < 100 C) it will be regarded as quite unstable. During manufacturing a risk of elevated temperatures exist – and in mixture with excipients the melting point will be lowered. If the compound melts, the risk of unwanted reactions increases. Even when the temperature is lowered again, the crystal form of the compound might change. The thermal behaviour is usually determined by Differential Scanning Calorimetry (DSC): By heating/cooling the compound while measuring the “energy”, you obtain information about melting point and other thermal events. Further, thermal transitions of a compound can be followed by Hot Stage Microscopy.

Setting up limits

Physical characterisation with regard to water/humidity: If an API absorps a large amount of water a high humidity, it might be relative unstable: Water is a “catalyser” for many reaction, thus a very water absorbing (hygroscopic) compound has a higher risk of unwanted reactions. The tendency of an API to absorb water is determined by Dynamic Vapor Sorption (DVS): In these measurements the weight of the API is measured very accurately while increasing the relative humidity. If an API is very hygroscopic, it is sometimes chosen to change it into a salt, which might solve the problem.

Physical characterisation with regard to crystal form: Most API’s are able to form different crystal forms. As the different forms will have different properties with regard to stability (for instance melting point and water uptake), one should be sure to control which of the crystal forms are present in the final product. Usually, the more stable form will be prefered. The crystal form is determined by X-ray Powder Diffraction (XRD): Different crystal forms will give rise to different diffraction patterns in an XRD measurement. All new crystal forms are further analysed by Thermogravimetric Analysis (TGA) in order to show if they are “true” crystal forms or solvates (i.e. if solvent molecules are part of the crystal structure.) In a TGA measurement, the solvent molecules will evaporate.

Pills on Drug Information Sheet

Physical characterisation with regard to solubility and dissolution: In order for an API to be bioavailable, it has to dissolve when it enters the “biological system”. Thus, it is always examined whether the solubility of the given API is expected to be sufficient to dissolve the needed dose in the patient. Not only the solubilty is of interest: The dissolution rate is also measured, as it describes how fast the compound will dissolve.

Physical characterisation with regard to size: The size of the particles in the final product is directly linked to the dissolution rate of the API (and many other parameters). The particle sizes are determined by a number of various techniques such as laser diffraction and SEM.

 

 

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