Fundamental Physical and Physicochemical Properties of APIs and Excipients
Solid pharmaceutical ingredients exist in crystalline, semi-crystalline or fully amorphous form whereas the amorphous state is either inherent or generated by processing (milling, freeze-drying, spray-drying, etc.). With differential scanning calorimetry (DSC), it is possible to determine various specific characteristic properties of the raw materials such as melting/CrystallizationCrystallization is the physical process of hardening during the formation and growth of crystals. During this process, heat of crystallization is released.crystallization temperatures, heats of fusion or Glass Transition TemperatureThe glass transition is one of the most important properties of amorphous and semi-crystalline materials, e.g., inorganic glasses, amorphous metals, polymers, pharmaceuticals and food ingredients, etc., and describes the temperature region where the mechanical properties of the materials change from hard and brittle to more soft, deformable or rubbery.glass transition temperatures to study PolymorphismPolymorphism is the ability of a solid material to form different crystalline structures (synonyms: forms, modifications).polymorphism and to investigate their purity. Thermogravimetric analysis (TGA) is able to detect residual solvents (and to identify them when combined with a gas analyzer such as FT-IR) or the water content of hydrates and also to investigate the maximum temperature up to which the material is thermally stable – under inert conditions as well as under defined humidity. Finally, by means of kinetic evaluation (with NETZSCH Kinetics Neo), predictions concerning stability based on thermoanalytical measurements can be calculated that allow for statements which would otherwise experimentally not be accessible or only at great expense.
Drug-Excipient Compatibility Screening in the Early Development of Dosage Forms
In a dosage form, an API (active pharmaceutical ingredient) is mixed up with excipients. Excipients facilitate administration and release of the active ingredient and protect the API from the environment. However, any physical or chemical interaction between the API and a certain excipient can affect both the bioavailability and stability of the dosage form. Thermal analysis plays an important role in compatibility studies and is frequently employed for quick assessment of physicochemical incompatibility. From these techniques, differential scanning calorimetry (DSC) is currently the dominating one although thermogravimetric analysis (TGA) can also help. The main benefit of DSC is its ability to quickly check potential excipients for incompatibilities, derived from the appearance/disappearance or shift of peaks and/or variations in the corresponding transition enthalpies.
From Lab to Production
During the development phase of the drug, the manufacturing technology is worked out in the lab. Afterwards, however, the manufacturing process must be transferred into production scale. This needs profound knowledge of the physical properties of all APIs and excipients involved along with all intermediate products. Differential scanning calorimetry (DSC), for example, can be used to derive the critical formulation temperature during lyophilization of thermolabile substance which is close to the Glass Transition TemperatureThe glass transition is one of the most important properties of amorphous and semi-crystalline materials, e.g., inorganic glasses, amorphous metals, polymers, pharmaceuticals and food ingredients, etc., and describes the temperature region where the mechanical properties of the materials change from hard and brittle to more soft, deformable or rubbery.glass transition temperature of the maximally concentrated solution (Tg‘), a substance or formulation specific value. A very efficient way of producing pills is direct tableting whereas the compaction properties of pharmaceutical powders are depending on their compressibility and compactibility. Compressibility describes the relative change in volume of a sample resulting from a pressure change. As the compression of an API or a drug product can lead to a conversion into another modification, its compressibility may be influenced as well. DSC is a fast and easy method to monitor if structural changes occur during processing.
Ensuring Product Quality
While regular checks during production are part of the in-process control, the term quality control is typically used after production. However, testing and release of raw materials are often included. Depending on the defined attributes using thermal analysis, similar tests can be applied like during the development process. This implies determination of melting or CrystallizationCrystallization is the physical process of hardening during the formation and growth of crystals. During this process, heat of crystallization is released.crystallization temperatures, melting enthalpies (heats of fusion) or glass transition temperatures by differential scanning calorimetry (DSC) for identification of a particular substance or its polymorphic form. Drug products must have an expiration date imprinted on their packaging. This requires a stability test program to determine its lifespan and thus to ensure that safety and efficacy of the drug do not change within this period. As a consequence, time-consuming tests are necessary. In order to get first information about the shelf life of a pharmaceutical much faster, thermogravimetric analysis (TGA) along with kinetic evaluation can help.