The impact of preformulation on successful drug development

By Stephen Byard, Head of Molecule Development and Scientific Direction at Arcinova

Stephen Byard, Head of Molecule Development and Scientific Direction at Arcinova, explains how extensive preformulation studies ca

Stephen Byard, Head of Molecule Development and Scientific Direction at Arcinova, explains how extensive preformulation studies can help reduce risk during pharmaceutical development by supplying evidence of the optimal physical form of a drug molecule.
The main goal of preformulation studies is to understand the physicochemical properties of the drug substance and how they affect drug performance. These studies are the foundation for developing a robust dosage form and can increase cost efficiency by reducing challenges during formulation development.1 By combining chemistry expertise with state-of-the-art instrumentation, scientists can investigate drug substances both at the bulk and molecular level. The results enable accurate predictions of how drug substances will formulate – with or without excipients present.
Bulk characterization of drug molecules involves defining solid-state properties that are likely to change during process development. Assessing crystallinity and polymorphism is critical for solid dosage forms in order to understand the exposure of the product following administration. It is also vital that the post-formulation physical form of the active is defined because of the possible variation in absorption profile. A polymorphism screen recrystallizes the drug compound under various conditions to determine the most thermodynamically stable form. The polymorphs are then characterized and analysed to understand whether they have different properties, such as solubility, stability and melting point.
Because the techniques that are used to quantify physical form are not nearly as sensitive as those that are available for quantifying chemical impurities, a large variety of methodologies must be applied on a case-by-case basis. This includes dynamic vapour absorption, for quantifying amorphous material, and differential scanning colorimetry, which can be used to quantify both crystalline and amorphous components of a drug substance.
Technological advancements have enabled scientists to access the molecular level for enhanced preformulation studies. Solid-state nuclear magnetic resonance (NMR) is highly sensitive to slight changes in molecular arrangement, making it particularly useful for identifying variation in crystalline forms.2 The technique can also be used in conjunction with more conventional approaches, such as X-ray powder diffraction. The latest state-of-the-art technologies can provide high-quality data that enable predictions of the best formulation for swift progress to clinical trials.
Thermal analysis is also an important part of preformulation studies. Differential scanning colorimetry measures how a material’s heat capacity changes with temperature and provides information on the most thermodynamically stable form. For amorphous material, it is a good way of assessing information about the glass transition temperature – a physical property that can influence chemical stability, physical stability and viscoelastic properties.3 By combining differential scanning colorimetry and dynamic vapour absorption, scientists can introduce water to the substance and lower the glass transition temperature. This permits a greater understanding of how the drug substance may crystallize over a period of time, or how stability may be compromised throughout the formulation process.
The hygroscopic character of a pharmaceutical material – its ability to absorb or adsorb moisture – is also analysed using dynamic vapour absorption. This is critical from both a formulation and analytical perspective as any changes to the mass of the drug substance from either acquiring or losing water can have an impact on quantitative analytical data. Moreover, hygroscopicity studies enable the prediction of how a drug substance will behave when formulated at different locations around the world, particularly in territories with a very high relative humidity. Without dynamic vapour absorption data, problems during the formulation or manufacture of a drug product could be easily missed.
Determining the level of solubility is another important procedure during preformulation as soluble drugs tend to be better absorbed when administered by the oral route. It is also imperative that scientists investigate the consequences of adding water as part of the formulation programme. This involves asking whether it will partially solubilize the drug substance and, if so, what are the downstream consequences? Analysing the aqueous solubility of a substance can provide results that influence the type of formulation and how it will be administered in clinical studies.
Preformulation investigators apply a wide range of chromatography capabilities to supply accurate solubility data. They can also carry out solubility tests using non-aqueous solvents for instances where they offer better solubility of a drug substance. Solubility studies are not just about determining the instantaneous solubility. It is also critical to determine the potential for crystallisation or solvate formation to affect bioavailability following administration.
Preformulation studies also need to circumvent any chemical degradation and physical changes that can occur either during the optimization of the process or following the manufacture of a product. Through the application of appropriate, predictive techniques, stability studies can start to assess physical and chemical stability either alone or in the presence of different excipients under various conditions. This involves subjecting the drug substance to elevated temperatures and relative humidity over a short period of time and then looking at the degradation profile of that drug substance following exposure to stress.
Effective preformulation requires a wide range of cutting-edge instrumentation that can be used to characterize the physical form of drug substances and the actives in drug products. However, many of the techniques do not necessarily run in a protocol fashion and there are a lot of parameters that can be adjusted to probe different aspects of a drug substance or product. It is therefore essential that scientists have the background knowledge and experience to understand any red flags. By utilizing a wide range of methodologies and combining them with the expertise of skilled scientists, preformulation can significantly reduce the time, cost and risk involved in developing a new pharmaceutical product.
  1. Hasan M et al. Int J Pharm Ther 2017;8:16-32.
  2. Tishmack PA et al. J Pharm Sci 2003;92:441-74.
  3. Hancock BC, Zografi Pharm Res 1994;4:471-7.
Stephen Byard is Head of Molecule Development and Scientific Direction at Arcinova, Taylor Drive, Alnwick, Northumberland, NE66 2DH, UK
T: +44 (0) 1665 608 300