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Why pre-formulation studies are crucial to successful drug development

by biopharmacharis in BTL News, BTL News Cat 1, BTL Right Sidebar Content, Intelligent Freeze Drying

As featured in ‘International Labmate’ – April 2018 – Page 59

Why pre-formulation studies are crucial to successful drug development

Understanding the behaviour of a new active pharmaceutical ingredient (API) under various stress conditions is critical to provide a solid foundation for development of a robust dosage form that can survive processing and allow for a prolonged shelf life. The result of a poor, or in some circumstances, no pre-formulation study, could be increased time and cost of drug development, an unstable product, or worse. Efforts taken on comprehensive pre-formulation studies are more than repaid in cost and time savings.

Newly discovered proteins identified through genomics, proteomics, or traditional medical research have historically been utilised in drug development with limited knowledge about their mechanisms of action, structural characteristics and biochemical properties.

Protein structures highly sensitive to physical and/or chemical stress, which has potential to alter the desired form and, in turn, could significantly compromise not only the drug  efficacy, but also the end-user or patient safety.

In this regard, the pre-formulation phase is such an essential part of the drug development as it relies on studies undertaken at the earliest stages prior to formulation development, and a focus on determining the physicochemical properties of a new drug molecule. They will affect safety and/or efficacy of the final product and consequent dosage form. It provides a scientific schematic of the drug in development.  

Having a clear understanding of a protein’s Critical Quality Attributes (CQA) along with awareness of any adverse effects related to a product, demonstrates the worth of conducting pre-formulation studies. Based on the specific drug molecule and excipients, the overall formulation properties can be affected. The solid state properties of the drug and its solubility in the solvent, the median characteristics, the molecule thermal behaviour, reactivity and degradation are only some of the parameters that can impact the formulation behaviour. In addition, the understanding of properties, such as the material bulk density, powder flowability and compactibility, is beneficial to control issues related to the development of a particular dosage form for oral or parenteral administration. The variable factors clearly evident that the formulation can be very sensitive and susceptible to damage and alterations throughout the stages of the production process. For this reason, excipients are often used to improve the formulation properties to protect the active ingredient from stresses without damaging the bioavailability and activity.

Product characterization is the starting point of formulation development, providing a detailed map of the product’s thermal characteristics before any reformulation has taken place.  In particular, the understanding of both physical and chemical properties is necessary. Thermal behaviour is usually assessed by using a differential thermal analysis (DTA) or differential scanning calorimetry (DSC). In addition the combined use of an impedometer allows users to build a more detailed picture of the formulation.  Moisture content and water activity within the material are generally evaluated by performing a Karl Fisher Titration, water activity test and a Dynamic Vapour Sorption (DVS) analysis. Structural parameters are generally investigated through microscopy. In this case, micro Computed Tomography (µCT), Scanning Electron Microscopy (SEM) and Confocal Microscopy give detailed information about the product structure, especially in terms of porosity as well as shape, direction and distribution of single components comprised in the formulation.  


Getting things right the first time is much more preferable to making costly mistakes and it is also a much faster route to market. Furthermore, patent expirations and a reduction in the development of new, first-in-class molecules over the past 15 years has occasioned the strategy of drug repurposing. This is yet another reason to conduct comprehensive pre-formulation studies. Many companies outsource pre-formulation studies to service providers such as the R&D consultancy division of Biopharma Group to address setbacks and process inefficiencies.

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