Small Molecule Drug Development:
Understanding the physicochemical properties of a compound such as solubility, stability, form definition, solid-state properties, partition coefficient and ionization constant(s) is essential so that the formulation process can be rational and streamlined. By integrating this knowledge with the biopharmaceutical properties, Wolfe Laboratories is able to make informed decisions regarding formulation development and the ultimate performance of the drug product. This knowledge also provides valuable insight into process development and manufacturing. Given the fundamental importance of these activities, they must be well-designed from the outset. Wolfe Laboratories characterization techniques include:
It has been Wolfe Laboratories’ repeated observation that many translational teams do not put adequate efforts into ensuring that their compounds are soluble and achieve reasonable exposure. The consequence is that most of these programs fail in the clinic due to poor PK profiles or lack of efficacy. However, a translational development strategy that addresses the multifaceted solubility issues will increase the likelihood of advancing promising molecules in early development.
A high proportion of experimental drugs have low solubility, which creates challenges in the development of parenteral formulations and causes poor dissolution, low and variable bioavailability and prandial effects in oral formulations. For orally dosed drugs, achieving meaningful exposure is not only dependent on the solubility, but also on the permeability. The FDA provides guidance on the Biopharmaceutics Classification System (BCS) to inform different aspects of the drug development pathway. A summary of the BCS classifications, presented in the following table, shows that as the ranking of a compound increases, it becomes increasingly difficult to deliver.
Summary of BCS classifications
Class I: High Permeability, High Solubility
Class III: Low Permeability, High Solubility
Class II: High Permeability, Low Solubility
Class IV: Low Permeability, Low Solubility
Wolfe Laboratories’ scientists have a clear understanding of the types of solubility studies that are required to inform downstream product development activities.
For ionizable compounds, development of a salt form versus free base can provide improved solubility, stability and physicochemical properties. The feasibility of development of the free base and the assessment of which approach is likely to be more advantageous drive the decision on whether to develop a free base or a salt form. The prioritization of criteria for rank-ordering of salts will vary depending on the reasons for pursuing a salt form.
Form and Polymorph Screen
Polymorph screens are an important tool to identify and characterize different forms that are likely to be encountered over the course of product development and to mitigate the risks associated with form definition, such as variable product performance, regulatory issues and manufacturing. Amorphous and crystalline forms can exist, and within the crystalline forms, there can be multiple polymorphs, hydrates and solvates. Because of their different lattice energies, these forms can have dramatically different physical stabilities, processing performance and dissolution rates, which can significantly affect bioavailability and therefore product performance. During the translational stage, Wolfe Laboratories will screen for polymorphs and, if different forms are identified, will characterize the properties, including propensity for interconversion. If the properties are sufficiently different, then one must determine if the product performance will be affected.
Stability Studies to Inform Formulation Development
The chemical and physical stability of the drug substance and the drug product are of paramount importance to the compound’s success. Chemical instability must be understood because loss of the active ingredient leads to loss of efficacy and degradation products may cause side effects or toxicities. Physical instability and form changes can cause changes in appearance and performance, which can have repercussions on manufacturing processes and on bioavailability. With a molecular understanding of the degradation pathways, whether chemical or physical, one can then rationally design a strategy to stabilize the compound. Wolfe Laboratories employs multiple approaches to characterize drug stability:
Stability in Solution
Solution state stability behavior informs formulation and process development and the associated complexity, timing, and costs of product development.
The pH-stability profile is essential for understanding how the compound behaves in different environments and informs formulation development, process development, drug product stability and the route of administration of the molecule. Knowledge of the degradation pathways at different pH values is also useful so one can develop approaches to stabilize the molecule.
The stability of the solid form is an important factor to consider early in the translational stage, since there are serious and expensive repercussions if the form changes. If different forms are found late in development, it could cause delays to the overall timeline, drive up costs and potentially jeopardize the entire program. Therefore, understanding the stability of the solid form is warranted.
Many “solid-state” reactions occur at the surface and are in reality solution state reactions. The solvent is frequently water, residual processing solvents or moisture that is sorbed on excipients. As a consequence of these reactions, there can be changes to the physical form, the particle size and the morphology.
By performing a broad excipient screen during the preformulation stage, Wolfe Laboratories identifies potential problems and defines boundary conditions for formulation screening. Therefore, fewer formulations are examined, saving considerable resources.