Preformulation study forms an important part of the drug development process as it helps formulation scientist to build the foundation of the drug product to be used in the preclinical safety/efficacy studies and early human trials. A precise and well-planned formulation study not only helps to reduce the overall timelines for drug development process but also reduces the chance of failure of clinical trial owing to CMC issues.
In the preformulation phase of drug development, medicinal chemists investigate the important aspects of new chemical entity such as ionisation constant (pKa), partition coefficient (log P). Formulation scientists also take advantage of these intrinsic parameters of active moiety to plan the preformulation studies. These physicochemical parameters determine the stability of the active in the final formulation and drive the bioavailability (upon oral administration). The preformulation studies also involve studying the stability of the active in solid state as well in dissolved state. Furthermore, drug-excipient interactions are studied in this phase to guide the selection of excipients in the final formulation (to be used in the clinical phases followed by commercial launch). For the complex formulations such as injectables (i.v, s.c and i.m.) and those containing poorly soluble drugs, the preformulation studies are of prime importance as it forms foundation of the drug product development. A precise design and execution of the preformulation studies reduces the risk of the failure of the drug development owing to CMC issues.
Planning preformulation studies is actively initiated as soon as the lead candidate is nominated for preclinical studies followed by phase 1 clinical (First in Man studies). Any red flags for the drug under development arising from the physicochemical properties of the active moiety as well as its interaction with the excipient and associated issues with the attainment of the bioavailability could be detected at the earliest due to careful planning of the preformulation studies.
The Big Pharma companies have in-house set ups to plan these preformulation studies to gain time. However, start-up and mid-size pharma companies often need to rely on external partners to execute these studies. Careful selection of third party CROs is very important as specific skillsets are required to execute these studies due to the less amount of API available at this stage and timelines and budget consideration also play an important role.
As indicated above, the preformulation studies aim to study the physicochemical parameters of the drug such as pKa, Log P, permeability as well as stability of API in solid and solution state, polymorphism, drug excipient-interactions etc. The techniques/methods used to perform the preformulation studies are as below
The most important aspect of the preformulation studies is to focus on solid state and solution stage stability of API. If there are any bioavailability issues for the API to be developed (linked to BCS-II category), preformulation studies must aim to identify the excipients which can improve the dissolution rate followed by bioavailability. For BCS class IV compounds, the focus should be to select the excipients and optimise the formulation accordingly to improve permeability in vivo. For poorly stable drugs, excipients must be selected to enhance the chemical stability of the drug in the final formulation. Regulatory authorities are also keen to understand the rationale behind the selection of type and concentration of an excipient and hence drug-excipient interactions must be planned carefully.
The amount of API available at the preclinical or early clinical phase of the drug development process is always a major challenge and hence formulation scientist must strive to design the preformulation studies at microscale (microformulation studies) rather than conventional preformulation screening. This will help economize the API consumption and yield the speedy outcome. Often at this stage of drug development there are multiple compounds to be screened, hence preformulation studies must be able to rule out the compounds which would be difficult to develop from the Pharmaceutical development point of view.
Start-up and mid-size pharma companies need to identify the right partner to perform these studies. Lack of knowledge and non-availability of the required techniques will significantly jeopardise the outcome of the preformulation studies which would hard the preclinical safety and early clinical studies.
There is abundant literature available and significant work has been done related to the preformulation studies for small molecules. However, these days the pipeline of drug development is heavily dominated by large molecules (peptides, proteins, nucleic acids, and antibodies). Hence, having a flowchart or guidance to execute the preformulation studies of biomolecules will be of great importance to speed up the drug development process.