**1. Introduction**

Preformulation studies are synonymously known as "Learning before doing". The Preformulation concept emerged between 1950 and 1960 and since then the pharmaceutical product development emphasis has transformed. Therefore, preformulation studies are required for the early step of data collecting relating to the physicochemical properties of the therapeutic molecule, assessing possible salts and excipient appropriateness. Hence, preformulation is the interface between new chemical entities (NCE) and the formulation development phase therefore it is the sole study to provide a complete pathway of drug formulation development [1]. These studies are most and much important before formulation development and they give us an idea about the stages of drug formulation development related

to the physicochemical properties of new chemical entities (NCEs) or any drug substances [2–4]. During drug development stages, the physical and chemical properties are categorised and standardised to establish the optimum mark for formulation development and ensure that these properties are helpful for formulation development [5, 6]. Key preformulation factors are thermal particle size, shape, dissociation and partition coefficient, drug/API stability, absorption behaviour, and solid-state characters like polymorphism. Furthermore, the structural, degradable, biophysical, and physicochemical characteristics of the macromolecules are also evaluated at the preformulation stage [3, 7].

Characterisation of the drug at the initial stage is the most important step for an early stage of drug product development to have the understanding and behaviour of drug molecules at the entry level in the cycle of drug development (**Figure 1**). Hence, the preformulation studies are the optimum available tool for API and drug product development. It comprises a set of physicochemical parameters and biopharmaceutical principles to design and develop appropriate drug delivery systems [8, 9]. Therefore, the experimental confirmation of the interaction of drug molecule and excipients are well studied at the preformulation level hence it gives an idea about their interaction and adduct formulation results in intelligent selection of drug molecules and excipients. The primary drug degradation profile is also studied to guide the formulation stability and storage conditions for final dosage forms leads the quick development of desired dosage forms [10].

Post-drug discovery with strong basic knowledge of the physicochemical behaviour of candidate molecules, solid state, and relevant powder characteristics of drug molecules are required to develop the most appropriate intended form of formulation to be administered to humans. Each drug molecule proceeds through various physical and chemical checkpoints before being developed into a final dosage form. Furthermore, these properties are helpful to get information about the combination of drug molecules and ingredients. Preformulation studies were performed for NCEs or any extracted compounds to get information about toxicity, pharmacokinetics, drug distribution, degradation process, adverse conditions, and finally bioavailability [11].

Deep understanding and thorough information of physicochemical and related biopharmaceutical properties of the drug direct scientists to design optimum and appropriate formulation delivery methods to get strong proof of concept (POC) and

**Figure 1.** *Stages of preformulation studies.*

pre-clinical studies to have a clear understanding of active pharmaceutical ingredients (API) characters and relevant additives that might affect the final formulation and drug performance [5].

Preformulation studies performed post-scientific literature survey of some type of drug molecules to recognise the following parameters [2, 12–14]:


Preformulation studies provide a path for formulation development and drug product development in respect of drug form, adjuvants, composition, physical structure, and chemistry of drug molecules, facilitating pharmacokinetic and biopharmaceutical properties evaluation, adjustments, and their implementation to get an appropriate end product, product process development support for Process Analytical Technology to get qualified products, harvest essential and suitable scientific facts for analytical method development and validation [15]. Preformulation research is performed to generate data related to biopharmaceutical, physicochemical, and physic-mechanical properties of molecules, and adjuvants (**Figure 2**) [16, 17]. These analytical investigations inspire formulation strategies and manufacturing methods for drug substances and drug products [18].

Various regulatory guidelines like the ICH and US-FDA support and recommend basic concepts for preformulation development. Preformulation studies are advised by NDA, IND, and ANDA and released by the ICH and the US FDA regulatory agencies. ICH guidelines state that all technical requirements for drug approval applications should be submitted in a standardised e-CTD format. This format, known as QOS-QbR, is even more comprehensive technically and is used by the US-FDA. Additionally, the Quality by Design method, which improves the effectiveness of the FDA review process, is the foundation of the QbR format.

There are various scientific and regulatory descriptions available for acquiring preformulation data that are helpful for the predetermination of the final dosage form. These are 1. Setting up drug product specifications for clinical supply preparations and toxicological testing. 2. Creating initial specifications for clinical supplies and their formulation. 3. Provide scientific evidence to support the creation of dosage forms and assessments of the effectiveness, quality, stability, and bioavailability of products. 4. Review of the stability of early dosage formulations produced. 5. Meeting the CMC section's requirements for the IND and any subsequent NDAs or ANDAs submissions [19, 20].

**Figure 2.** *Preformulation study schematic representation.*
