In the pre-clinical study design, a careful selection of the formulation development strategy is of high importance. The basic goal of pre-clinical formulation development is to assess potential therapeutic effects of the substance on living organisms and gather sufficient data to determine reasonable safety of the substance in humans through laboratory experimentation animal investigations. Pre-clinical investigation usually takes about 30 months to complete. If enough data are gathered to reach the goal of potential therapeutic effect and reasonable safety, the product sponsor must formally notify the FDA to test the potential new drug on humans. The use of different formulation systems for the various in vivo studies may lead to completely different exposures. Therefore, a structured approach to the development of pre-clinical formulations is mandatory.

The Key Elements of Pre-clinical Formulation Development

Drug Solubility

Drug solubility is an important parameter for both oral and intravenous administration. Poor water solubility has been acclaimed to reduce the performance of more than 10% of successfully marketed drugs. Saturation solubility can be carried out by adding aliquots of drug substance to the volume of the solvent. Careful selections of the formulation concentration and buffer system are essential for pH solubility screening. The type of the buffer salt and its concentration can have a significant impact on the solubility of the drug substance. Buffers at identical concentrations may show a difference in the solubility of the drug substance attributed to the structural properties of the drug substance and/or the salt form. A very high buffer concentration may lead to an erroneously high solubility number but may not be feasible for intravenous administration.

Dose Selection

Dose level selection is perhaps the most popular strategy for the design of formulation. The approach is usually well suited for drugs with a wide therapeutic window and where clinical trials may cause tolerable levels of toxicity. In clinical practice, polypharmacy results in a high possibility of toxicity. Here clinical trials can inform dose guidance for formulation design, such as victim drug combinations. PK modeling (such as population pharmacokinetics), informed by clinical and drug-specific data, provides a useful tool for identifying dose level and allows predictions of formulation. Together with well-designed clinical trials and compound information may provide a powerful tool for selecting dose level involving multiple drugs and patient comorbidities.

Drug Polymorphs

Physical form of the drug substance characterization of polymorphism is critical for formulation studies. For drug substances existing in various polymorphs, there may be only one active form and one or more polymorphs may be meta-stable and can be converted to a more stable polymorph. Additionally, melting point, glass transition temperature, and the decomposition temperature can be determined to obtain valuable information about the drug substance. Generally, optical microscopy is utilized to distinguish the crystalline from the amorphous forms of material. Crystalline solids generally display birefringence, whereas amorphous solids usually do not display birefringence. Polymorphs may be characterized by Differential Scanning Calorimetry (DSC) experiments. DSC experiments coupled with X-Ray Powder diffraction (XRPD) can show a difference in structural morphology.

Based on the study, various strategies should be adopted to develop formulation for pre-clinical studies. Over the years, prediction of pharmacokinetic properties of drugs in humans has been relatively critical to the pre-clinical data, due to the advancement of physiologically based pharmacokinetic modeling. The formulation development plan for pre-clinical study should be carried out based on the intended use of the drug in humans. Formulators need to overcome challenges due to limited availability of drug substance and tight timelines, in order to achieve the aspired goal.


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