Role of Preformulation Studies in Drug Development

Module 3 : Pharmaceutical Preformulation : Basics and Industrial Applications

Part – 1

What is Drug Development?

Drug development involves investigations on ‘lead molecules or candidate molecules’ identified in drug discovery stage. These investigations mainly involve clinical evaluation. Clinical trials (CTs) are conducted in human subjects and involve phase I, II and III. Phase IV trials involve post-marketing surveillance of the new drug.

Role of Preformulation Studies in Drug Development

Phases of CTs

Phase I

These trials involve initial safety trials on a new chemical entity (NCE), to establish the dose range tolerated by human volunteers for single and for multiple doses. These are usually carried out on healthy subjects and sometimes on severely ill patients (e.g., in the field of cancer). They provide information on safety and pharmacokinetics of the molecule.

Phase II

Phase II trials are carried out to establish evidence of efficacy and generate more information on safety of the NCE. They are further classified as phase IIA and IIB. Phase IIA is specifically designed to assess dosing requirements and phase IIB is specifically designed to study efficacy in the prescribed doses.

Phase III

This phase of CT is also categorized into IIIA and IIIB. Phase IIIA includes trials conducted after efficacy of the medicine is demonstrated, but prior to regulatory submission of a New Drug Application (NDA) or other dossier. These trials are randomized, multi-centric and focus on generating definitive evidence of efficacy of the NCE against the current ‘gold standard’ treatment.

Phase IIIB includes trials that continue after submission of the NDA and continue till marketing approval is obtained. These trials may supplement earlier trials, complete earlier trials, or may be directed toward new types of trials (e.g., quality of life, marketing).

Phase IV

Studies or trials conducted after a medicine is marketed to provide additional details about the medicine’s efficacy or safety profile.

Need for Formulations

Formulation development is required at various stages during drug development. As we have discussed earlier, drugs are rarely administered alone. Incorporation of the drug into a formulation provides various advantages like ease of handling, ease of administration, better stability or better bioavailability. Different stages of clinical trials as described above require different formulations. Preclinical stage is performed in animals and requires simple liquid formulations that can be easily administered to animals.

Pre-clinical phase is proceeded by human clinical trials, consisting of phase I, II and III. Formulations used for phase I clinical trial are called as ‘first time in human’ or ‘first time in man’ formulations. These can be simple solid or liquid formulations and includes formulations like ‘chemical in capsule’ and ‘chemical in bottle’. Sometimes Phase ICTs can also be initiated using the proposed commercial formulation. The sophistication of the formulation increases as the stage of clinical trial progresses. It is desirable to initiate late phase 2 or phase 3 clinical trials with the proposed commercial formulation.

Part – 2

Preformulation Studies during Drug Development

Preformulation studies are an essential component of drug development wherein it supports development of formulations, for different stages of clinical trials. The word preformulation is composed of two words pre and formulation. Activities done prior to formulation development are called as preformulation studies. It provides the scientific basis for formulation development.

Classification of Preformulation Studies

Preformulation studies can be broadly classified into two classes – (i) fundamental properties and (ii) derived properties. Fundamental preformulation properties are specific to the drug molecule and are dependent on the chemical structure of the drug molecule. In contrast, derived preformulation pre-formulation properties are carried out to learn about the issues related to development of a particular dosage form like solid oral, liquid oral or parenteral.

Fundamental preformulation properties include – (i) Solubility – Various studies performed during solubility assessment include – solubility in different solvents, dissociation constant (pKa), salt formation, partition or distribution coefficient (log P or log D), pH solubility profile and dissolution kinetics, (ii) permeability, (iii) solid state properties like solid form, polymorphism, solvated forms and amorphous form and (iv) solid state stability and solution state stability, wherein inherent stability, pH – stability profile and photo-stability are studied.

Derived preformulation properties for solid oral dosage form like tablet, include – (i) characterization of particle properties like morphology and particle size, (ii) bulk density, (iii) flow properties and (iv) compaction behavior. As discussed, derived preformulation properties are specific to the intended dosage form to be developed. In case a capsule dosage form is to be developed, compaction behavior, shall not be required. The last activity performed in pre-formulation studies is the compatibility studies, wherein the physical and chemical stability of the drug molecule is studied in presence of excipients. Obviously, the choice of excipients is dictated by the type of dosage form to be developed.

Preformulation lays Foundation for Formulation Development

A comprehensive preformulation study helps in understanding the physico-chemical properties of the drug molecule. It provides the foundation for development of a robust dosage form that can sustain the rigors of processing and shelf life. Efforts spent on preformulation provide cost savings in the long run, by reducing challenges during formulation development.

Dr. Arvind Bansal 


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