Role of Preformulation Studies in Drug Discovery

Module 2 : Pharmaceutical Preformulation : Basics and Industrial Applications

What is Drug Discovery?

Drug discovery and development is a multi – disciplinary activity involving inputs from various departments like medicinal chemistry, molecular biology, pharmacology, toxicology, pharmacokinetics and pharmaceutical development. The average time from drug discovery to product launch is almost 10 to 12 years. Drug discovery is defined as the process by which drugs are discovered or designed. Drug development is a term used to describe process of bringing a new drug to market, after drug candidate has been selected in drug discovery. Activities in drug discovery include disease selection, target identification, target validation, lead generation, lead selection, lead optimization and candidate selection. These activities are pre-clinical in nature and to use host of tools that may be in vitro, in situ, ex situ and in vivo animal models. Drug development involves clinical trials on ‘new chemical entities’ and shall be discussed in next module.

Biopharmaceutical properties and ‘Drugability’

Selectivity and potency of the molecule for target site, had been the classical criteria during the discovery. However, last few decades, have witnessed paradigm shift, with ADME and material properties playing crucial roles in lead selection. Drug discovery companies have realized that a large number of molecules fail to become drugs, because of non-optimal biopharmaceutical properties, that includes, pharmacokinetics and drug delivery characteristics. Overall therapeutic efficacy of a molecule is dictated by its selectivity / potency and the efficiency with which it is delivered to the site of action. Pharmacokinetics and material properties govern the delivery of the molecule to the site of action and thus contribute to its ‘drugability’.

Modern drug discovery tools like combinatorial chemistry and high throughput screening have also contributed to the non-optimal material properties. Combinatorial chemistry involves reaction of a small number of chemicals to produce simultaneously, a very large number of compounds, called libraries. These compounds are then screened using high throughput screening to identify drug candidates. Prior to this, computational tools like target docking studies are performed to propose the lead molecules that are then synthesized using combinatorial chemistry platforms. Initial lead generation and selection is thus solely guided by molecule- target interactions. This approach, over the years, has led to gradual increase in molecular weight and lipophilicity of the lead molecules.

Preliminary Preformulation

Material properties are a set of physicochemical properties that include solubility, dissolution rate, partition coefficient, solid-state properties, stability and hygroscopicity. Preformulation studies during drug discovery, aid candidate selection having optimal physicochemical properties, those are essential for effective drug delivery. Various terms like ‘preliminary preformulation’ and ‘discovery pharmaceutics’ are used to describe this preformulation activity done during drug discovery. Main objective of this preformulation activity is candidate selection.

In silico tools for preliminary preformulation

Preliminary preformulation can be carried out using in silico and experimental platforms, to generate preformulation profile, of the lead molecule. Numerous computational softwares like PALLAS, gastro plus, ACD / Phys Chemand ALOGPS are available and require structural formula as an input to calculate physicochemical parameters like ionization constant, pH dependence of partition coefficient, solubility and permeability is. Similarly computation of ADME properties is also possible.

Experimental tools for preliminary preformulation

Despite enhanced accuracy of predictive tools, experimental measurements are essential as the level of complexity of prediction, renders calculations of little utility. High throughput miniaturized experimental tools are used during drug discovery stage, to enable screening of large number of candidates, using small quantities of NCEs. The most important issue at this stage is oral absorption of the molecule. High throughput solubility screening can be carried out using commercially available equipment like PION-pSOL and Sirius CheqSOL. However, these equipments require solid sample for solubility analyses which may not be available in early stages. A popular means for early solubility experiments is the ‘precipitative solubility’ using DMSO stock solutions. Automation using robotics allows faster screening of large number of compounds. Similarly high throughput permeability studies can be performed using ‘parallel artificial membrane permeability assay’ (PAMPA).

Fail early – fail cheap

Every pharmaceutical company targets the goal of ‘fail early – fail cheap’, during drug discovery, by short listing molecules that have all the criteria of drugability. It is disastrous to spend lot of money on research of molecules that fail later in the drug development. We can thus conclude that preliminary preformulation helps in candidate selection during drug discovery and thus enhances of conversion of ‘a molecule’ to ‘a drug’. Additionally it lays out a framework for designing of preformulation protocol, to support drug development activities later on.

Dr. Arvind Bansal 


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