1. Physiochemical properties of drugs Some background to the Sirius T3

2. LADMET and drug discovery and development The following extract is taken from an article by Dr Jianling Wang and Dr Laszlo Urban in Drug Discovery World (2004). The increased costs in the discovery and development of new drugs, due in part to the high attrition rate of drug candidates in development, has led to a new strategy to introduce early, parallel evaluation of efficacy and biopharmaceutical properties of drug candidates. Investigation of terminated projects revealed that the primary cause for drug failure in the development phase was the poor pharmacokinetic and ADMET (Absorption, Distribution, Metabolism, Discretion and Toxicity) properties rather than unsatisfactory efficacy. In addition, the applications of parallel synthesis and combinatory chemistry to expedite lead finding and lead optimisation processes has shifted the chemical libraries towards poorer biopharmaceutical properties. Establishments of high throughput and fast ADMET profiling assays allow for the prioritisation of leads or drug candidates by their biopharmaceutical properties in parallel with optimisation of their efficacy at early discovery phases. This is expected to not only improve the overall quality of drug candidates and therefore the probability of their success, but also shorten the drug discovery and development process. Physiochemical properties of drugs

3. An opportunity Measurement of the physiochemical properties of drugs has always been important, but high throughput and fast ADME profiling has become increasingly important as scientists seek ways of shortening the drug discovery and development process. In this short video sequence John Cromer, Chief Scientific Officer at Sirius Analytical, describes where the need or an instrument that determined pK a values came from and how this led to the development of the T3. Physiochemical properties of drugs Reminder:LADME are the stages that happen when a medicinal drug is taken (usually in a formulation): Liberation – Absorption – Distribution – Metabolism – Excretion The development, construction and use of the T3 brought together aspects of chemistry, engineering, technology, mathematics and computer programming. On the next slide john describes what it can do.

4. The Sirius T3 The Sirius T3 can determine a number of physiochemical properties that influence the potential of a compound to be a medicinal drug. The four most important ones are: acid dissociation constant, K a, and pK a; partition coefficient, P, and logP; solubility, s, and logs; dissolution. These are important in two main areas of research and development: drug discovery, drug formulation. Physiochemical properties of drugs Reminder:The solubility, dissolution rate, ionisation (pK a ) and lipophilicity (logP) of a drug have a significant effect on its LADME properties.

5. Making the T3 The Sirius T3 consist of over 5000 parts. These are manufactured around the world and brought to the UK where they are assembled in the Sirius workshops. The software that controls the robot and that carries out the complex mathematical calculations is written at Sirius. Once assembled an instrument is tested for about two weeks using standard samples (substances whose characteristics are well established). Following successful testing it is packaged and shipped to the purchaser. Physiochemical properties of drugs