tailieunhanh - HPLC for Pharmaceutical Scientists 2007 (Part 12)

Preformulation is a bridge between discovery and development where development scientists participate in selection and optimization of lead compounds. It is very critical at this stage to evaluate the developability of potential drug candidates in order to select new chemical entities and decrease the number of failures during future drug development. On average, only one out of ten new chemical entities (NCE) entering firstin-human testing reaches registration, approval, and marketing stage. The reasons for failures of development compounds include problems with biopharmaceutical properties, clinical safety, toxicology, efficacy, cost of goods, and marketing (see Figure 12-1) [1, 2]. . | 12 ROLE OF HPLC IN PREFORMULATION Irina Kazakevich INTRODUCTION Preformulation is a bridge between discovery and development where development scientists participate in selection and optimization of lead compounds. It is very critical at this stage to evaluate the developability of potential drug candidates in order to select new chemical entities and decrease the number of failures during future drug development. On average only one out of ten new chemical entities NCE entering first-in-human testing reaches registration approval and marketing stage. The reasons for failures of development compounds include problems with biopharmaceutical properties clinical safety toxicology efficacy cost of goods and marketing see Figure 12-1 1 2 . The biopharmaceutical properties such as gastrointestinal and plasma solubility lipophilicity LogD permeability first-pass metabolism systemic metabolism protein binding and in vivo bioavailability are related to the solubility chemical stability and permeability of drug candidates and have to be considered at discovery lead selection before recommendation to the development stage. A major challenge in any drug discovery program is achieving reasonable bioavailability upon oral administration therefore any information that highlights potential problems with cell permeability and absorption is valuable when reviewing structural families as leads for drug discovery. Lipinski et al. 3 have reviewed 2245 compounds selected from the United States Adopted HPLC for Pharmaceutical Scientists Edited by Yuri Kazakevich and Rosario LoBrutto Copyright 2007 by John Wiley Sons Inc. 577 578 ROLE OF HPLC IN PREFORMULATION Figure 12-1. Reasons for attrition from 1991 to 2000. Reprinted with permission from reference 1. Name USAN International Nonproprietary Name INN and World Drug Index WDI comparing calculated physical properties and clinical exposure. Four parameters were chosen that were associated with solubility and permeability namely .