University of Wisconsin–Madison

Drug Candidate Selection

Physiochemical Characterization, Solubilization, and Solid Form Screening

A hand holding a test tube used for experiments in drug candidate slectionDrug candidate selection is a difficult part of the drug development process. Failure in lead optimization can lead to loss of valuable time and money.

This course teaches you the strategies of lead optimization and selection. Each module of the course focuses on a major topic in lead optimization. The course addresses factors in drug candidate selection such as:

  • Solubility
  • Partition coefficients
  • Oral bioavailability
  • salt and crystal forms
  • chemical stability

You will learn to integrate these factors into a practical framework. The framework is flexible and scalable for candidate selection on all drug development projects. Companies will save time and money utilizing this framework.

This course is part of the Applied Drug Development Certificate. It fulfills one of three required courses. You may take this course as is or as part of the certificate. Students interested in mastering drug development should complete the certificate program.

Developed & Conducted by the Division of Pharmacy Professional Development, School of Pharmacy, University of Wisconsin-Madison.

Registration Information

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Refund Policy

Course date:Feb 1, 2019 - Feb 1, 2022
Location:
Course fee:

$1300/$1050 each two or more from same company
$650 Academic/$350 Graduate Student

Course Objectives

Goals and Objectives

This course is organized into sessions that are didactic in nature, covering background and experimental design aspects for each of the topics, illustrated by literature examples.  Problem set sessions are “case driven” in which attendees will learn how to analyze and interpret preformulation data through case examples.  For some problem sets, data will be provided in spreadsheet format and analyzed using a laptop computer in an instructor-led manner.  Upon completion of the program, the learner will be able to:

  • Design and conduct solubility experiments with an ability to analyze data for pKa, intrinsic solubility and salt solubility product constants
  • Apply major solubilization strategies and analyze solubilization data for key parameters that enable optimization of formulations with minimal experimental data
  • Understand oral bioavailability concepts in the context of the biopharmaceutics classification system (BCS) and distinctions between dissolution rate, solubility and permeability limited absorption
  • Assess the relevance of solid state forms, including physicochemical properties of solid forms and applicability to salt and crystal form screening and selection
  • Design, conduct and analyze solid state stability experiments for early developability assessment and candidate selection
  • Integrate all of the preformulation data into a composite profile to assess the developability of a candidate drug, identifying low and high risk features in the decision process

Who Should Attend

Scientists and technical managers working in preformulation at the drug discovery interface responsible for lead optimization and candidate selection.  Attendees should include MS/PhD graduates new to the discipline and BS level scientists with significant experience in preformulation.  Additional disciplines that would benefit from attendance include pharmaceutics/formulations scientists and managers interested in gaining better understanding of preformulation issues and discovery scientists desiring to increase their understanding of physical/chemical characterization principles.  For individuals who are engaged in the Applied Drug Development Certificate program, this course is a requirement.

Course Outline

Module 1

Introduction and overview of course

Module 2

Solubility and pKa

The relevance of dissociation equilibria for drug acids, bases, ampholytes and zwitterions; definition of pKa; fractional species concentrations; pKa of some major functional groups and heterocycles; pKa databases and software; solubility concept; solubility of ionizable molecules; pH-solubility profile for weak acids, bases and ampholytes/zwitterions; solubility of salts; common ion effect; experimental aspects of solubility experiments; importance of controlling pH, ionic strength and temperature; role of purity, particle size and powder processing; curve fitting the pH-solubility profile for pKa, intrinsic solubility and salt solubility products; solubility in biologically relevant media; solubility and BCS; solubility in topical and MDI formulations

Module 3

Problem Set - Interpretation of the pH-solubility profile of a weak base and its salts

The pH-solubility profile for a weak base and four salts are examined in detail; pH-stat methodology; differences in profile shapes for different counterions; salt stoichiometry; potential errors in the data; reasons for deviations from theoretical profiles

Module 4

Problem Set - Analysis of the pH-solubility profile of a weak acid and its salts

Calculate the pH-solubility profile of the weak acid; data for the pH-solubility profile of a weak acid and several salts thereof will be provided in Excel; data will be analyzed by nonlinear regression to extract pKa, intrinsic solubility and salt solubility product constants

Module 5

Oral Bioavailability

GI tract pH and transit times; modes of transport; Lipinski’s “rule of five”; permeability including pH dependence for ionizable molecules; human intestinal permeability and maximum absorbable dose; Caco2 permeability and relation to human dose absorbed; artificial membrane permeability (PAMPA); dissolution rate vs. solubility vs. permeability limited absorption

Module 6

Solubilization

Introduction; pH-adjustment, pH-dilution and precipitation; cosolvents, log-linear relation for cosolvent solubilization; combined pH-adjustment and cosolvents; cosolvent dilution and precipitation; common surfactants used often with cosolvents; in vitro assessment of hemolysis; complexation with cyclodextrins, common binding models; combined pH-adjustment and complexation; dilution of complexed solutes; static serial dilution procedure and cosolvents; cosolvent dilution and precipitation; common surfactants used often with cosolvents; in vitro assessment of hemolysis; complexation with cyclodextrins, common binding models; combined pH-adjustment and complexation; dilution of complexed solutes; static serial dilution procedure

Module 7

Enhancing Oral Bioavailability

Oils and lipids; some common materials and formulations used; solubilization summary and strategy; nonsolubilization approaches – particle size reduction and amorphous solids; flow chart for solubilization strategy

Module 8

Problem Set - Formulation for Enhanced Oral BA

Solubility and oral bioavailability data for multiple formulations will be given for a poorly soluble candidate; an analysis of dose, solubility and practical limitations for capsules will be done to assess viability of a solution dosage form in comparison to an alternative amorphous solid dispersion; a decision will be made regarding the best formulation to advance

Module 9

Problem Set - Solubilization of a Compound for Parenteral Delivery

A weak base drug has a target solubility required for IV delivery; a set of physicochemical data will be provided; solubility will be calculated at the lowest pH practical in saline and D5W; solubility will be calculated in a cosolvent mixture and in a cyclodextrin vehicle; solubility in some oils will be considered; based on solubility results and estimations from calculations, a decision will be reached on the best formulation to use to advance the compound

Module 10

Relevance of Solid Forms

Introduction; crystalline and amorphous solids; polymorphs, hydrates/solvates, cocrystals and salts and their distinct properties; pharmaceutically acceptable counterions and frequency of use in marketed salts; key physical properties relevant to drug development

Module 11

Screening and Selection of Solid Forms

Crystallization techniques; high throughput screening; key selection criteria inclusive of relative physical stability, moisture sorption, solubility, bioavailability and stability; decision flow charts for salt and crystal form selection

Module 12

Problem Set - Case Example of a Salt and Crystal Form Selection

Give data for multiple salts and decide on best form; give data on multiple crystal forms of selected salt and decide on best crystal form

Module 13

Solid State Stability for Candidate Selection

Practical considerations; accelerated conditions inclusive of light; use of accelerated data to estimate long term stability of drug candidates; statistical evaluation of data

Module 14

Overview of Early Pharmaceutical Development

Working with small sample amounts for solubility; solubilization for animal studies and salt screening; identifying critical physical properties and prioritizing work; review of strategies and flow charts; key criteria to consider in selecting drugs for development

Module 15

Problem Set - Candidate Selection Example 1

Integrating preformulation and salt/crystal form data to decide on the developability of a candidate drug 1

Module 16

Problem Set - Candidate Selection Example 2

Integrating preformulation and salt/crystal form data to decide on the developability of a candidate drug 2

Instructors

Edmund (Ed) Elder, Jr., RPh, PhD
Director, University of Wisconsin-Madison, Zeeh Pharmaceutical Experiment Station

Mark Sacchetti, PhD
Scientific Director, University of Wisconsin-Madison, Zeeh Pharmaceutical Experiment Station

Program Coordinator

Eric Buxton, PhD

Division of Pharmacy Professional Development
777 Highland Avenue
Madison, WI 53705
(608) 262-2431 FAX
(608) 265-2259
eric.buxton@wisc.edu

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