Physiochemical Characterization, Solubilization, and Solid Form Screening
Drug 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 Drug Product 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.
$1500 (please contact us for group rates)
$750 Academic rate/$375 Graduate student rate
Please contact Eric Buxton to qualify for the academic or graduate student rate.
This course is online and self-paced. You may register at any time and complete the curriculum at your own pace by June 30, 2025
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
Drug candidate selection is a difficult part of the drug development process. Failure in lead optimization can lead to loss of valuable time and money. 