Speaker:  Joe Lubach, distinguished scientist, Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc.

Seminar:  Molecular-Level Insights into Pharmaceutical

Drug Products via Multinuclear Solid-State NMR Spectroscopy

Host: Tim White

Abstract
High resolution characterization of pharmaceutical solid dosage forms represents an ever-challenging problem facing pharmaceutical scientists.  Detailed solid-state analysis of a drug product should include active ingredients as well as excipients, and potential interactions among them.  Historically, pharmaceutical solid-state NMR has primarily been applied to cases of relatively simple solid form determination, where it naturally excels, particularly in formulated products.  This presentation will focus on modern applications of solid-state NMR spectroscopy to gain insights into complex solid dosage forms, including crystalline and amorphous materials, protonation states, drugs and excipients, and ubiquitous water.

Historically for pharmaceutical solids, 13C is the most widely studied nucleus due to the information content available, its presence in nearly all pharmaceutical ingredients, and high resolution spectra that can be obtained.  It is primarily accessed via cross polarization (CP) experiments due to its low natural abundance and relatively long relaxation times, which have hindered its use in quantitative analysis.  We will illustrate practical examples of quantitative CP experiments in amorphous solid dispersion tablets, a commonly used modern dosage form.

19F is a friendlier nucleus from an NMR standpoint due to its relative sensitivity, and continues to become more widespread in pharmaceutical materials.  It is highly useful when present in active ingredients and enables exquisitely selective analysis of the physical state of the active within a formulated product, even at very low drug loading.  We will examine how it can be used for quantitative solid form determination in complex drug products.

15N is particularly useful in protonation state investigations, but suffers from extremely poor sensitivity and sometimes prohibitively long experiment times.  We will examine a case where it was utilized to show proton transfer from drug to excipient in an amorphous solid dispersion, and help to gain a better understanding of the overall landscape of these materials.

Finally, water content is a frequently measured quantity is solid dosage forms, and is often considered a critical quality attribute.  The methods used to quantitate water content, such as Karl Fischer titration, loss on drying, or thermogravimetric analysis, generally sample a bulk powder or tablet and report back the overall water percentage in a given quantity of material.  However, the distribution of this water is far from homogeneous.  We will demonstrate how 1H NMR relaxation times, detected through 13C CP experiments, can be used to ascertain how ubiquitous water is distributed among various ingredients in a formulation.  This deeper understanding of the distribution of water molecules throughout a given formulation can provide valuable insight into dosage form design for more robust drug products and processes.

Biosketch
Joe Lubach is a distinguished scientist in the Synthetic Molecule Pharmaceutical Sciences department at Genentech, Inc., where he has been since 2007. In his current role, he leads the Solid-State Chemistry & Characterization group within Synthetic Molecule Pharmaceutics, working on physical form screening and solid-state characterization of small molecule drug substances and drug products.  His personal research interests center around solid-state chemistry and characterization of pharmaceutical materials, studying the role of water in organic molecular crystals and amorphous solids, and expanding applications of solid-state NMR spectroscopy across the pharmaceutical discovery and development landscape.  He has authored or co-authored over 50 peer-reviewed publications and three reference chapters stemming from his work.  Lubach holds a PhD in pharmaceutical chemistry from the University of Kansas (2007), where he worked with Professor Eric Munson.