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Steven W Baertschi

Steven W Baertschi
Baertschi Consulting, LLC

PhD

About

79
Publications
32,397
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2,396
Citations
Citations since 2017
7 Research Items
682 Citations
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2017201820192020202120222023020406080100120
2017201820192020202120222023020406080100120
Introduction
30+ years of in-depth scientific / technical experience in pharmaceutical R&D. Consultant for pharmaceutical / biotech, animal health, agrochemicals, and consumer healthcare industries on a wide range of topics including: chemical and physical stability and degradation, analytical and impurity (including genotoxic impurity) control strategies, method development, formulation stability, photostability / photochemistry, preformulation, and CM&C regulatory issues.
Additional affiliations
August 1989 - February 2015
Eli Lilly
Position
  • Senior Researcher
August 1985 - July 1989
Vanderbilt University
Position
  • PhD Student
July 1981 - July 1985
Daily Analytical Laboratories
Position
  • Residues Chemist

Publications

Publications (79)
Article
Full-text available
Stress testing (also known as forced degradation) of pharmaceutical products has long been recognized as a critical part of the drug development process, providing foundational information related to intrinsic stability characteristics and to the development of stability-indicating analytical methods. A benchmarking study was undertaken by nine pha...
Article
Prasugrel hydrochloride is the active ingredient in Effient™, a thienopyridine platelet inhibitor. An extensive study of the degradation chemistry of prasugrel hydrochloride (LY640315 hydrochloride)has been carried out on the drug substance (part I)and on the drug product (part II, future article)using a multidimensional approach including hydrolyt...
Article
Degradation rates of solid-state drug products generally increase as the drug load decreases. A model for quantifying this effect based on surface area ratios is proposed here. This model relates the degradation rate to an estimate of the proportion of drug substance in contact with the excipient, and that the drug substance in contact with excipie...
Article
Thorough knowledge and control of impurities is an expectation for the registration of pharmaceuticals. Actual and potential impurity investigations are phased during drug development to acquire the appropriate information necessary to ensure drug safety from the standpoint of patient exposure to impurities. Regulatory expectations and common pract...
Article
Accelerated stability studies of pharmaceutical products are commonly conducted at various combinations of temperature and relative humidity (RH). The RH of the sample environment can be controlled to set points using humidity-controlled stability chambers or via storage of the sample in a closed container in the presence of a saturated aqueous sal...
Article
Edivoxetine (LY2216684 HCl), although a chemically stable drug substance, has shown the tendency to degrade in the presence of carbohydrates that are commonly used tablet excipients, especially at high excipient:drug ratios. The major degradation product has been identified as N-formyl edivoxetine. Experimental evidence including solution and solid...
Article
Stress-testing (forced degradation) studies have been conducted on pemetrexed disodium heptahydrate (1) (LY231514·2Na·7H2O) drug substance in order to identify its likely degradation products and establish its degradation pathways. Solid samples of the drug substance were stressed under various conditions of heat, humidity, and light, and solutions...
Article
The ICH Q1B guidance and additional clarifying manuscripts provide the essential information needed to conduct photostability testing for pharmaceutical drug products in the context of manufacturing, packaging, and storage. As the previous 2 papers in this series highlight for drug products administered by injection (part 1) and drug products admin...
Article
An analytical artifact peak appearing to be an impurity was observed intermittently among several laboratories performing HPLC analyses of olanzapine drug substance and formulation samples. The artifact peak was identified as Cu(I) that was formed from the reaction of trace amounts of Cu(II) with olanzapine in the sample solution. Unlike Cu(II), Cu...
Article
This paper outlines strategies in alignment with ICH M7 for systematically assessing the potential risk posed by mutagenic degradants in active pharmaceutical ingredients (API) and formulated products. A mutagen risk assessment (MRA) process that involves degradation should include results from focused drug substance and drug product stress testing...
Article
We report artifactual degradation of pharmaceutical compounds containing primary and secondary amines during peroxy radical-mediated oxidative stress carried out using azoalkane initiators. Two degradation products were detected when model drug compounds dissolved in methanol/water were heated to 40°C with radical initiators such as 2,2'-azobis(2-m...
Article
Although essential guidance to cover the photostability testing of pharmaceuticals for manufacturing and storage is well-established, there continues to be a significant gap in guidance regarding testing to support the effective administration of photosensitive drug products. Continuing from Part 11, where the focus was drug products administered b...
Article
Galunisertib is a kinase inhibitor designed to selectively inhibit TGF-beta signaling. Drug substance stress degradation studies performed during clinical development demonstrated two degradation products via oxidation of the nitrogen(s) of the pyridine moieties in the presence of dilute hydrogen peroxide. These “N-oxide” potential degradation prod...
Article
Zeneth is a new software application capable of predicting degradation products derived from small molecule active pharmaceutical ingredients. This study was aimed at understanding the current status of Zeneth's predictive capabilities and assessing gaps in predictivity. Using data from 27 small molecule drug substances from five pharmaceutical com...
Article
Mitosis inhibitor (R)-litronesib (LY2523355) is a 1,3,4-thiadiazoline, bearing phenyl and N-(2-ethylamino)ethanesulfonamido-methyl substituents on tetrahedral C5. Chiral instability has been observed at pH 6 and above with the rate of racemization increasing with pH. A positively charged trigonal intermediate is inferred from the fact that a p-meth...
Article
The American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues was held on 13–14 October 2012 at the McCormick Place in Chicago, IL, USA. The goal of the workshop was to discuss control strategies of chemical and physical changes of a...
Article
Although essential guidance to cover the photostability testing of pharmaceuticals for manufacturing and storage is well-established, there continues to be a significant gap in guidance regarding testing to support the effective administration of photosensitive drug products. Continuing from Part 1, (Baertschi SW, Clapham D, Foti C, Jansen PJ, Kris...
Article
The availability of high performance liquid chromatography (HPLC) columns capable of operation at pH values up to 12 has allowed a greater selectivity space to be explored for method development in pharmaceutical analysis. Ammonium hydroxide is of particular value in the mobile phase because it is compatible with direct interfacing to electrospray...
Article
Mass balance is an important concept in pharmaceutical development, but it often proves challenging to assess accurately. This article explores the various methods by which mass balance can and should be measured, expressed, and evaluated in conjunction with degradation chemistry. Causes of mass-balance issues and potential solutions are summarized...
Article
The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with develop...
Article
This article provides a compilation of summaries of many of the presentations at the two- day workshop held in conjunction with the Annual Meeting of American Association of Pharmaceutical Scientists (AAPS) on October 21-22, 2011 in Washington, D.C. The workshop program comprised of twenty presentations encompassing many scientific aspects impactin...
Article
The objective of this chapter is to give guidance with degradation and impurity structure elucidation for pharmaceutical drug candidates. Stress testing knowledge is provided as guidance in developing and executing forced degradation experiments. Impurity and degradant structure elucidation is a collaborative effort involving the degradation chemis...
Article
Duloxetine hydrochloride, a secondary amine containing pharmaceutical, currently marketed as Cymbalta, is shown to undergo N-formylation as an artifact of sample preparation prior to HPLC analysis for impurities. The reaction was discovered as a result of an investigation into variability in the levels of N-formyl duloxetine observed upon HPLC anal...
Chapter
Forced degradation (stress testing) studies are fundamental to the developing stability-indicating analytical methods as part of the overall analytical control strategy. Stress testing studies conducted on both the drug substance and product are useful for gaining an understanding of the degradation chemistry of a drug. The degradation products obs...
Article
The ICH guideline on photostability (ICH Topic Q1B) was published in November 1996 and has been implemented in all three regions (US, EU, and Japan). The guideline describes a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution, but it does not cover the photostability o...
Article
An in-depth analysis of the web-based CambridgeSoft Pharmaceutical Drug Degradation Database, Pharma D3, was conducted in two phases in an attempt to generate some general rules for the prediction of alerting structures for genotoxicity that may arise as a result of degradation. The first phase involved interrogation of the database to determine th...
Article
Abstract The ultimate carcinogenic form of aflatoxin B1, the exo-8,9-epoxide, has long evaded both isolation and synthesis. The epoxide has now been prepared in essentially quantitative yield by oxidation of aflatoxin B1 with dimethyldioxirane. The epoxide is sufficiently stable that it can be isolated and characterized but it undergoes rapid solvo...
Article
Two impurities found in both stressed and aged solid-state formulations of olanzapine have been identified as (Z)-1,3-dihydro-4-(4-methyl-1-piperazinyl)-2-(2-oxopropylidene)-2H-1,5-benzodiazepin-2-one (1) and (Z)-1-[1,2-dihydro-4-(4-methyl-1-piperazinyl)-2-thioxo-3H-1,5-benzodiazepin-3-ylidene]propan-2-one (2). The structures indicate that the two...
Article
The analytical technologies currently in use for profiling degradation-related impurities (DRI’s) are powerful, but not without their limitations. This article critically assesses the technologies, their strengths and limitations, and recommends strategies for successful DRI profiling. Improvements in analytical separations and detection technologi...
Article
This chapter discusses the strategies for investigation and control of process- and degradation-related impurities. The chapter describes strategies for the investigation of process-related and degradation-related impurities in drug substances and drug products. Particular emphasis is given to a chemistry-guided approach and the iterative nature of...
Article
Twenty pharmaceutical companies responded to this survey that addressed a range of stress testing issues such as study design, procedures, and types of conditions.
Article
Ultraviolet (UV) absorbance is the most widely used detection method for high-performance liquid chromatography (HPLC) separations. In pharmaceutical analysis, purity determinations often include quantitation of related impurities based on relative HPLC peak areas obtained at a specific wavelength. In order for this quantitation to accurately refle...
Article
Photostability is an important component of assessing the overall stability of a photosensitive drug substance or drug product. Part II of this article discusses how successful photostability experiments depend on the accurate measure of the output from photolysis sources and the understanding of the principles of photodegradation.
Article
We report the development of a new 'photochemical titration' actinometric method for measurement of UV-B (290-320 nm) and UV-A (320-400 nm) light dose during drug photostability testing. It is based upon photolysis of aqueous 2-nitrobenzaldehyde solution, a well-characterized reaction that has been previously demonstrated to be useful as an accurat...
Article
We report the development of a new 'photochemical titration' actinometric method for measurement of UV-B (290-320 nm) and UV-A (320-400 nm) light dose during drug photostability testing. It is based upon photolysis of aqueous 2-nitrobenzaldehyde solution, a well-characterized reaction that has been previously demonstrated to be useful as an accurat...
Article
The purpose of this study was to identify a degradation product in a tablet formulation of raloxifene hydrochloride (R-HCl), delineate the role of excipients in its formation, and develop a rational strategy for its control. The degradant was identified as an N-oxide derivative of the drug substance based upon spectroscopic characterization and chr...
Article
A study of the degradation kinetics of gemcitabine hydrochloride (2′-deoxy-2′,2′-difluorocytidine) in aqueous solution at pH 3.2 was conducted. The degradation of gemcitabine followed pseudo first-order kinetics, and rate constants were determined at four different temperatures. These rates were used to construct an Arrhenius plot from which degrad...
Article
The aqueous acidic degradation of the oral cephalosporin cefaclor was investigated. A number of degradation products were isolated and characterized. The degradation products can be loosely classified into three categories: thiazole derivatives, pyrazine derivatives, and simple hydrolysis or rearrangement products. Degradation pathways are proposed...
Article
The purpose of this study was to identify a degradation product in a tablet formulation of raloxifene hydrochloride (R-HCl), delineate the role of excipients in its formation, and develop a rational strategy for its control. The degradant was identified as an N-oxide derivative of the drug substance based upon spectroscopic characterization and chr...
Article
Transdermal devices are unique with respect to in-use photostability, and current International Conference on Harmonization (ICH) guidelines do not address many of the issues involved. The authors used data collected for a transdermal device containing xanomeline to discuss some of these in-use photostability issues. This article describes why the...
Article
Analysis of commercially available generic formulations of fluoxetine HCl revealed the presence of lactose as the most common excipient. We show that such formulations are inherently less stable than formulations with starch as the diluent due to the Maillard reaction between the drug, a secondary amine hydrochloride, and lactose. The Amadori rearr...
Article
Duloxetine hydrochloride ((S)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine hydrochloride) has been found to react with polymer degradation products or residual free acids present in the enteric polymers hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP) in dosage formulations to for...
Article
Previous work by Hafkemeyer et al. (1991) [Nucleic Acids Research 19: 4059–4065] indicated that a degradation product of ceftazidime, termed HP 0.35, was active against the RNase H activity of human immunodeficiency virus type 1 (HIV-1) and feline immunodeficiency virus (FIV) reverse transcriptase (RT) in vitro. Attempting to repeat these results,...
Article
Cefaclor is a beta-lactam antibiotic that degrades slowly under normal storage conditions to several minor products. To obtain samples large enough to permit structure elucidation, cefaclor was allowed to degrade at 40 degrees C (75% relative humidity) and at 85 degrees C. The profile of degradation products formed under these conditions is qualita...
Article
The aqueous degradation of the carbacephalosporin loracarbef under moderately acidic conditions (pH range, 2.7-4.3) is described. Structures of a total of 10 compounds isolated by preparative reversed-phase HPLC have been proposed. Five of these 10 degradation compounds arose from hydrolysis of the beta-lactam ring followed by structural changes in...
Article
A multidimensional approach is described for characterizing impurities in samples of generic cefaclor and cephalexin antibiotics. High-performance liquid chromatography (HPLC) with gradient elution followed by photodiode array or mass spectrometric detection provides valuable information concerning the nature of impurities observed. Results are pre...
Article
The acidic aqueous degradation of cefaclor, an orally administered cephalosporin antibiotic, has been investigated. The most prominent peak in the high-performance liquid chromatography profile of a degraded solution of cefaclor was isolated by preparative high-performance liquid chromatography. Mechanistically, the formation of this degradent from...
Article
Full-text available
The allene oxide synthase (hydroperoxide dehydrase) of flaxseed is a cytochrome P450 that exhibits an exceptionally high catalytic turnover (> or = 1000/s) for hydroperoxy substrates. In a previous study, using a crude extract of flaxseed, we detected a secondary activity that could offer an insight into the mechanism of the enzymatic transformatio...
Article
Albumin catalyzes the transformation of prostaglandin D2 to 9-deoxy-delta 9,delta 12(E)-prostaglandin D2 and to isomeric prostaglandin D2 compounds including delta 12(E)-prostaglandin D2. Both of these compounds are alpha,beta-unsaturated ketones, which should render them susceptible to nucleophilic addition. We therefore examined the ability of th...
Article
Full-text available
One potential biosynthetic route to the prostaglandins involves the participation of lipoxygenase and allene oxide synthase enzymes, giving a hydroxylated allene oxide, which then might cyclize to form prostaglandin A or a close analogue. We have tested a model of this type of transformation using 8-hydroxy-15S-hydroperoxy eicosanoids as substrates...
Article
Albumin catalyzes the transformation of prostaglandin Dâ to 9-deoxy-Î⁹, ι²(E)-prostaglandin Dâ and to isomeric prostaglandin Dâ compounds including ι²(E)-prostaglandin Dâ. Both of these compounds are α,β-unsaturated ketones, which should render them susceptible to nucleophilic addition. The authors therefore examined the ability of the co...
Article
Incubation of arachidonic acid (I) with an acetone powder of the title coral leads to the formation of the title cyclopropyl eicosanoid (III) (no yield given) and several other products.
Article
The genotoxicity of the dihydrofurans aflatoxin B1 (AFB1), aflatoxin G1 (AFG1), and sterigmatocystin (STG) was examined in a bacterial system in which the induction of SOS repair is monitored with the umuC gene linked to a lacZ reporter gene in plasmid pSK1002. Human liver microsomal cytochrome P-450NF oxidized the dihydrofurans (in the presence of...
Article
The title epoxide (II) (no yield given) is presumed to be the metabolite which is responsible for the mutagenic properties of aflatoxin B1 (I).
Article
Allene oxides are unstable epoxides that have been implicated as intermediates in the biotransformation of hydroperoxyicosatetraenoic acids and related hydroperoxides to ketols and cyclopentenones. Direct proof of the structure of the putative allene oxide intermediates has been hampered by their extreme instability under the conditions of their bi...
Article
cis-12-Oxophytodienoic acid (cis-12-oxo-PDA) is a C18 cyclopentenone formed from the 13-(S)-hydroperoxide of linolenic acid in flaxseed and other plant tissues. Although the structure of cis-12-oxo-PDA is well established, the absolute configuration of the side chains has not been determined. We have now measured this important parameter by two ind...
Article
Full-text available
Plexaura homomalla is a rich natural source of prostaglandins and recent evidence suggest the prostaglandin biosynthesis could occur through a lipoxygenase pathway. We have investigated the metabolism of arachidonic acid in homogenates and acetone powders of the fresh frozen coral. The biosynthesis of natural prostaglandins was not detected. Howeve...

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