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Gregory A Stephenson

Gregory A Stephenson
Eli Lilly · Product Research and Development

Ph.D.

About

63
Publications
8,659
Reads
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2,970
Citations
Citations since 2016
4 Research Items
1147 Citations
2016201720182019202020212022050100150
2016201720182019202020212022050100150
2016201720182019202020212022050100150
2016201720182019202020212022050100150
Additional affiliations
February 2017 - present
Crystal Pharmatech
Position
  • Consultant
Description
  • https://www.linkedin.com/in/greg-stephenson-95543518/ http://www.crystalpharmatech.com/ Crystal Pharmatech is a technology-driven CRO) that focuses on materials science for drug development.
October 1990 - present
Eli Lilly
Position
  • Consultant
Description
  • Work closely with discovery and development teams to select viable solid state forms of pharmaceuticals. Work closely with legal to secure and defend associated intellectual property.
August 1990 - December 1994
Purdue University
Position
  • Graduate Assistant

Publications

Publications (63)
Article
Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C → A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel, or compressed in a tablet press, at pressures ranging...
Article
Disproportionation propensity of salts (HCl, HBr, hemi-napadisylate) and adipic acid co-crystal of corticotropin releasing hormone receptor-1 antagonist, was studied using model free kinetics. Using thermogravimetic weight loss profile or heat flow curves from differential scanning calorimetry, an activation energy plot for salts and co-crystal was...
Article
Transmembrane AMPA Receptor Regulatory Proteins (TARP) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP gamma-8 (γ-8) is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative a...
Article
High energy solids, such as salts, co-crystals, or amorphous solid dispersions, have been widely used to generate supersaturated aqueous solutions and improve drug bioavailability. However, most research on solubility enhancing strategies has focused on the kinetics of dissolution, and there is relatively little comparison of the different degrees...
Article
Crystallization of trehalose dihydrate (C12H22O11·2H2O) was induced by storing tablets of amorphous anhydrous trehalose (C12H22O11) at 65% RH (RT). Our goal was to evaluate the advantages and limitations of two approaches of profiling spatial distribution of drug crystallization in tablets. The extent of crystallization, as a function of depth, was...
Article
The supersaturation potential of poorly water soluble compounds is of interest in the context of solubility enhancing formulations for enhanced bioavailability. In this regard, the amorphous "solubility", i.e. the maximum increase in solution concentration that can be obtained relative to the crystalline form, is an important parameter, albeit a ve...
Article
Tablets of amorphous indomethacin were compressed at 10, 25, 50 or 100 MPa using either an unlubricated or lubricated die and stored individually at 35 °C in sealed Mylar® pouches. At selected time points, tablets were analyzed by two dimensional X-ray diffractometry (2D-XRD), which enabled us to profile the extent of drug crystallization in tablet...
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...
Patent
The present invention provides novel selective androgen receptor modulators and their salts and pharmaceutical compositions thereof.
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
The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by co...
Article
As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect of structural modifications of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740), a potent and pharmacologically balanced mGlu2/3 receptor agonist. Incorporation of relatively small subs...
Article
Serotonin norepinephrine reuptake inhibitor (SNRI), pyrrolidinyl ether 2 was synthesized by employing a dynamic kinetic resolution (DKR) with enantio- and diastereoselective hydogenation on beta-keto-gamma-lactam 8 to afford beta-hydroxy-gamma-lactam 9 with 96% ee and 94% de. Reduction of 9 and purification via the dibenzoyl-(L)-tartaric acid diast...
Article
Crystal structure prediction methods have been used to explore the potential energy landscape for crystals of a melatonin agonist (MA). All known experimental polymorphs were found in the search for crystal packing alternatives with a single molecule in the asymmetric unit, and the predicted order of stability agrees with experiment. The crystal st...
Article
Full-text available
Purpose: Salts of active pharmaceutical ingredients are often used to enhance solubility, dissolution rate, or take advantage of other improved solid-state properties. The selected form must be maintained during processing and shelf-life to ensure quality. We aimed to develop a model to quantify risk of disproportionation, where the salt dissociat...
Article
Enantiomeric pairs of molecules should crystallize in identical crystalline structures, though of opposite chirality, when grown separately from achiral media. The inactive enantiomer produced two polymorphs of very different energy. The active enantiomer yields only the metastable form. The reluctance of the stable form to nucleate is attributed t...
Article
This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/...
Conference Paper
Full-text available
Active pharmaceutical ingredients (API) typically fall into the category of weak electrolytes. That is they can be classified as molecules with weakly acidic or basic functional groups. In their neutral state, API’s are often poorly water-soluble, which can limit the bioavailability of the compound. Salt formation is often a useful handle t...
Article
When selecting the physical form of an active pharmaceutical substance, there is often a question of when a molecule's pKa renders it too low for salt formation and formulation into a product that will be sufficiently physically stable to provide adequate shelf life. In the paper, a graph is provided that tabulates pKa values of active pharmaceutic...
Article
The design, synthesis, and biological characterization of an orally active prodrug (3) of gemcitabine are described. Additionally, the identification of a novel co-crystal solid form of the compound is presented. Valproate amide 3 is orally bioavailable and releases gemcitabine into the systemic circulation after passing through the intestinal muco...
Article
A commercial synthesis was developed for the production of (4-benzylmorpholin-2-(S)-yl)-(tetrahydropyran-4-yl)methanone mesylate, 1a, a key starting material for a phase 2, new investigational drug candidate at Eli Lilly and Company. The target compound was produced in the clinical pilot plant by the combination of two key steps: resolution of a mo...
Article
Under near neutral and mildly basic conditions, primary N4-(α-aminoacyl)cytidines (4a–g) undergo a facile rearrangement to form N-(4-cytidinyl)amino acid amides (5a–g). Secondary aminoacyl derivatives rearrange with other competing pathways. Tertiary aminoacyl derivatives do not rearrange.
Chapter
IntroductionDiscussion of Solid-State FormsMonitoring Processing StepsMeasuring Transitions and Solid-Form Transformations in the Low-Dose TabletCommon Methods Used for Examination of Solid FormsConclusions References
Article
A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.
Article
A two step procedure for the regioselective synthesis of 3-substituted-2-aminoimidazo[1,2-a]pyrimidines is described. The key step is a Dimroth rearrangement of a mixture of 2 and 3-substituted aminoimidazo[1,2-a]pyrimidines that yields quantitatively one regioisomer. Reaction screening for the rearrangement step is reported. A multicomponent isocy...
Article
(-)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-3) is a highly potent and selective agonist of metabotropic glutamate receptors 2 (mGlu2) and 3 (mGlu3). As part of our ongoing research program, we have prepared S-oxidized variants of (-)-3, compounds (-)-10, (+)-11 (LY404040), and (-)-12 (LY404039). Each of these chiral het...
Article
Synthesis of 3-benzazepinones by palladium-catalyzed intramolecular addition of amides to alkynes is achieved. Phenyl acetylenes substituted in the ortho-position with tethered amide functionality were prepared in a few steps from readily available starting materials. It was found that 5% Pd(OAc)2(PPh3)2 and KOH most effectively promoted cyclizatio...
Article
Stratteratrade mark is the first FDA-approved nonstimulant medication for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children, adolescents, and adults. Two polymorphic forms and an amorphous form of the active pharmaceutical ingredient, atomoxetine HCl, were discovered during drug development. The thermodynamically stable p...
Article
Two novel one-step microwave mediated syntheses of arrays of 3-iminoaryl-imidazo[1,2-a]pyridines and imidazo[1,2-a]pyridyn-3-ylamino-2-acetonitriles are reported. Reactions are performed under microwave condition in methanol by simply mixing α-amino-pyridines, aldehydes, and trimethylsilylcyanide (TMSCN) with distinct reagent stoichiometries, catal...
Article
The following article examines the influence of thermal expansion on X-ray powder diffraction patterns. With the increasing percentages of structures that are being solved using low-temperature data sets and the nearly exclusive collection of room-temperature experimental datasets by X-ray powder diffraction, considerable discrepancies are observed...
Article
This article describes the development and optimization of chemical reactions and subsequent preparation of the API LY503430 under cGMPs to fund first human dose (FHD) clinical evaluation as a potential therapeutic agent for Parkinson's disease. Reasons and rationale are presented for changes in solvents and reagents. One of the major developments...
Article
This article describes the development and optimization of chemical reactions and subsequent preparation of the API LY503430 under cGMPs to fund first human dose (FHD) clinical evaluation as a potential therapeutic agent for Parkinson's disease. Reasons and rationale are presented for changes in solvents and reagents. One of the major developments...
Article
The stereospecific synthesis of the PPAR alpha/gamma agonist 1 was accomplished via ethylation of the optically pure trihydroxy derivative 6, itself derived via an enzymatic resolution. The ethylation can be accomplished without epimerization only under strict control of the reaction conditions and the choice of base (sodium tert-amylate), temperat...
Article
The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (...
Article
Residual dipolar couplings (RDCs), in combination with molecular order matrix calculations, were used to unambiguously determine the complete relative stereochemistry of an organic compound with five stereocenters. Three simple one-dimensional experiments were utilized for the measurements of (13)C-(1)H, (13)C-(19)F, (19)F-(1)H, and (1)H-(1)H RDCs....
Article
Olanzapine, a novel benzodiazepine agent used in the treatment of schizophrenia and related psychoses, crystallizes in 25+ crystal forms, seven of which are pharmaceutically relevant:  three anhydrates (I−III), three dihydrates (B, D, and E), and a higher hydrate. X-ray crystal structures of the thermodynamically stable anhydrous form (I), two dihy...
Article
A series of amino–borane complexes of structure type 2 are the key intermediates in the preparation of 3-(piperidyl) indole derivatives. The selective reduction of the tetrahydro-4-pyridyl double bond via 2 under strongly acidic conditions is feasible only when the pyridyl double bond is conjugated with electron rich substituents, such as indoles....
Article
Full-text available
The International Union of Crystallography (IUCr) Commission on Powder Diffraction (CPD) has sponsored a round robin on the determination of quantitative phase abundance from diffraction data. The aims of the round robin have been detailed by Madsen et al. [J. Appl. Cryst. (2001), 34, 409–426]. In summary, they were (i) to document the methods and...
Article
2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through AMPA receptors. To further define the structural requirements for ac...
Article
The reaction of α,β-unsaturated cyclic ketones with methyl dichloroacetate anion in the presence of DBU leads to the corresponding bicyclic chlorocyclopropanes in a highly diastereoselective fashion. In the cases of 2-cyclopentenone and 2-cyclohexenone the reaction affords exclusively the endo-Cl isomer.
Article
Quantitative analysis of solid state composition is often used to ensure the safety and efficacy of drug substances or to establish and validate the control of the pharmaceutical production process. There are a number of common techniques that can be applied to quantify the phase composition and numerous different methods for each technique. Each q...
Article
Recent advances in crystallographic computing have made it possible to solve by powder diffraction methods structures that have not been possible to solve by single-crystal methods. Although there is vast improvement in the quality of data obtained from high-intensity synchrotron radiation, we found that surprisingly reliable results can be obtaine...
Article
Recent advances in crystallographic computing have made it possible to solve by powder diffraction methods structures that have not been possible to solve by single‐crystal methods. Although there is vast improvement in the quality of data obtained from high‐intensity synchrotron radiation, we found that surprisingly reliable results can be obtaine...
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 hydrated crystal structures of cromolyn, cefazolin, and fenoprofen sodium salts are reported. The former two compounds are non-stoichiometric hydrates, whereas the fenoprofen lattice maintains its stoichiometry over a broad range of relative humidity. The relationship between composition, lattice parameters, and relative humidity is studied usi...
Article
5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile has been crystallized as six solvent-free polymorphs, which differ in the mode of packing and in molecular conformation. The conformational difference results principally from the thiophene torsion relative to the o-nitroaniline fragment, which leads to different crystal colors (red, orange,...
Article
The synthesis and biological evaluation of trans-2,3-dihydroraloxifene, 2, is described. The synthesis proceeds in 8 steps in 20% overall yield. Relative trans 2,3-stereochemistry is definitively established in ester 6, which is converted to the title compound via derivatization, Grignard addition, and deprotection. Evaluation in vitro shows the co...
Article
The potential impact of changing crystal forms during late-stage drug development, in terms of cost and product delay, justifies systematic and early characterization of polymorphism. A thorough understanding of polymorph characteristics also allows selection of the best form to market. The authors review the key elements of polymorph characterizat...
Article
The objective of this work was to investigate a common but poorly understood category of crystalline organic substances: isomorphic desolvates. When solvent is lost from a crystal lattice but the lattice retains its three-dimensional order, a lattice is created which is in a high-energy state relative to the original solvate structure. The desolvat...
Article
The stereoselective formation of six-membered nitrogen heterocycles that contain an asymmetric quaternary carbon center was achieved through aza-annulation of β-enamino amide substrates with activated acrylate derivatives. Condensation of a racemic β-keto amide with an optically active primary amine, either (R)-α-methylbenzylamine or α-amino esters...
Data
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and...
Article
The crystal structures of the commercially available form of erythromycin A dihydrate and clarithromycin anhydrate, in addition to the structure of erythromycin B dihydrate, are reported in this paper. In light of the crystallographic data, analysis of the structural information provides insight into the physical properties of these pharmaceuticals...
Article
The manufacture of dirithromycin [9S(R)-deoxo-11-deoxy-9,11-[imino[2-(2-methoxyethoxy)ethylidene]oxy]- erythromycin] from commercially available erythromycin A results in a drug substance containing impurities at the level of several percent. A five-step plan for the development of a commercial-scale recrystallization procedure is presented. A puri...
Article
Polymorphism of the anti-diabetic drug acetohexamide has been investigated by numerous techniques. On the basis of Fourier-transform infrared (FT-IR) data, one of the most common forms, form A, has been proposed to exist in the enol-tautomeric state, whereas form B has been proposed to be in the keto-tautomeric state. The following article examines...
Article
The spectrum of a flexible molecule changes with its conformation. In gas and solution phases, it is difficult to obtain significantly different conformations for study without resorting to chemical substitution. A unique approach to studying the conformation-spectrum relationship is through the solid-state phenomenon of conformational polymorphism...
Article
C12H21N5S2O2, Mr = 331.46, triclinic, P1̄, a = 7.3645(5), b = 8.8785(9), c = 25.678(4) Å, α = 89.35(1)°, β = 82.49(1)°, γ = 87.46(1)°, V = 1662.9(5) Å3, Z = 4, Dx = 1.324 g cm−3, λ(Cu Kα) = 1.54184 Å, μ = 29.57 cm−1, F(000) = 704.0, T = 293 K, final R = 0.057 for 4830 observed reflections. Nizatidine, Axid®, is a selective H2-receptor antagonist us...
Article
Solid-state pharmaceutical chemistry encompasses a wide range of studies on pharmaceutical solids including (1) determination of the physical properties of polymorphs and solvates, (2) physical transformations between polymorphs and solvates, (3) chemical reactions in the solid state, and (4) solid-solid reactions which occur in pharmaceutical prep...
Article
Dirithromycin, a semisynthetic macrolide antibiotic, crystallizes in two anhydrous polymorphic forms, an amorphous form and at least nine stoichiometric solvate forms. Six of the known solvates are isomorphic, having nearly identical X-ray powder diffraction (XRPD) patterns. Differences are observed in the CP/MAS C-13 solid-state NMR spectra, which...
Article
The following thesis uses the complimentary techniques of single crystal X-ray diffraction, $\sp{13}$C solid-state NMR spectroscopy, X-ray powder diffraction, FT-IR spectroscopy and vapor adsorption to investigate the solid-state properties of specific classes of pharmaceuticals. The first four parts of the thesis examine the macrolide class of ant...

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