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Papers by Susan Reutzel-edens

Journal of the Chemical Society, Perkin Transactions 2, 2000

ABSTRACT Tazofelone (1) has been crystallized as two polymorphic racemic compounds (1a), designat... more ABSTRACT Tazofelone (1) has been crystallized as two polymorphic racemic compounds (1a), designated I and II, and as an (S)-(−) enantiomorph (1b). These crystal forms have been characterized using FTIR and solid-state NMR spectroscopy, single crystal X-ray analysis, and differential scanning calorimetry. The stability relationship of the racemic polymorphs has been established as enantiotropic, with form II being low-temperature stable and form I being high-temperature stable (transition temperature 138 °C). These two forms have similar enthalpies, entropies, and free energies (thermodynamic stability), which may be related to their similar molecular conformations, hydrogen-bonding patterns, and crystal packing efficiencies. The racemic crystals are significantly more stable than the physical mixture of the enantiomorphs. The spontaneous conversion of the racemic crystals into the conglomerate is not feasible thermodynamically at any temperature (monotropy). The weak lattice of the enantiomorphs may result, in part, from the high energy conformers that are the building blocks of the enantiomorphs and weaker dipole–dipole interactions.

Acta Crystallographica Section A Foundations of Crystallography, 2013

Acta Crystallographica Section A Foundations of Crystallography, 2013

Organic Process Research & Development, 2000

... 11) Byrn, SR; Curtin, DY; Paul, IC J. Am. Chem. Soc.1972, 94, 890; Yang, Q.-C.; Richardson, M... more ... 11) Byrn, SR; Curtin, DY; Paul, IC J. Am. Chem. Soc.1972, 94, 890; Yang, Q.-C.; Richardson, MF; Dunitz, JD Acta Crystallogr. 1989, B45, 312. ...

Organic Process Research & Development, 2000

... 11) Byrn, SR; Curtin, DY; Paul, IC J. Am. Chem. Soc.1972, 94, 890; Yang, Q.-C.; Richardson, M... more ... 11) Byrn, SR; Curtin, DY; Paul, IC J. Am. Chem. Soc.1972, 94, 890; Yang, Q.-C.; Richardson, MF; Dunitz, JD Acta Crystallogr. 1989, B45, 312. ...

Acta crystallographica. Section C, Crystal structure communications, Jan 15, 1991

N-Acetylbenzamide, C9H9NO2 (I) Mr = 163.18, orthorhombic, Pbca, a = 8.990 (2), b = 9.208 (3), c =... more N-Acetylbenzamide, C9H9NO2 (I) Mr = 163.18, orthorhombic, Pbca, a = 8.990 (2), b = 9.208 (3), c = 19.619 (3) A, V = 1624 (1) A3, Z = 8, Dx = 1.335 (1) g cm-3, lambda(Mo K alpha) = 0.710569 A, mu = 0.89 cm-1, F(000) = 688, T = 295 K, R = 0.031 for 865 observed reflections. N-Propionylbenzamide, C10H11NO2 (II), Mr = 177.20, monoclinic, P2(1)/c, a = 10.485 (2), b = 23.236 (4), c = 8.132 (2) A, beta = 108.43 (2) degrees, V = 1880 (1) A3, Z = 8, Dx = 1.252 (1) g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.82 cm-1, F(000) = 752, T = 297 K, R = 0.044 for 1407 observed reflections. N-Butyrylbenzamide, C11H13NO2 (III), Mr = 191.23, monoclinic, P2(1)/n, a = 8.270 (4), b = 12.600 (3), c = 10.459 (3) A, beta = 108.16 (3) degrees, V = 1040 (1) A3, Z = 4, Dx = 1.221 (1) g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.79 cm-1, F(000) = 408, T = 298 K, R = 0.038 for 1060 observed reflections. Compound (I) crystallizes in the Z,Z(trans-trans) conformation in chains linked by N-H...O hydrogen bonds. ...

Molecular Pharmaceutics, 2015

Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic h... more Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7(z)). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.

Acta crystallographica. Section C, Crystal structure communications, Jan 15, 1991

N-Acetylbenzamide, C9H9NO2 (I) Mr = 163.18, orthorhombic, Pbca, a = 8.990 (2), b = 9.208 (3), c =... more N-Acetylbenzamide, C9H9NO2 (I) Mr = 163.18, orthorhombic, Pbca, a = 8.990 (2), b = 9.208 (3), c = 19.619 (3) A, V = 1624 (1) A3, Z = 8, Dx = 1.335 (1) g cm-3, lambda(Mo K alpha) = 0.710569 A, mu = 0.89 cm-1, F(000) = 688, T = 295 K, R = 0.031 for 865 observed reflections. N-Propionylbenzamide, C10H11NO2 (II), Mr = 177.20, monoclinic, P2(1)/c, a = 10.485 (2), b = 23.236 (4), c = 8.132 (2) A, beta = 108.43 (2) degrees, V = 1880 (1) A3, Z = 8, Dx = 1.252 (1) g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.82 cm-1, F(000) = 752, T = 297 K, R = 0.044 for 1407 observed reflections. N-Butyrylbenzamide, C11H13NO2 (III), Mr = 191.23, monoclinic, P2(1)/n, a = 8.270 (4), b = 12.600 (3), c = 10.459 (3) A, beta = 108.16 (3) degrees, V = 1040 (1) A3, Z = 4, Dx = 1.221 (1) g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.79 cm-1, F(000) = 408, T = 298 K, R = 0.038 for 1060 observed reflections. Compound (I) crystallizes in the Z,Z(trans-trans) conformation in chains linked by N-H...O hydrogen bonds. ...

Organic Process Research & Development, 2005

... E. LeTourneau, Bruce E. Parker, Susan M. Reutzel-Edens, John P. Schafer, Michael A. Staszak, ... more ... E. LeTourneau, Bruce E. Parker, Susan M. Reutzel-Edens, John P. Schafer, Michael A. Staszak, Gregory A. Stephenson, Shella L. Tameze, and Lisa MH Zollars. Eli Lilly and Company, Chemical Product Research and Development Division, Indianapolis, Indiana 46285. Org. ...

in the Pharmaceutical Industry, 2006

Page 1. Susan M. Reutzel-Edens and Ann W. Newman 9.1 Introduction The terms hygroscopic and hygro... more Page 1. Susan M. Reutzel-Edens and Ann W. Newman 9.1 Introduction The terms hygroscopic and hygroscopicity are widely used in the pharmaceuti-cal literature to describe the moisture uptake of materials. Water vapor, an ...

Pharmaceutical Science & Technology Today, 1998

Pharmaceutical Science & Technology Today, 1998

Organic Process Research & Development, 2009

An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generatio... more An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generation synthesis built the enantioenriched nitro-aminoindanol core from 6-nitroindanone using a five-step literature route. The second-generation route used a safe aromatic nitration ...

Organic Process Research & Development, 2009

An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generatio... more An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generation synthesis built the enantioenriched nitro-aminoindanol core from 6-nitroindanone using a five-step literature route. The second-generation route used a safe aromatic nitration ...

Journal of the American Chemical Society, 1991

ABSTRACT The cocrystallization behavior of acyclic imides is studied as a way to map out the hydr... more ABSTRACT The cocrystallization behavior of acyclic imides is studied as a way to map out the hydrogen bond directed molecular recognition properties of a class of small biochemically related molecules under conditions where there is no preorganized cavity controlling the recognition events. Cocrystallization of over 80 imide-guest pairs was examined by solution and solid-state cocrystallization methods. The crystal structures of nine host-guest pairs are reported. The hydrogen bond patterns of 16 other cocrystal pairs were characterized by noncrystallographic means. Common hydrogen bond patterns and hydrogen bond selectivity properties were analyzed and are presented in the form of a set of hydrogen bond rules. Diacetamide was found to be a versatile cocrystallizing agent, forming 10 different cocrystal pairs. Imides that have a cis-trans conformation in their homomeric forms retain that conformation in their cocrystal structures. Imides that have a trans-trans conformation in their homomeric structures do not usually form cocrystals. Three imide cocrystal hydrogen types were observed repeatedly, with the most common pattern involving cyclic imide dimers with pendant hydrogen-bonded guests or cyclic heteromeric patterns having bivalent contacts between the imide and guest species. Guest molecules that successfully formed cocrystals covered a wide range of chemical types, including phenols, acids, amides, phosphine oxides, pyridines, imidazoles, and ureas.

Journal of the American Chemical Society, 1993

Page 1. J. Am. Chem. SOC. 1993,115, 4411-4412 441 1 Self-organization of Adenine and Thymine in t... more Page 1. J. Am. Chem. SOC. 1993,115, 4411-4412 441 1 Self-organization of Adenine and Thymine in the Solid State? Margaret C. Etter,+ Susan M. Reutzel,* and Carolyn G. Choo' Department of Chemistry University of Minnesota Minneapolis, Minnesota 55455 ...

Journal of the American Chemical Society, 1993

Page 1. J. Am. Chem. SOC. 1993,115, 4411-4412 441 1 Self-organization of Adenine and Thymine in t... more Page 1. J. Am. Chem. SOC. 1993,115, 4411-4412 441 1 Self-organization of Adenine and Thymine in the Solid State? Margaret C. Etter,+ Susan M. Reutzel,* and Carolyn G. Choo' Department of Chemistry University of Minnesota Minneapolis, Minnesota 55455 ...

Journal of Physical Organic Chemistry, 1992

ABSTRACT The molecular recognition properties of 18 acyclic imides were studied to evaluate the r... more ABSTRACT The molecular recognition properties of 18 acyclic imides were studied to evaluate the relative contributions of conformational, hydrogen bonding and crystal packing forces to the stabilization of specific aggregate patterns in the solid state. The crystal structure of diisobutyramide and the aggregate patterns of the 18 imides are presented. The stabilization by hydrogen bonding was found to override the conformational preferences of imides, while packing forces often precluded the formation of the most stable hydrogen bonded aggregate. The aggregate patterns of imides were also found to be a function of the type of substituents present as R groups. Imides with R groups of similar shape and size prefer to pack as bifurcated hydrogen bonded chains, whereas dimers or singly hydrogen-bonded chains form when the R groups have significantly different spatial requirements. Analysis of imide aggregate patterns revealed the similar spatial requirements of isopropyl and phenyl groups. The molecular recognition properties of acyclic imides are summarized as a set of hydrogen bond rules, which can be used to design new imide aggregates.

Journal of the Chemical Society, Perkin Transactions 2, 2000

ABSTRACT Tazofelone (1) has been crystallized as two polymorphic racemic compounds (1a), designat... more ABSTRACT Tazofelone (1) has been crystallized as two polymorphic racemic compounds (1a), designated I and II, and as an (S)-(−) enantiomorph (1b). These crystal forms have been characterized using FTIR and solid-state NMR spectroscopy, single crystal X-ray analysis, and differential scanning calorimetry. The stability relationship of the racemic polymorphs has been established as enantiotropic, with form II being low-temperature stable and form I being high-temperature stable (transition temperature 138 °C). These two forms have similar enthalpies, entropies, and free energies (thermodynamic stability), which may be related to their similar molecular conformations, hydrogen-bonding patterns, and crystal packing efficiencies. The racemic crystals are significantly more stable than the physical mixture of the enantiomorphs. The spontaneous conversion of the racemic crystals into the conglomerate is not feasible thermodynamically at any temperature (monotropy). The weak lattice of the enantiomorphs may result, in part, from the high energy conformers that are the building blocks of the enantiomorphs and weaker dipole–dipole interactions.

Acta Crystallographica Section A Foundations of Crystallography, 2013

Acta Crystallographica Section A Foundations of Crystallography, 2013

Organic Process Research & Development, 2000

... 11) Byrn, SR; Curtin, DY; Paul, IC J. Am. Chem. Soc.1972, 94, 890; Yang, Q.-C.; Richardson, M... more ... 11) Byrn, SR; Curtin, DY; Paul, IC J. Am. Chem. Soc.1972, 94, 890; Yang, Q.-C.; Richardson, MF; Dunitz, JD Acta Crystallogr. 1989, B45, 312. ...

Organic Process Research & Development, 2000

... 11) Byrn, SR; Curtin, DY; Paul, IC J. Am. Chem. Soc.1972, 94, 890; Yang, Q.-C.; Richardson, M... more ... 11) Byrn, SR; Curtin, DY; Paul, IC J. Am. Chem. Soc.1972, 94, 890; Yang, Q.-C.; Richardson, MF; Dunitz, JD Acta Crystallogr. 1989, B45, 312. ...

Acta crystallographica. Section C, Crystal structure communications, Jan 15, 1991

N-Acetylbenzamide, C9H9NO2 (I) Mr = 163.18, orthorhombic, Pbca, a = 8.990 (2), b = 9.208 (3), c =... more N-Acetylbenzamide, C9H9NO2 (I) Mr = 163.18, orthorhombic, Pbca, a = 8.990 (2), b = 9.208 (3), c = 19.619 (3) A, V = 1624 (1) A3, Z = 8, Dx = 1.335 (1) g cm-3, lambda(Mo K alpha) = 0.710569 A, mu = 0.89 cm-1, F(000) = 688, T = 295 K, R = 0.031 for 865 observed reflections. N-Propionylbenzamide, C10H11NO2 (II), Mr = 177.20, monoclinic, P2(1)/c, a = 10.485 (2), b = 23.236 (4), c = 8.132 (2) A, beta = 108.43 (2) degrees, V = 1880 (1) A3, Z = 8, Dx = 1.252 (1) g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.82 cm-1, F(000) = 752, T = 297 K, R = 0.044 for 1407 observed reflections. N-Butyrylbenzamide, C11H13NO2 (III), Mr = 191.23, monoclinic, P2(1)/n, a = 8.270 (4), b = 12.600 (3), c = 10.459 (3) A, beta = 108.16 (3) degrees, V = 1040 (1) A3, Z = 4, Dx = 1.221 (1) g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.79 cm-1, F(000) = 408, T = 298 K, R = 0.038 for 1060 observed reflections. Compound (I) crystallizes in the Z,Z(trans-trans) conformation in chains linked by N-H...O hydrogen bonds. ...

Molecular Pharmaceutics, 2015

Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic h... more Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7(z)). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.

Acta crystallographica. Section C, Crystal structure communications, Jan 15, 1991

N-Acetylbenzamide, C9H9NO2 (I) Mr = 163.18, orthorhombic, Pbca, a = 8.990 (2), b = 9.208 (3), c =... more N-Acetylbenzamide, C9H9NO2 (I) Mr = 163.18, orthorhombic, Pbca, a = 8.990 (2), b = 9.208 (3), c = 19.619 (3) A, V = 1624 (1) A3, Z = 8, Dx = 1.335 (1) g cm-3, lambda(Mo K alpha) = 0.710569 A, mu = 0.89 cm-1, F(000) = 688, T = 295 K, R = 0.031 for 865 observed reflections. N-Propionylbenzamide, C10H11NO2 (II), Mr = 177.20, monoclinic, P2(1)/c, a = 10.485 (2), b = 23.236 (4), c = 8.132 (2) A, beta = 108.43 (2) degrees, V = 1880 (1) A3, Z = 8, Dx = 1.252 (1) g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.82 cm-1, F(000) = 752, T = 297 K, R = 0.044 for 1407 observed reflections. N-Butyrylbenzamide, C11H13NO2 (III), Mr = 191.23, monoclinic, P2(1)/n, a = 8.270 (4), b = 12.600 (3), c = 10.459 (3) A, beta = 108.16 (3) degrees, V = 1040 (1) A3, Z = 4, Dx = 1.221 (1) g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.79 cm-1, F(000) = 408, T = 298 K, R = 0.038 for 1060 observed reflections. Compound (I) crystallizes in the Z,Z(trans-trans) conformation in chains linked by N-H...O hydrogen bonds. ...

Organic Process Research & Development, 2005

... E. LeTourneau, Bruce E. Parker, Susan M. Reutzel-Edens, John P. Schafer, Michael A. Staszak, ... more ... E. LeTourneau, Bruce E. Parker, Susan M. Reutzel-Edens, John P. Schafer, Michael A. Staszak, Gregory A. Stephenson, Shella L. Tameze, and Lisa MH Zollars. Eli Lilly and Company, Chemical Product Research and Development Division, Indianapolis, Indiana 46285. Org. ...

in the Pharmaceutical Industry, 2006

Page 1. Susan M. Reutzel-Edens and Ann W. Newman 9.1 Introduction The terms hygroscopic and hygro... more Page 1. Susan M. Reutzel-Edens and Ann W. Newman 9.1 Introduction The terms hygroscopic and hygroscopicity are widely used in the pharmaceuti-cal literature to describe the moisture uptake of materials. Water vapor, an ...

Pharmaceutical Science & Technology Today, 1998

Pharmaceutical Science & Technology Today, 1998

Organic Process Research & Development, 2009

An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generatio... more An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generation synthesis built the enantioenriched nitro-aminoindanol core from 6-nitroindanone using a five-step literature route. The second-generation route used a safe aromatic nitration ...

Organic Process Research & Development, 2009

An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generatio... more An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generation synthesis built the enantioenriched nitro-aminoindanol core from 6-nitroindanone using a five-step literature route. The second-generation route used a safe aromatic nitration ...

Journal of the American Chemical Society, 1991

ABSTRACT The cocrystallization behavior of acyclic imides is studied as a way to map out the hydr... more ABSTRACT The cocrystallization behavior of acyclic imides is studied as a way to map out the hydrogen bond directed molecular recognition properties of a class of small biochemically related molecules under conditions where there is no preorganized cavity controlling the recognition events. Cocrystallization of over 80 imide-guest pairs was examined by solution and solid-state cocrystallization methods. The crystal structures of nine host-guest pairs are reported. The hydrogen bond patterns of 16 other cocrystal pairs were characterized by noncrystallographic means. Common hydrogen bond patterns and hydrogen bond selectivity properties were analyzed and are presented in the form of a set of hydrogen bond rules. Diacetamide was found to be a versatile cocrystallizing agent, forming 10 different cocrystal pairs. Imides that have a cis-trans conformation in their homomeric forms retain that conformation in their cocrystal structures. Imides that have a trans-trans conformation in their homomeric structures do not usually form cocrystals. Three imide cocrystal hydrogen types were observed repeatedly, with the most common pattern involving cyclic imide dimers with pendant hydrogen-bonded guests or cyclic heteromeric patterns having bivalent contacts between the imide and guest species. Guest molecules that successfully formed cocrystals covered a wide range of chemical types, including phenols, acids, amides, phosphine oxides, pyridines, imidazoles, and ureas.

Journal of the American Chemical Society, 1993

Page 1. J. Am. Chem. SOC. 1993,115, 4411-4412 441 1 Self-organization of Adenine and Thymine in t... more Page 1. J. Am. Chem. SOC. 1993,115, 4411-4412 441 1 Self-organization of Adenine and Thymine in the Solid State? Margaret C. Etter,+ Susan M. Reutzel,* and Carolyn G. Choo' Department of Chemistry University of Minnesota Minneapolis, Minnesota 55455 ...

Journal of the American Chemical Society, 1993

Page 1. J. Am. Chem. SOC. 1993,115, 4411-4412 441 1 Self-organization of Adenine and Thymine in t... more Page 1. J. Am. Chem. SOC. 1993,115, 4411-4412 441 1 Self-organization of Adenine and Thymine in the Solid State? Margaret C. Etter,+ Susan M. Reutzel,* and Carolyn G. Choo' Department of Chemistry University of Minnesota Minneapolis, Minnesota 55455 ...

Journal of Physical Organic Chemistry, 1992

ABSTRACT The molecular recognition properties of 18 acyclic imides were studied to evaluate the r... more ABSTRACT The molecular recognition properties of 18 acyclic imides were studied to evaluate the relative contributions of conformational, hydrogen bonding and crystal packing forces to the stabilization of specific aggregate patterns in the solid state. The crystal structure of diisobutyramide and the aggregate patterns of the 18 imides are presented. The stabilization by hydrogen bonding was found to override the conformational preferences of imides, while packing forces often precluded the formation of the most stable hydrogen bonded aggregate. The aggregate patterns of imides were also found to be a function of the type of substituents present as R groups. Imides with R groups of similar shape and size prefer to pack as bifurcated hydrogen bonded chains, whereas dimers or singly hydrogen-bonded chains form when the R groups have significantly different spatial requirements. Analysis of imide aggregate patterns revealed the similar spatial requirements of isopropyl and phenyl groups. The molecular recognition properties of acyclic imides are summarized as a set of hydrogen bond rules, which can be used to design new imide aggregates.