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Towards exhaustive and automated high-throughput screening for crystalline polymorphs.

Pfund LY, Matzger AJ - ACS Comb Sci (2014)

Bottom Line: Here PIHn is redeployed in a high density format in which 288 distinct polymers, each acting as a heteronucleant, are arrayed on one substrate.This format allows determining the outcome of thousands of crystallizations in an automated fashion with only a few milligrams of sample.Here the efficacy of this approach is demonstrated using four pharmaceutically relevant compounds: acetaminophen, tolfenamic acid, ROY, and curcumin.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and the Macromolecular Science and Engineering Program, University of Michigan , Ann Arbor, Michigan 48109, United States.

ABSTRACT
Methods capable of exhaustively screening for crystal polymorphism remain an elusive goal in solid-state chemistry. Particularly promising among the new generation of approaches is polymer-induced heteronucleation (PIHn), a tool utilizing hundreds of unique polymers for granting kinetic access to polymorphs. Here PIHn is redeployed in a high density format in which 288 distinct polymers, each acting as a heteronucleant, are arrayed on one substrate. This format allows determining the outcome of thousands of crystallizations in an automated fashion with only a few milligrams of sample. This technology enables the study of a broader range of targets, including preclinical candidates, facilitating determination of polymorphism propensity much earlier in the drug development process. Here the efficacy of this approach is demonstrated using four pharmaceutically relevant compounds: acetaminophen, tolfenamic acid, ROY, and curcumin.

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Raman spectraof the diagnostic nitrile region for ROY, in orderfrom left to right: red prism, yellow needles, orange needles, yellowprims, obtained directly from crystals on a μPIHn plate.
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fig4: Raman spectraof the diagnostic nitrile region for ROY, in orderfrom left to right: red prism, yellow needles, orange needles, yellowprims, obtained directly from crystals on a μPIHn plate.

Mentions: ROY, an intermediate in the production of the pharmaceuticalolanzapine, is known for the color of its red, orange, and yellowpolymorphs.21 Using μPIHn, four ofthe seven structurally characterized forms were obtained: red prism(R), yellow needle (YN), orange needle (ON), and yellow prism (Y)(Figure 4). Red and yellow prisms nucleatedon polymers within the polar nitrogen library. However, polymers inthe nonpolar aromatic library facilitated the formation of yellowneedles. Orange needles were found on polymers in the acidic library(see Supporting Information).


Towards exhaustive and automated high-throughput screening for crystalline polymorphs.

Pfund LY, Matzger AJ - ACS Comb Sci (2014)

Raman spectraof the diagnostic nitrile region for ROY, in orderfrom left to right: red prism, yellow needles, orange needles, yellowprims, obtained directly from crystals on a μPIHn plate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215906&req=5

fig4: Raman spectraof the diagnostic nitrile region for ROY, in orderfrom left to right: red prism, yellow needles, orange needles, yellowprims, obtained directly from crystals on a μPIHn plate.
Mentions: ROY, an intermediate in the production of the pharmaceuticalolanzapine, is known for the color of its red, orange, and yellowpolymorphs.21 Using μPIHn, four ofthe seven structurally characterized forms were obtained: red prism(R), yellow needle (YN), orange needle (ON), and yellow prism (Y)(Figure 4). Red and yellow prisms nucleatedon polymers within the polar nitrogen library. However, polymers inthe nonpolar aromatic library facilitated the formation of yellowneedles. Orange needles were found on polymers in the acidic library(see Supporting Information).

Bottom Line: Here PIHn is redeployed in a high density format in which 288 distinct polymers, each acting as a heteronucleant, are arrayed on one substrate.This format allows determining the outcome of thousands of crystallizations in an automated fashion with only a few milligrams of sample.Here the efficacy of this approach is demonstrated using four pharmaceutically relevant compounds: acetaminophen, tolfenamic acid, ROY, and curcumin.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and the Macromolecular Science and Engineering Program, University of Michigan , Ann Arbor, Michigan 48109, United States.

ABSTRACT
Methods capable of exhaustively screening for crystal polymorphism remain an elusive goal in solid-state chemistry. Particularly promising among the new generation of approaches is polymer-induced heteronucleation (PIHn), a tool utilizing hundreds of unique polymers for granting kinetic access to polymorphs. Here PIHn is redeployed in a high density format in which 288 distinct polymers, each acting as a heteronucleant, are arrayed on one substrate. This format allows determining the outcome of thousands of crystallizations in an automated fashion with only a few milligrams of sample. This technology enables the study of a broader range of targets, including preclinical candidates, facilitating determination of polymorphism propensity much earlier in the drug development process. Here the efficacy of this approach is demonstrated using four pharmaceutically relevant compounds: acetaminophen, tolfenamic acid, ROY, and curcumin.

Show MeSH