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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 spectra of tolfenamic acid formsI, II, III, VI, and V, obtaineddirectly from crystals on a μPIHn plate.
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fig5: Raman spectra of tolfenamic acid formsI, II, III, VI, and V, obtaineddirectly from crystals on a μPIHn plate.

Mentions: Tolfenamic acid (TA) is a pentamorphic,nonsteroidal anti-inflammatory drug.16 Previously,when TA was subjected to traditional PIHn screening, five polymorphswere found, with three forms discovered for the first time.16 Now with μPIHn all five known forms ofTA were obtained using only 0.2 mg of TA (Figure 5). Forms I, II, and V of TA were found to nucleate on polymerswithin the polar nitrogen library, whereas forms III and IV nucleatedon polymers in the nonpolar aromatic library (see Supporting Information).


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

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

Raman spectra of tolfenamic acid formsI, II, III, VI, and V, obtaineddirectly from crystals on a μPIHn plate.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Raman spectra of tolfenamic acid formsI, II, III, VI, and V, obtaineddirectly from crystals on a μPIHn plate.
Mentions: Tolfenamic acid (TA) is a pentamorphic,nonsteroidal anti-inflammatory drug.16 Previously,when TA was subjected to traditional PIHn screening, five polymorphswere found, with three forms discovered for the first time.16 Now with μPIHn all five known forms ofTA were obtained using only 0.2 mg of TA (Figure 5). Forms I, II, and V of TA were found to nucleate on polymerswithin the polar nitrogen library, whereas forms III and IV nucleatedon polymers in the nonpolar aromatic 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