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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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Pin tool used for deposition of material onto a μPIHn plate.
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fig2: Pin tool used for deposition of material onto a μPIHn plate.

Mentions: To overcome the limitations ofcurrent approaches to high throughputpolymorph screening, a platform which takes advantage of the benefitsof a high density microtiter plate but limits the drawbacks currentlyassociated with them was devised. A CO2 laser was utilizedto create an array of 288 depressions approximately 300 μm deepon a standard quartz microscope slide (75 mm × 25 mm × 1mm). This geometry eliminates any constraints to in situ analysisand crystal harvesting (Figure 1) (see Supporting Information). This precisely definedarray possesses the spacing of a 1536 well plate (2.25 mm from thecenter of one depression to another) maintaining compatibility withliquid handling robots. For demonstration purposes the three distinctpolymer libraries commonly employed in PIHn studies were chosen; theseare characterized by the functionalities of their constituent monomers:acidic, nonpolar aromatic, and polar nitrogen.14 For each of these libraries, there are 96 cross-linkedpolymers, for a total of 288 unique cross-linked polymers. Therefore,the three libraries can be deposited on a single quartz slide witha unique polymer in each depression. This manipulation was accomplishedby taking advantage of the geometry of a 1536 well plate relativeto a 384 well plate. On a 384 microtiter plate the spacing from thecenter of one well to another is 4.5 mm (exactly double the spacingin a 1536 well plate). With this in mind, a custom pin tool24 was fabricated composed of five Delrin combsheld together in a poly(methyl methacrylate) lattice (Figure 2). This pin tool enables rapid contact-printingof up to 80 distinct monomer solutions simultaneously from a 384 wellplate containing the monomer solutions onto the individual depressionson the laser-etched quartz slide. The number of monomer solutionsprinted onto the quartz slide can be easily changed by removing acomb from the lattice; depending on the number of combs present, 16–80distinct monomer solutions can be dispensed at one time. Immediatelyafter each print from the 384 well plate onto the quartz slide, themonomer solutions were photopolymerized, yielding thin polymer filmsin each depression. Four applications of the printing tool were requiredto print all 288 distinct monomer solutions (see Supporting Information) and after polymerization was completed,the μPIHn plate was applied to crystallization studies. An additionalcomb was then used to dispense the crystallization solution of themolecule to be investigated onto the μPIHn plate. This contactprinting leads to very low volume transfer (∼0.3 μL perwell) and therefore small sample requirements. The extremely thinpolymer films allow for analysis of polymorphs directly on the platewithout significant signal interference from the polymer heteronucleant,thus enabling automated Raman microscopy mapping. The efficacy ofthis platform was demonstrated with four model polymorphic compounds:acetaminophen (ACM), tolfenamic acid (TA), ROY, and curcumin.


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

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

Pin tool used for deposition of material onto a μPIHn plate.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Pin tool used for deposition of material onto a μPIHn plate.
Mentions: To overcome the limitations ofcurrent approaches to high throughputpolymorph screening, a platform which takes advantage of the benefitsof a high density microtiter plate but limits the drawbacks currentlyassociated with them was devised. A CO2 laser was utilizedto create an array of 288 depressions approximately 300 μm deepon a standard quartz microscope slide (75 mm × 25 mm × 1mm). This geometry eliminates any constraints to in situ analysisand crystal harvesting (Figure 1) (see Supporting Information). This precisely definedarray possesses the spacing of a 1536 well plate (2.25 mm from thecenter of one depression to another) maintaining compatibility withliquid handling robots. For demonstration purposes the three distinctpolymer libraries commonly employed in PIHn studies were chosen; theseare characterized by the functionalities of their constituent monomers:acidic, nonpolar aromatic, and polar nitrogen.14 For each of these libraries, there are 96 cross-linkedpolymers, for a total of 288 unique cross-linked polymers. Therefore,the three libraries can be deposited on a single quartz slide witha unique polymer in each depression. This manipulation was accomplishedby taking advantage of the geometry of a 1536 well plate relativeto a 384 well plate. On a 384 microtiter plate the spacing from thecenter of one well to another is 4.5 mm (exactly double the spacingin a 1536 well plate). With this in mind, a custom pin tool24 was fabricated composed of five Delrin combsheld together in a poly(methyl methacrylate) lattice (Figure 2). This pin tool enables rapid contact-printingof up to 80 distinct monomer solutions simultaneously from a 384 wellplate containing the monomer solutions onto the individual depressionson the laser-etched quartz slide. The number of monomer solutionsprinted onto the quartz slide can be easily changed by removing acomb from the lattice; depending on the number of combs present, 16–80distinct monomer solutions can be dispensed at one time. Immediatelyafter each print from the 384 well plate onto the quartz slide, themonomer solutions were photopolymerized, yielding thin polymer filmsin each depression. Four applications of the printing tool were requiredto print all 288 distinct monomer solutions (see Supporting Information) and after polymerization was completed,the μPIHn plate was applied to crystallization studies. An additionalcomb was then used to dispense the crystallization solution of themolecule to be investigated onto the μPIHn plate. This contactprinting leads to very low volume transfer (∼0.3 μL perwell) and therefore small sample requirements. The extremely thinpolymer films allow for analysis of polymorphs directly on the platewithout significant signal interference from the polymer heteronucleant,thus enabling automated Raman microscopy mapping. The efficacy ofthis platform was demonstrated with four model polymorphic compounds:acetaminophen (ACM), tolfenamic acid (TA), ROY, and curcumin.

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