Multiple-component solid phases containing at least one active pharmaceutical ingredient

a technology of solid phase and active ingredients, applied in the field of multi-component solid phase, can solve the problems of limiting the therapeutic benefit of drugs, crystal structure prediction and even composition prediction remains a largely unmet goal, and drug solubility, stability and bioavailability, and the effect of improving the solubility of drugs

Inactive Publication Date: 2017-12-21
RGT UNIV OF MICHIGAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text discusses the invention of multiple-component solids that contain active pharmaceutical ingredients, such as aspirin, and other molecules that can form crystals with the pharmaceutical ingredients. These new crystal structures can improve the solubility, dissolution rate, and stability of the pharmaceutical ingredients, leading to better bioavailability.

Problems solved by technology

However, whereas crystal structure determination has been a tool used by scientists since the 1920's, crystal structure prediction remains a largely unmet goal (Ball, P.
Furthermore, the existence of more than one crystalline form of a given molecular compound, typically in the form of polymorphs or solvates, represents both a problem and an opportunity (Desiraju, G. R. Science, 1997, 278:404-405; Bernstein, J. et al., Angew, Chem. Int. Ed. Engl., 1999, 38:3441-3461).
Specifically, physical properties of crystalline solids are critically dependent on the internal arrangement of molecules or ions, making prediction of composition, crystal structure and morphology from knowledge of molecular structure a scientific challenge of the highest order.
However, crystal structure prediction and even prediction of composition remains a largely unmet goal.
Undesirable physicochemical properties, physiological barriers, or issues of toxicity often limit the therapeutic benefit of drugs.
In this context, the existence of more than one crystalline form of a given compound, typically in the form of polymorphs or solvates, represents both a problem and an opportunity.
Several factors further complicate the situation.
The need to ensure that processing produces both purity and ease of processing is problematic because many drug molecules are prone to form multiple phases, and crystal size and morphology can vary for a given phase.
The commercial and public image costs of not ensuring that processing is reliable and reproducible is at best very high, as demonstrated by the recent pull back and reformulation of NORVIR by ABBOTT LABORATORIES).
That XPD patterns have been relied on for quality control is convenient but is in many ways unfortunate since XPD is not as foolproof as single crystal X-ray crystallography (e.g. similar patterns can be obtained for different phases, composition is not unambiguously determined), and XPD does not determine crystal packing.

Method used

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  • Multiple-component solid phases containing at least one active pharmaceutical ingredient
  • Multiple-component solid phases containing at least one active pharmaceutical ingredient
  • Multiple-component solid phases containing at least one active pharmaceutical ingredient

Examples

Experimental program
Comparison scheme
Effect test

example 1

Multi-Component Crystal of Acetaminophen:Acetominophen / 4,4′-Bipyridine / Water (1:1:1 Stoichiometry)

[0058]50 mg (0.3307 mmol) acetaminophen and 52 mg (0.3329 mmol) 4,4′-bipyridine were dissolved in hot water and allowed to stand. Slow evaporation yielded colorless needles of a 1:1:1 acetaminophen / 4,4′-bipyridine / water co-crystal, as shown in FIG. 4B.

[0059]Crystal data: (Bruker SMART-APEX CCD Diffractometer). C36H44N2O4, M=339.84, triclinic, space group PĪ; a=7.0534(8), b=9.5955(12), c=19.3649(2) Å, α=86.326(2), β=80.291(2), γ=88.880(2)°, U=1308.1(3) Å3, T=200(2) K, Z=2, μ(Mo-Kα)=0.090 mm−1, Dc=1.294 Mg / m3, λ=0.71073 Å3, F(000)=537, 2θmax=25.02°; 6289 reflections measured, 4481 unique (Rint=0.0261). Final residuals for 344 parameters were R1=0.0751, wR2=0.2082 for I>2σ(I), and R1=0.1119, wR2=0.2377 for all 4481 data.

[0060]Crystal packing: The co-crystals contain bilayered sheets in which water molecules act as a hydrogen bonded bridge between the network bipyridine moieties and the ace...

example 2

Multi-Component Crystal of Phenytoin:Phenytoin / Pyridone (1:1 Stoichiometry)

[0062]28 mg (0.1109 mmol) phenytoin and 11 mg (0.1156 mmol) 4-hydroxypyridone were dissolved in 2 mL acetone and 1 mL ethanol with heating and stirring. Slow evaporation yielded colorless needles of a 1:1 phenytoin / pyridone co-crystal, as shown in FIG. 5B.

[0063]Crystal data: (Bruker SMART-APEX CCD (Diffractometer), C20H17N3O3, M=347.37, monoclinic P2l / c; a=16.6583(19), b=8.4878(10), c=11.9546(14) Å, β=96.618(2)°, U=1750.2(3) Å3, T=200(2) K, Z=4, μ(Mo-Kα)=0.091 mm−1, Dc=1.318 Mg / m3, λ=0.71073 Å3, F(000)=728, 2θmax=56.60°; 10605 reflections measured, 4154 unique (Rint=0.0313). Final residuals for 247 parameters were R1=0.0560, wR2=0.1356 for I>2σ(I), and R1=0.0816, wR2=0.1559 for all 4154 data.

[0064]Crystal packing: The co-crystal is sustained by hydrogen bonding of adjacent phentoin molecules between the carbonyl and the amine closest to the tetrahedral carbon, and by hydrogen bonding between pyridone carbonyl...

example 3

Multi-Component Crystal of Aspirin (Acetylsalicylic Acid):Aspirin / 4,4′-bipyridine (2:1 Stoichiometry)

[0069]50 mg (0.2775 mmol) aspirin and 22 mg (0.1388 mmol) 4,4′-bipyridine were dissolved in 4 mL hexane. 8 mL ether was added to the solution and allowed to stand for one hour, yielding colorless needles of a 2:1 aspirin / 4,4′-bipyridine co-crystal, as shown in FIG. 6D. Alternatively, aspirin / 4,4′-bipyridine (2:1 stoichiometry) can be made by grinding the solid ingredients in a pestle and mortar.

[0070]Crystal data: (Bruker SMART-APEX CCD Diffractometer), N2O8, M=516.49, orthorhombic Pbcn; a=28.831(3), b=11.3861(12), c=8.4144(9) Å, U=2762.2(5) Å3, T=173(2) K, Z=4, μ(Mo-Kα)=0.092 mm−1, Dc=1.242 Mg / m3, λ=0.71073 Å3, F(000)=1080, 2θmax=25.02°; 12431 reflections measured, 2433 unique (Rint=0.0419). Final residuals for 202 parameters were R10.0419, wR2=0.1358 for I>2σ(I), and R1=0.0541, wR2=0.1482 for all 2433 data.

[0071]Crystal packing: The co-crystal contains the carboxylic acid-pyridine ...

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Abstract

The subject invention concerns a method for identifying complementary chemical functionalities to form a desired supramolecular synthon. The subject invention also pertains to multiple-component phase compositions comprising one or more pharmaceutical entities and methods for producing such compositions.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]The present application claims the benefit of priority of U.S. Provisional Application Ser. No. 60 / 360,768, filed Mar. 1, 2002, which is hereby incorporated by reference herein in its entirety, including any figures, tables, or drawings.BACKGROUND OF THE INVENTION[0002]The last decade has witnessed tremendous advances in the understanding of, and the ability to manipulate, molecular and supramolecular assemblies (Moulton, B. et al., Chem. Rev., 2001, 101:1629-1658). There are new paradigms concerning the design and synthesis of a new generation of functional materials and molecules. Such advances are a consequence of the fundamental importance of intermolecular interactions, structure and cooperativity in many aspects of molecular science, from environmental science to molecular biology, to pharmacology, to materials science. Thus, the prospects for control and manipulation of materials at the molecular level, particularly in areas related...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): C07D223/26A61K9/16C07D213/82C07D213/79C07D213/69C07D213/22C07D213/06C07C317/04C07C233/75C07C233/25C07C233/03C07C205/57C07C69/157C07C63/307C07C61/135C07C57/58C07C57/30C07C53/124C07C53/08C07C53/02C07C51/43C07C51/41C07C47/544A61K47/32A61K47/10A61K31/616A61K31/55A61K31/4166A61K31/192A61K31/167C07D233/74C07D275/06A61K9/00A61K47/12A61K47/20A61K47/22C07C53/21C07C53/23C07C233/18
CPCC07C53/08C07C51/43C07C57/58C07C61/135C07C63/307C07C69/157C07C205/57C07C233/03C07C233/75C07C317/04C07D213/06C07D213/22C07D275/06C07D213/79C07D213/69C07D213/82C07C47/544C07C53/02C07C53/124A61K31/167A61K31/192A61K31/4166A61K47/32A61K31/55A61K31/616A61K47/10C07C233/25C07D223/26C07D233/74C07C57/30C07C51/412A61K9/1652A61P25/04A61P25/08A61P29/00C07C53/06C07C53/10
InventorZAWOROTKO, MICHAEL J.RODRIGUEZ-HORNEDO, NAIRMOULTON, BRIAN
OwnerRGT UNIV OF MICHIGAN