polymorphism (materials science)
Information about polymorphism (materials science)
Polymorphism in materials science is the ability of a solid material to exist in more than one form or crystal structure. Polymorphism can potentially be found in any crystalline material including polymers and metals and is related to allotropy which refers to elemental solids. Together with polymorphism the complete morphology of a material is described by other variables such as crystal habit, amorphous fraction or Crystallographic defects. Polymorphism is relevant to the fields of pharmaceuticals, agrochemicals, pigments, dyestuffs, foods and explosives.
When polymorphism exists as a result of difference in crystal packing it is called packing polymorphism. Polymorphism can also result from the existence of different conformers of the same molecule in conformational polymorphism. In pseudopolymorphism the different crystal types are the result of hydration or solvation. An example of an organic polymorph is glycine which is able to form monoclinic and hexagonal crystals.
An analogous phenomenon for amorphous materials is polymorphism, when a substance can take on several different amorphous modifications.
The first observation of this property is attributed to Friedrich Wöhler and Justus von Liebig when in 1832 they [1] examined a boiling solution of benzamide: on cooling the benzamide initially crystallised as silky needles but on standing these were slowly replaced by rhombic crystals. Present-day analysis [2] identifies three polymorphs for benzamide: the least stable one, formed by flash cooling is the monoclinic form II. This type is followed by the centrosymmetric form III (observed by Wöhler/Liebig) in which aromatic stacking is the dominant feature. The most stable form is monoclinic form I which is optimized for hydrogen bonding.
Despite the potential implications, polymorphism is not always well understood. In 2006 a new crystal form was discovered of maleic acid 124 years after the first crystal structure determination [3]. Maleic acid is a chemical manufactured on a very large scale in the chemical industry and is a salt forming component in medicine. The new crystal type is produced when a caffeine - maleic acid co-crystal (2:1) is dissolved in chloroform and when the solvent is allowed to evaporate slowly. Whereas form I has monoclinic space group P21/c, the new form has space group Pc. Both polymorphs consist of sheets of molecules connected through hydrogen bonding of the carboxylic acid groups but in form I the sheets alternate with respect of the net dipole moment whereas in form II the sheets are oriented in the same direction.
1,3,5-Trinitrobenzene is more than 125 years old and was used as an explosive before the arrival of the safer 2,4,6-trinitrotoluene. Only one crystal form of 1,3,5-trinitrobenzene has been known in the space group Pbca. In 2004, a second polymorph was obtained in the space group Pca21 when the compound was crystallized in the presence of an additive, trisindane. This experiment shows that additives can induce the appearance of polymorphic forms. [4]
Cefdinir is a drug appearing in 11 patents from 5 pharmaceutical companies in which a total of 5 different polymorphs are described. The original inventor Fuijsawa now Astellas (with US partner Abbott) extended the original patent covering a suspension with a new anhydrous formulation. Competitors in turn patented hydrates of the drug with varying water content which were importantly only described with basic techniques such as infrared spectroscopy and XRPD, a practise criticised by in one review [5] because these techniques at the most suggest a different crystal structure but are unable to specify one. These techniques also tend to overlook chemical impurities or even co-components. Abbott researchers realized this the hard way when in one patent application it was ignored that their new cefdinir crystal form was in fact that of a pyridinium salt. The review also questioned whether the polymorphs offered any advantages to the existing drug something clearly demanded in a new patent.
Acetylsalicylic acid elusive 2nd polymorph was first discovered by Vishweshwar et al. [6], fine structural details were given by Bond et al. [7] A new crystal type was found after attempted co-crystallization of aspirin and levetiracetam from hot acetonitrile. The form II is only stable at 100 K and reverts back to form I at ambient temperature. In the (unambiguous) form I two salicylic molecules form centrosymmetric dimers through the acetyl groups with the (acidic) methyl proton to carbonyl hydrogen bonds and in the newly claimed form II each salicylic molecule forms the same hydrogen bonds but then with two neighboring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups both polymorphs form identical dimer structures.
Crystal Polymorphs can disappear. There have been cases of individual laboratories growing one crystal form. They then grow a different crystal form, and are unable to make the first form again. Alternatively, they find that they can make the first form again but it now converts to the second form over time. The drug Paroxetine was subject to a law suit that hinged on such a pair of polymorphs (A link to a discussion of cases in Canada and the US has been given below). An example is known when a so-called 'disappeared' polymorph re-appeared after 40 years. These so-called 'disappearing' polymorphs are probably metastable kinetic forms.
Glycine (abbreviated as Gly or G)[1] is the organic compound with the formula HO2CCH2NH2.
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When polymorphism exists as a result of difference in crystal packing it is called packing polymorphism. Polymorphism can also result from the existence of different conformers of the same molecule in conformational polymorphism. In pseudopolymorphism the different crystal types are the result of hydration or solvation. An example of an organic polymorph is glycine which is able to form monoclinic and hexagonal crystals.
An analogous phenomenon for amorphous materials is polymorphism, when a substance can take on several different amorphous modifications.
Background
In terms of thermodynamics, there are two types of polymorphism. For a monotropic system, a plot of the free energy of the various polymorphs against temperature do not cross before all polymorphs melt - in other words, any transition from one polymorph to another will be irreversible. For an enantiotropic system, a plot of the free energy against temperature shows a crossing point before the various melting points, and it may be possible to convert reversibly between the two polymorphs on heating and cooling.The first observation of this property is attributed to Friedrich Wöhler and Justus von Liebig when in 1832 they [1] examined a boiling solution of benzamide: on cooling the benzamide initially crystallised as silky needles but on standing these were slowly replaced by rhombic crystals. Present-day analysis [2] identifies three polymorphs for benzamide: the least stable one, formed by flash cooling is the monoclinic form II. This type is followed by the centrosymmetric form III (observed by Wöhler/Liebig) in which aromatic stacking is the dominant feature. The most stable form is monoclinic form I which is optimized for hydrogen bonding.
Despite the potential implications, polymorphism is not always well understood. In 2006 a new crystal form was discovered of maleic acid 124 years after the first crystal structure determination [3]. Maleic acid is a chemical manufactured on a very large scale in the chemical industry and is a salt forming component in medicine. The new crystal type is produced when a caffeine - maleic acid co-crystal (2:1) is dissolved in chloroform and when the solvent is allowed to evaporate slowly. Whereas form I has monoclinic space group P21/c, the new form has space group Pc. Both polymorphs consist of sheets of molecules connected through hydrogen bonding of the carboxylic acid groups but in form I the sheets alternate with respect of the net dipole moment whereas in form II the sheets are oriented in the same direction.
1,3,5-Trinitrobenzene is more than 125 years old and was used as an explosive before the arrival of the safer 2,4,6-trinitrotoluene. Only one crystal form of 1,3,5-trinitrobenzene has been known in the space group Pbca. In 2004, a second polymorph was obtained in the space group Pca21 when the compound was crystallized in the presence of an additive, trisindane. This experiment shows that additives can induce the appearance of polymorphic forms. [4]
Ostwald's rule
Ostwald's rule or Ostwald's step rule conceived by Wilhelm Ostwald states that in general it is not the most stable but the least stable polymorph that crystallizes first. See for examples the aforementioned benzamide, dolomite or phosphorous which on sublimation first forms the less stable white and then the more stable red allotrope.Polymorphism in pharmaceuticals
Polymorphism is important in the development of pharmaceutical ingredients. Many drugs are receiving regulatory approval for only a single crystal form or polymorph. In a classic patent case the pharmaceutical company GlaxoSmithKline defended its patent for the polymorph type II of the active ingredient in Zantac against competitors while that of the polymorph type I had already expired. Polymorphism in drugs can also have direct medical implications. Medicine is often administered orally as a crystalline solid and dissolution rates depend on the exact crystal form of a polymorph.Cefdinir is a drug appearing in 11 patents from 5 pharmaceutical companies in which a total of 5 different polymorphs are described. The original inventor Fuijsawa now Astellas (with US partner Abbott) extended the original patent covering a suspension with a new anhydrous formulation. Competitors in turn patented hydrates of the drug with varying water content which were importantly only described with basic techniques such as infrared spectroscopy and XRPD, a practise criticised by in one review [5] because these techniques at the most suggest a different crystal structure but are unable to specify one. These techniques also tend to overlook chemical impurities or even co-components. Abbott researchers realized this the hard way when in one patent application it was ignored that their new cefdinir crystal form was in fact that of a pyridinium salt. The review also questioned whether the polymorphs offered any advantages to the existing drug something clearly demanded in a new patent.
Acetylsalicylic acid elusive 2nd polymorph was first discovered by Vishweshwar et al. [6], fine structural details were given by Bond et al. [7] A new crystal type was found after attempted co-crystallization of aspirin and levetiracetam from hot acetonitrile. The form II is only stable at 100 K and reverts back to form I at ambient temperature. In the (unambiguous) form I two salicylic molecules form centrosymmetric dimers through the acetyl groups with the (acidic) methyl proton to carbonyl hydrogen bonds and in the newly claimed form II each salicylic molecule forms the same hydrogen bonds but then with two neighboring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups both polymorphs form identical dimer structures.
Trivia
Walter McCrone stated that every compound has different polymorphic forms, and that, in general, the number of forms known for a given compound is proportional to the time and money spent in research on that compound.Crystal Polymorphs can disappear. There have been cases of individual laboratories growing one crystal form. They then grow a different crystal form, and are unable to make the first form again. Alternatively, they find that they can make the first form again but it now converts to the second form over time. The drug Paroxetine was subject to a law suit that hinged on such a pair of polymorphs (A link to a discussion of cases in Canada and the US has been given below). An example is known when a so-called 'disappeared' polymorph re-appeared after 40 years. These so-called 'disappearing' polymorphs are probably metastable kinetic forms.
References
1. ^ F. Wöhler, J. Liebig, Ann. Pharm. 1832, 249 – 282.
2. ^ Polymorphism in Benzamide: Solving a 175-Year-Old Riddle Jorgen Thun, Lena Seyfarth, Jorgen Senker, Robert E. Dinnebier, and Josef Breu Angew. Chem. Int. Ed. 2007, 46, 6729 –6731 doi:10.1002/anie.200701383
3. ^ Graeme M. Day, Andrew V. Trask, W. D. Samuel Motherwell and William Jones (2006). "Investigating the latent polymorphism of maleic acid". Chemical Communications 1: 54 - 56. DOI:10.1039/b513442k.
4. ^ Thallapally PK, Jetti RKR, Katz AK (2004). "Polymorphism of 1,3,5-trinitrobenzene induced by a trisindane additive". Angewandte Chemie International Edition 43 (9): 1149-1155.
5. ^ Polymorphisms and Patent, Market, and Legal Battles: Cefdinir Case Study Walter Cabri, Paolo Ghetti, Giovanni Pozzi, and Marco Alpegiani Org. Process Res. Dev.; 2007; 11(1) pp 64 - 72; (Review) doi:10.1021/op0601060
6. ^ Peddy Vishweshwar, Jennifer A. McMahon, Mark Oliveira, Matthew L. Peterson, and Michael J. Zaworotko (2005). "The Predictably Elusive Form II of Aspirin". J. Am. Chem. Soc. 127 (48): 16802 - 16803. DOI:10.1021/ja056455b.
7. ^ Andrew D. Bond, Roland Boese, Gautam R. Desiraju (2007). "On the Polymorphism of Aspirin: Crystalline Aspirin as Intergrowths of Two "Polymorphic" Domains". Angewandte Chemie International Edition 46 (4): 618-622. DOI:10.1002/anie.200603373.
2. ^ Polymorphism in Benzamide: Solving a 175-Year-Old Riddle Jorgen Thun, Lena Seyfarth, Jorgen Senker, Robert E. Dinnebier, and Josef Breu Angew. Chem. Int. Ed. 2007, 46, 6729 –6731 doi:10.1002/anie.200701383
3. ^ Graeme M. Day, Andrew V. Trask, W. D. Samuel Motherwell and William Jones (2006). "Investigating the latent polymorphism of maleic acid". Chemical Communications 1: 54 - 56. DOI:10.1039/b513442k.
4. ^ Thallapally PK, Jetti RKR, Katz AK (2004). "Polymorphism of 1,3,5-trinitrobenzene induced by a trisindane additive". Angewandte Chemie International Edition 43 (9): 1149-1155.
5. ^ Polymorphisms and Patent, Market, and Legal Battles: Cefdinir Case Study Walter Cabri, Paolo Ghetti, Giovanni Pozzi, and Marco Alpegiani Org. Process Res. Dev.; 2007; 11(1) pp 64 - 72; (Review) doi:10.1021/op0601060
6. ^ Peddy Vishweshwar, Jennifer A. McMahon, Mark Oliveira, Matthew L. Peterson, and Michael J. Zaworotko (2005). "The Predictably Elusive Form II of Aspirin". J. Am. Chem. Soc. 127 (48): 16802 - 16803. DOI:10.1021/ja056455b.
7. ^ Andrew D. Bond, Roland Boese, Gautam R. Desiraju (2007). "On the Polymorphism of Aspirin: Crystalline Aspirin as Intergrowths of Two "Polymorphic" Domains". Angewandte Chemie International Edition 46 (4): 618-622. DOI:10.1002/anie.200603373.
External links
- "Small Molecule Crystalization" (PDF) at Illinois Institute of Technology website
- "A discussion of crystal form litigation to develop generic versions of Paroxetine] ]"
Materials science or materials engineering is an interdisciplinary field involving the properties of matter and its applications to various areas of science and engineering. This science investigates the relationship between the structure of materials and their properties.
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CRYSTAL is a quantum chemistry ab initio program, designed primarily for calculations on crystals (3 dimensions), slabs (2 dimensions) and polymers (1 dimension) using translational symmetry, but it can be used for single molecules.[1] It is written by V.R. Saunders, R.
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polymer is a substance composed of molecules with large molecular mass composed of repeating structural units, or monomers, connected by covalent chemical bonds. The word is derived from the Greek, πολυ, polu, "many"; and μέρος, meros,
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The Macro Expansion Template Attribute Language complements TAL, providing macros which allow the reuse of code across template files. Both were created for Zope but are used in other Python projects as well.
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Allotropy (Gr. allos, other, and tropos, manner) is a behavior exhibited by certain chemical elements: these elements can exist in two or more different forms, known as allotropes of that element.
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chemical element, or element, is a type of atom that is defined by its atomic number; that is, by the number of protons in its nucleus. The term is also used to refer to a pure chemical substance composed of atoms with the same number of protons.
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habit of crystals.
The many terms used by mineralogists to describe crystal habits are useful in communicating what specimens of a particular mineral often look like. Recognizing numerous habits helps a mineralogist to identify a large number of minerals.
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The many terms used by mineralogists to describe crystal habits are useful in communicating what specimens of a particular mineral often look like. Recognizing numerous habits helps a mineralogist to identify a large number of minerals.
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An amorphous solid is a solid in which there is no long-range order of the positions of the atoms. (Solids in which there is long-range atomic order are called crystalline solids or morphous). Most classes of solid materials can be found or prepared in an amorphous form.
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crystal defects. The various types of defects are enumerated here.
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Point defects
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A pharmaceutical company, or drug company, is a commercial business whose focus is to research, develop, market and/or distribute drugs, most commonly in the context of healthcare. They can deal in generic and/or brand medications.
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Agrichemical (or agrochemical), a contraction of agricultural chemical, is a generic term for the various chemical products used in agriculture.
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pigment is a material that changes the color of light it reflects as the result of selective color absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which the material itself emits light.
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dye can generally be described as a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and may require a mordant to improve the fastness of the dye on the fiber.
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Food is any substance, usually composed primarily of carbohydrates, fats, water and/or proteins, that can be eaten or drunk by an animal or human being for nutrition or pleasure.
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explosive material is a material that either is chemically or otherwise energetically unstable or produces a sudden expansion of the material usually accompanied by the production of heat and large changes in pressure (and typically also a flash and/or loud noise) upon initiation;
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In chemistry, conformational isomerism is a form of stereoisomerism involving the phenomenon of molecules with the same structural formula existing as different conformational isomers or conformers due to atoms rotating about a bond.
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Hydration may refer to:
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- Rehydration, the replenishment of water and electrolytes lost through dehydration
- The biological absorption of water by plant tissues, often resulting in a shape change.
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Solvation, commonly called dissolution, is the process of attraction and association of molecules of a solvent with molecules or ions of a solute. As ions dissolve in a solvent they spread out and become surrounded by solvent molecules.
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For the plant, see .
Glycine (abbreviated as Gly or G)[1] is the organic compound with the formula HO2CCH2NH2.
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monoclinic crystal system is one of the 7 lattice point groups. A crystal system is described by three vectors. In the monoclinic system, the crystal is described by vectors of unequal length, as in the orthorhombic system. They form a rectangular prism with a parallelogram as base.
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In geometry, a hexagon is a polygon with six edges and six vertices. A regular hexagon has Schläfli symbol .
The internal angles of a regular hexagon (one where all sides and all angles are equal) are all 120° and the hexagon has 720 degrees.
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Regular hexagon
The internal angles of a regular hexagon (one where all sides and all angles are equal) are all 120° and the hexagon has 720 degrees.
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An amorphous solid is a solid in which there is no long-range order of the positions of the atoms. (Solids in which there is long-range atomic order are called crystalline solids or morphous). Most classes of solid materials can be found or prepared in an amorphous form.
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In general, polymorphism describes multiple possible states for a single property (it is said to be polymorphic, or polymorphous).
Polymorphism may specifically refer to:
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Polymorphism may specifically refer to:
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Friedrich Wöhler
German chemist
Born July 31 1800
Eschersheim, Frankfurt am Main, Germany
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German chemist
Born July 31 1800
Eschersheim, Frankfurt am Main, Germany
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Justus von Liebig
Justus von Liebig-chemist
Born 12 May 1803
Darmstadt, Grand Duchy of Hesse
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Justus von Liebig-chemist
Born 12 May 1803
Darmstadt, Grand Duchy of Hesse
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Benzamide is an off-white solid with the chemical formula of C6H5CONH2. It is a derivative of benzoic acid. It is slightly soluble in water, and soluble in many organic solvents.
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Benzamides
Benzamides are a class of amides of benzoic acid...... Click the link for more information.
monoclinic crystal system is one of the 7 lattice point groups. A crystal system is described by three vectors. In the monoclinic system, the crystal is described by vectors of unequal length, as in the orthorhombic system. They form a rectangular prism with a parallelogram as base.
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The term centrosymmetric, as generally used in crystallography, refers to a space group which contains an inversion center as one of its symmetry elements. In such a space group, for every point (x, y, z) in the unit cell there is an indistinguishable point (-x, -y, -z).
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Stacking in supramolecular chemistry refers to a stacked arrangement of aromatic molecules, which interact through aromatic interactions. The most popular example of a stacked system is found for consecutive base pairs in DNA.
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monoclinic crystal system is one of the 7 lattice point groups. A crystal system is described by three vectors. In the monoclinic system, the crystal is described by vectors of unequal length, as in the orthorhombic system. They form a rectangular prism with a parallelogram as base.
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