Polymorphism (materials science)
Polymorphism in materials science
Materials science
Materials science is an interdisciplinary field applying the properties of matter to various areas of science and engineering. This scientific field investigates the relationship between the structure of materials at atomic or molecular scales and their macroscopic properties. It incorporates...

 is the ability of a solid material to exist in more than one form or crystal
A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions. The scientific study of crystals and crystal formation is known as crystallography...

 structure. Polymorphism can potentially be found in any crystalline material including polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...

s, mineral
A mineral is a naturally occurring solid chemical substance formed through biogeochemical processes, having characteristic chemical composition, highly ordered atomic structure, and specific physical properties. By comparison, a rock is an aggregate of minerals and/or mineraloids and does not...

s, and metal
A metal , is an element, compound, or alloy that is a good conductor of both electricity and heat. Metals are usually malleable and shiny, that is they reflect most of incident light...

s, and is related to allotropy
Allotropy or allotropism is the property of some chemical elements to exist in two or more different forms, known as allotropes of these elements...

, which refers to chemical elements. The complete morphology of a material is described by polymorphism and other variables such as crystal habit
Crystal habit
Crystal habit is an overall description of the visible external shape of a mineral. This description can apply to an individual crystal or an assembly of crystals or aggregates....

, amorphous fraction
Amorphous solid
In condensed matter physics, an amorphous or non-crystalline solid is a solid that lacks the long-range order characteristic of a crystal....

 or crystallographic defect
Crystallographic defect
Crystalline solids exhibit a periodic crystal structure. The positions of atoms or molecules occur on repeating fixed distances, determined by the unit cell parameters. However, the arrangement of atom or molecules in most crystalline materials is not perfect...

s. Polymorphism is relevant to the fields of pharmaceuticals, agrochemicals, pigment
A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...

s, dyestuffs, food
Food is any substance consumed to provide nutritional support for the body. It is usually of plant or animal origin, and contains essential nutrients, such as carbohydrates, fats, proteins, vitamins, or minerals...

s, 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
Mineral hydration
Mineral hydration is an inorganic chemical reaction where water is added to the crystal structure of a mineral, usually creating a new mineral, usually called a hydrate....

 or solvation
Solvation, also sometimes called dissolution, is the process of attraction and association of molecules of a solvent with molecules or ions of a solute...

. An example of an organic polymorph is glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

, which is able to form monoclinic and hexagonal crystals. Silica is known to form many polymorphs, the most important of which are; α-quartz
Quartz is the second-most-abundant mineral in the Earth's continental crust, after feldspar. It is made up of a continuous framework of SiO4 silicon–oxygen tetrahedra, with each oxygen being shared between two tetrahedra, giving an overall formula SiO2. There are many different varieties of quartz,...

, β-quartz
Quartz is the second-most-abundant mineral in the Earth's continental crust, after feldspar. It is made up of a continuous framework of SiO4 silicon–oxygen tetrahedra, with each oxygen being shared between two tetrahedra, giving an overall formula SiO2. There are many different varieties of quartz,...

, tridymite
Tridymite is a high-temperature polymorph of quartz and usually occurs as minute tabular white or colorless pseudo-hexagonal triclinic crystals, or scales, in cavities in acidic volcanic rocks. Its chemical formula is SiO2. Tridymite was first described in 1868 and the type location is in Hidalgo,...

, cristobalite
The mineral cristobalite is a high-temperature polymorph of silica, meaning that it has the same chemical formula, SiO2, but a distinct crystal structure. Both quartz and cristobalite are polymorphs with all the members of the quartz group which also include coesite, tridymite and stishovite...

, coesite
Coesite[p] is a form of silicon dioxide SiO2 that is formed when very high pressure , and moderately high temperature , are applied to quartz. Coesite was first synthesized by Loring Coes, Jr., a chemist at the Norton Company, in 1953. In 1960, coesite was found by Edward C. T...

, and stishovite
Stishovite is an extremely hard, dense tetragonal form of silicon dioxide. It was long considered the hardest known oxide; however, boron suboxide has recently been discovered to be much harder...


An analogous phenomenon for amorphous materials is polyamorphism
Polyamorphism is the ability of a substance to exist in several different amorphous modifications. It is analogous to the polymorphism of crystalline materials. Many amorphous substances can exist with different amorphous characteristics . However, polyamorphism requires two distinct amorphous...

, when a substance can take on several different amorphous modifications.


In terms of thermodynamics
Thermodynamics is a physical science that studies the effects on material bodies, and on radiation in regions of space, of transfer of heat and of work done on or by the bodies or radiation...

, 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 polymorphism in organic materials is attributed to Friedrich Wöhler
Friedrich Wöhler
Friedrich Wöhler was a German chemist, best known for his synthesis of urea, but also the first to isolate several chemical elements.-Biography:He was born in Eschersheim, which belonged to aau...

 and Justus von Liebig
Justus von Liebig
Justus von Liebig was a German chemist who made major contributions to agricultural and biological chemistry, and worked on the organization of organic chemistry. As a professor, he devised the modern laboratory-oriented teaching method, and for such innovations, he is regarded as one of the...

 when in 1832 they examined a boiling solution of benzamide
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.- External links :* *...

: on cooling the benzamide initially crystallised as silky needles but on standing these were slowly replaced by rhombic crystals. Present-day analysis identifies three polymorphs for benzamide: the least stable one, formed by flash cooling is the orthorhombic form II. This type is followed by the monoclinic form III (observed by Wöhler/Liebig). The most stable form is monoclinic form I. The hydrogen bonding motif is the same for all three phases, however they differ strongly in their pi-pi interactions.


Polymorphs have different stabilities and may spontaneously convert from a metastable form (unstable form) to the stable
A stable is a building in which livestock, especially horses, are kept. It most commonly means a building that is divided into separate stalls for individual animals...

 form at a particular temperature. They also exhibit different melting points, solubilities (which affect the dissolution rate of drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

 and consequently its bioavailability in the body), X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...

 crystal and diffraction
Diffraction refers to various phenomena which occur when a wave encounters an obstacle. Italian scientist Francesco Maria Grimaldi coined the word "diffraction" and was the first to record accurate observations of the phenomenon in 1665...


Various conditions in the crystallisation process is the main reason responsible for the development of different polymorphic forms. These conditions include:
  • solvent
    A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...

     effects (the packing of crystal may be different in polar and nonpolar solvents)
  • certain impurities inhibiting growth pattern and favour the growth of a metastable polymorphs
  • the level of supersaturation from which material is crystallised (in which generally the higher the concentration above the solubility
    Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...

    , the more likelihood of metastable formation)
  • temperature
    Temperature is a physical property of matter that quantitatively expresses the common notions of hot and cold. Objects of low temperature are cold, while various degrees of higher temperatures are referred to as warm or hot...

     at which crystallisation is carried out
  • geometry of covalent bonds (differences leading to conformational polymorphism)
  • change in stirring conditions

Despite the potential implications, polymorphism is not always well understood. In 2006 a new crystal form was discovered of maleic acid
Maleic acid
Maleic acid is an organic compound that is a dicarboxylic acid, a molecule with two carboxyl groups. Maleic acid is the cis-isomer of butenedioic acid, whereas fumaric acid is the trans-isomer...

 124 years after the first crystal form was studied. 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 co-crystal of caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...

 and maleic acid (2:1) is dissolved in chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...

 and when the solvent is allowed to evaporate slowly. Whereas form I has monoclinic space group
Space group
In mathematics and geometry, a space group is a symmetry group, usually for three dimensions, that divides space into discrete repeatable domains.In three dimensions, there are 219 unique types, or counted as 230 if chiral copies are considered distinct...

 P21/c, the new form has space group Pc. Both polymorphs consist of sheets of molecules connected through hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...

ing of the carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...

 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 a nitrated benzene-derivative that is classified as a high explosive, being moderately explosive in liquid form and extremely explosive in its dry powder form. It has a clear to light yellow sludgy appearance. It will detonate under strong shock...

 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 crystallised in the presence of an additive, trisindane. This experiment shows that additives can induce the appearance of polymorphic forms.

Ostwald's rule

Ostwald's rule or Ostwald's step rule,
conceived by Wilhelm Ostwald
Wilhelm Ostwald
Friedrich Wilhelm Ostwald was a Baltic German chemist. He received the Nobel Prize in Chemistry in 1909 for his work on catalysis, chemical equilibria and reaction velocities...

, states that in general it is not the most stable but the least stable polymorph that crystallises first. See for examples the aforementioned benzamide, dolomite
Dolomite is a carbonate mineral composed of calcium magnesium carbonate CaMg2. The term is also used to describe the sedimentary carbonate rock dolostone....

 or phosphorus
Phosphorus is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus as a mineral is almost always present in its maximally oxidized state, as inorganic phosphate rocks...

, which on sublimation first forms the less stable white and then the more stable red allotrope.

Ostwald suggested that the solid first formed on crystallisation of a solution or a melt would be the least stable polymorph. This can be explained on the basis of irreversible thermodynamics, structural relationships, or a combined consideration of statistical thermodynamics and structural variation with temperature. Ostwald's rule is not a universal law but is only a possible tendency in nature.

Polymorphism in pharmaceuticals

Polymorphism is important in the development of pharmaceutical ingredients
Active ingredient
An active ingredient is the substance of a pharmaceutical drug or a pharmaceutical ingredient and bulk active in medicine; in pesticide formulations active substance may be used. Some medications and pesticide products may contain more than one active ingredient...

. Many drugs
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 receive regulatory approval
Regulation is administrative legislation that constitutes or constrains rights and allocates responsibilities. It can be distinguished from primary legislation on the one hand and judge-made law on the other...

 for only a single crystal form or polymorph. In a classic patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....

 case the pharmaceutical company GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...

 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
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....

 is often administered orally as a crystalline solid and dissolution
Solvation, also sometimes called dissolution, is the process of attraction and association of molecules of a solvent with molecules or ions of a solute...

 rates depend on the exact crystal form of a polymorph.

Cefdinir is a semi-synthetic, broad-spectrum antibiotic in the third generation of the cephalosporin class, proven effective for common bacterial infections of the ear, sinus, throat, and skin. It was approved by the U.S...

 is a drug appearing in 11 patents from 5 pharmaceutical companies in which a total of 5 different polymorphs are described. The original inventor Fujisawa now Astellas (with US partner Abbott
Abbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....

) extended the original patent covering a suspension
Suspension (chemistry)
In chemistry, a suspension is a heterogeneous fluid containing solid particles that are sufficiently large for sedimentation. Usually they must be larger than 1 micrometer. The internal phase is dispersed throughout the external phase through mechanical agitation, with the use of certain...

 with a new anhydrous
As a general term, a substance is said to be anhydrous if it contains no water. The way of achieving the anhydrous form differs from one substance to another...

 formulation. Competitors in turn patented hydrate
Hydrate is a term used in inorganic chemistry and organic chemistry to indicate that a substance contains water. The chemical state of the water varies widely between hydrates, some of which were so labeled before their chemical structure was understood....

s of the drug with varying water content, which were described with only basic techniques such as infrared spectroscopy
Infrared spectroscopy
Infrared spectroscopy is the spectroscopy that deals with the infrared region of the electromagnetic spectrum, that is light with a longer wavelength and lower frequency than visible light. It covers a range of techniques, mostly based on absorption spectroscopy. As with all spectroscopic...

 and XRPD, a practice criticised by in one review because these techniques at the most suggest a different crystal structure but are unable to specify one however, given the recent advances in XRPD, it is perfectly feasible to obtain the structure of a polymorph of a drug, even if there is no single crystal available for that polymorphic form. These techniques also tend to overlook chemical impurities or even co-components. Abbott researchers realised 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
Pyridinium refers to the cationic form of pyridine. This can either be due to protonation of the ring nitrogen or because of addition of a substituent to the ring nitrogen, typically via alkylation. The lone pair of electrons on the nitrogen atom of pyridine is not delocalized, and thus pyridine...

 salt. The review also questioned whether the polymorphs offered any advantages to the existing drug: something clearly demanded in a new patent.

Acetylsalicylic acid has an elusive 2nd polymorph that was first discovered by Vishweshwar et al., fine structural details were given by Bond et al. A new crystal type was found after attempted co-crystallization of aspirin and levetiracetam from hot acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...

. The form II is stable only at 100 K
The kelvin is a unit of measurement for temperature. It is one of the seven base units in the International System of Units and is assigned the unit symbol K. The Kelvin scale is an absolute, thermodynamic temperature scale using as its null point absolute zero, the temperature at which all...

 and reverts to form I at ambient temperature. In the (unambiguous) form I, two salicylic molecules form centrosymmetric dimers through the acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

 groups with the (acidic) methyl proton to carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....

 hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...

s, and, in the newly-claimed form II, each salicylic molecule forms the same hydrogen bonds, but then with two neighbouring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...

 groups, both polymorphs form identical dimer structures.
  • Paracetamol powder has poor compression properties: this poses difficulty in making tablets, so a new polymorph of paracetamol
    Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

     is discovered which is more compressible.

  • Due to differences in solubility of polymorphs, one polymorph may be more active therapeutically than another polymorph of same drug

  • Cortisone acetate exists in at least five different polymorphs, four of which are unstable in water and change to a stable form.

  • Carbamazepine
    Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...

     (used in epilepsy and trigeminal neuralgia) beta-polymorph developed from solvent of high dielectric constant
    Dielectric constant
    The relative permittivity of a material under given conditions reflects the extent to which it concentrates electrostatic lines of flux. In technical terms, it is the ratio of the amount of electrical energy stored in a material by an applied voltage, relative to that stored in a vacuum...

     ex aliphatic alcohol
    In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

    , whereas alpha polymorph crystallized from solvents of low dielectric constant such as carbon tetrachloride

  • Estrogen and chloroamphenicol also show polymorphism

Interesting occurrences of polymorphs

Walter McCrone
Walter McCrone
Walter Cox McCrone was an American chemist who was considered a leading expert in microscopy. To the general public, however, he was best known for his work on the Shroud of Turin, the Vinland map, and Forensic science.-Biography:...

 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. Also, they find that they can make the first form again, but it now converts to the second form over time. The drug paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...

 was subject to a lawsuit that hinged on such a pair of polymorphs. 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.

External links

  • "Small Molecule Crystallization" (PDF) at Illinois Institute of Technology
    Illinois Institute of Technology
    Illinois Institute of Technology, commonly called Illinois Tech or IIT, is a private Ph.D.-granting university located in Chicago, Illinois, with programs in engineering, science, psychology, architecture, business, communications, industrial technology, information technology, design, and law...

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