The importance of chirality in API development - Veranova

Understanding Chirality
Most of the organic chiral molecules in the pharmaceutical industry contain an asymmetric carbon center, meaning they have a unique three-dimensional shape and are not completely identical to their mirror image.

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The human body is chirally selective, therefore it will interact with each component of a racemic drug differently and metabolize each enantiomer by a separate pathway. As such, the chirality of a molecule can influence key pharmacological activities, which impact a drug’s tolerability, safety, and bioavailability. As such, the control of enantiomeric purity and determination of individual enantiomeric drug molecules is a necessity, especially for clinical, analytical, and regulatory purposes.

Chirality in Drug Discovery & Development
In the early s, the FDA recommended using optically pure drugs, requiring that the drug labeling should include a unique, established name and a chemical name with the appropriate stereochemical descriptors to specify strength, quality, and purity from a stereochemical viewpoint.

Furthermore, regulatory authorities in Europe, China, and Japan also provided guidelines indicating that only the active enantiomer of a chiral drug should be brought to market.

Since then, for pharma companies, single enantiomer drugs have become the standard when working with compounds containing asymmetric centers.

Shortening timelines for chiral drug discovery and development usually depends on the efficiency of enantiomeric separation and asymmetric synthesis. Therefore, it’s become increasingly crucial for developers to partner with organizations that can offer a reliable, high-quality chiral resolution to streamline drug development while still meeting project timelines and budgets.

Increasing Chiral Purity
Chiral resolution is often focused on a molecule’s solid form state. This is because the properties unique to enantiomers tend to manifest themselves predominantly in the crystalline state and it can be difficult to obtain single enantiopure compounds through solution-phase chemistry.

For today’s developers, there is a variety of tools available for separation techniques such as chiral chromatography, enantioselective membrane separation, and spontaneous or preferential crystallization. But as small molecule drug candidates in the development pipeline become more complex, choosing the right tool is increasingly important to avoid scale-up hurdles and minimize the barriers that could disrupt the journey to market.

Classical Resolution
Classical resolution via the formation of diastereomeric salt pairs and precipitation of the least soluble salts is one of the most widely used methods to produce optically pure enantiomers. This approach harnesses the variation in solid state and solubility properties between diastereomeric salts, by seeding racemic mixtures with pure enantiomer or a chiral resolving agent during crystallization. When successful, this is the best method for the manufacturer of a single enantiomer at moderate costs and is particularly amenable to scale-up.

Figure 1: Diastereomeric Crystallization

Veranova’s Pharmorphix Solid Form and Particle Engineering team offer a classical resolution screening service to identify diastereomeric salts that are effective in the separation of racemic compounds into its two enantiomers. Initial screening experiments are performed in parallel, typically on a milligram scale to reduce material requirements and rapidly identify a suitable salt form.

The Pharmorphix team’s solid form experience is built on 2,000+ completed solid form projects across a range of structurally diverse and complex APIs. This provides us with a wide-ranging perspective of the development landscape, ensuring we’re able to quickly identify potential challenges and develop effective solutions.

In addition, to solubility differences, diastereomeric salts may exhibit different crystal morphology, thermal stability (melting point and melting enthalpy), processability, dissolution rate, hygroscopicity, and unequal tendency to crystallize. As such leveraging our history of excellence, Veranova is able to appreciate the need for thorough solid form characterization of the diastereomeric salts to provide a deeper understanding of the resolution process. This allows us to avoid the challenges caused by different polymorphic forms and/or solvates that can provide varying and conflicting resolution results.

Veranova’s capabilities for crystallization resolution

• Capability to develop custom chiral HPLC analytical methods
• Diverse selection of chiral acids and bases for resolution of racemic acids and bases, pre-selected for commercial availability
• Rapid screening and characterization of crystalline diastereomeric salts or cocrystals
• Comprehensive suite of complementary physicochemical techniques (e.g. DSC, TGA, XRPD, IR, RAMAN) for the characterization of physical properties of individual and combined crystalline forms
• Onsite single crystal X-ray diffraction (SXRD) service for structure determination and absolute stereochemical assignment including light atom only
• Optimization of crystallization procedure for scale-up using Process analytical technology (PAT) tools (in situ Raman or IR)
• Development of effective racemic synthetic processes
• Onsite kilo lab facilities for smooth process transfer
• Full-integrated capabilities for GMP manufacturing of clinical and commercial needs

An understanding of crystallization principles and techniques is an essential competence to develop an isolation process for enantiomerically pure material and underpins any commercial manufacturing processes.

Screening of chiral resolving agents
A non-rationalized approach to the screening of resolving agents can often result in poor recovery, low chiral purity, and inefficient, non-scalable crystallization protocols.

We aim to understand the crystallization process to optimize the separation conditions of the enantiomers.

• Development of suitable analytical methodologies such as chiral HPLC or GC if these are not available
• Screening of up to 70 chiral resolving agents which are available and appropriate for commercial-scale resolutions (with the option to screen in-house resolving agents)
• Screening performed in a broad range of solvents suited to forming diastereomeric salts
• Once crystalline solids are obtained, the diastereomeric excess (d.e.) is determined by chiral HPLC or GC.
• Solid state characterization of the crystalline solid.
• Determination of solubility points and assessment of efficiency of resolving agents

Resolution of neutral molecules
For small molecule compounds that lack an ionizable center, separation of racemic mixtures may be achieved by kinetic entrainment1 of conglomerates.

Crystallization of a conglomerate2 (racemic material composed of a 50:50 mixture of enantiomerically pure crystals) can give an efficient purification to provide the single enantiomer. For this, it is especially important to build up a full understanding of each particular system.

Figure 2: Crystal Forms of Racemic Mixtures

Using our industry-leading solid form understanding, Veranova can screen for conglomerates, having specific solid phase properties. Using phase diagrams constructed from thermal and solubility data, experiments are then designed to identify suitable entrainment through tightly controlled process parameters and specific crystal seeding methodology. A new technique known as Viedma ripening or attrition-enhanced deracemization has been developed in the last 10 years, this approach can also be employed to efficiently increase recovery of the desired enantiomer by utilizing grinding/milling technologies3, we have in-house wet milling capability to optimize such processes.

Cocrystal formation offers a new way of isolating chiral molecules; it is a variant of the classical chiral resolution but with chiral conformers. The molecule to resolve is forming enantiospecific interactions with a chiral former, allowing the precipitation of a solid cocrystal which is then isolated by filtration. The other enantiomer can be isolated from the mother liquor. The conformers are selected based on the potential intermolecular interactions they can form with the molecule to resolve. Single crystal data generated in-house can also help to design unique conformers which may be included in the cocrystal screen to maximize the chance of finding a suitable resolution system.

Recently, we have developed processes utilizing cocrystal technology to resolve racemic Praziquantel, the active ingredient of the antiparasitic drug, Biltricide. A simple process was developed after Dea Herrera-Ruiz4 in acetone to yield a cocrystal of L-malic acid/ Praziquantel in 98% de and 70% yield.

Figure 3: Structure of Praziquantel

Process Development and Kilo lab production
To develop a scalable process, crystallization development may be required to understand the process and kinetic activity, to avoid any problems upon scaling. Process analytical technology (PAT) and determination of points of the ternary phase diagram are employed to assess the process.

Figure 4: Phase diagram of L-malic acid/Praziquantel/acetone

Our onsite kilo lab can scale up and deliver material with full support from our crystallization team. In the last 15 years, we have developed chiral separation processes which have now been implemented for the production of commercial APIs.

Absolute Stereochemistry Determination
While developing an effective resolution or entrainment, determination of absolute stereochemistry can be achieved using single crystal X-ray diffraction. The state-of-the-art diffractometers at Pharmorphix allow structure elucidation with absolute stereochemical assignment of crystalline material, including light atom-only structures. These studies can be of critical importance in the support of regulatory submissions.

Supporting your success at every stage
Veranova has solutions to help you:

• Rapidly screen and identify single-enantiomer drug candidates for further testing.
• Support small-molecule drug discovery with stationary phases that isolate pure enantiomers effectively and efficiently.
• Protect your timeline by accelerating the selection of the optimal chiral column for your project.
• Improve analytical procedures with new methods that provide faster and more efficient analyses.
• Meet Pharmacopeia (USP/EP/JP/IP) and other industry quality standards for analytical methods.

1 P. Marchand, L. Lefebvre, G. Coquerel, Tetrahedron: Asymmetry 15 () -

2 J. Jacques, A. Collet, S. H. Wilen: Enantiomers, Racemates and Resolutions, Krieger Publishing Company Malabar, Florida,

3 W. L. Noorduin, P. van der Asdonk, A. A. C. Bode, H. Meekes, W. J. P. van Enckevort, E. Vlieg,,B. Kaptein, W. van der Meijden, R. M. Kellogg, and G. Deroover, Organic Process Research & Development , 14, 908–911

Geometric property of some molecules and ions "L-form" redirects here. For the bacterial strains, see L-form bacteria.

In chemistry, a molecule or ion is called chiral ( ) if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality ( ).[1][2][3][4] The terms are derived from Ancient Greek χείρ (cheir) 'hand'; which is the canonical example of an object with this property.

A chiral molecule or ion exists in two stereoisomers that are mirror images of each other,[5] called enantiomers; they are often distinguished as either "right-handed" or "left-handed" by their absolute configuration or some other criterion. The two enantiomers have the same chemical properties, except when reacting with other chiral compounds. They also have the same physical properties, except that they often have opposite optical activities. A homogeneous mixture of the two enantiomers in equal parts is said to be racemic, and it usually differs chemically and physically from the pure enantiomers.

Chiral molecules will usually have a stereogenic element from which chirality arises. The most common type of stereogenic element is a stereogenic center, or stereocenter. In the case of organic compounds, stereocenters most frequently take the form of a carbon atom with four distinct (different) groups attached to it in a tetrahedral geometry. Less commonly, other atoms like N, P, S, and Si can also serve as stereocenters, provided they have four distinct substituents (including lone pair electrons) attached to them.

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A given stereocenter has two possible configurations (R and S), which give rise to stereoisomers (diastereomers and enantiomers) in molecules with one or more stereocenter. For a chiral molecule with one or more stereocenter, the enantiomer corresponds to the stereoisomer in which every stereocenter has the opposite configuration. An organic compound with only one stereogenic carbon is always chiral. On the other hand, an organic compound with multiple stereogenic carbons is typically, but not always, chiral. In particular, if the stereocenters are configured in such a way that the molecule can take a conformation having a plane of symmetry or an inversion point, then the molecule is achiral and is known as a meso compound.

Molecules with chirality arising from one or more stereocenters are classified as possessing central chirality. There are two other types of stereogenic elements that can give rise to chirality, a stereogenic axis (axial chirality) and a stereogenic plane (planar chirality). Finally, the inherent curvature of a molecule can also give rise to chirality (inherent chirality). These types of chirality are far less common than central chirality. BINOL is a typical example of an axially chiral molecule, while trans-cyclooctene is a commonly cited example of a planar chiral molecule. Finally, helicene possesses helical chirality, which is one type of inherent chirality.

Chirality is an important concept for stereochemistry and biochemistry. Most substances relevant to biology are chiral, such as carbohydrates (sugars, starch, and cellulose), all but one of the amino acids that are the building blocks of proteins, and the nucleic acids. Naturally occurring triglycerides are often chiral, but not always. In living organisms, one typically finds only one of the two enantiomers of a chiral compound. For that reason, organisms that consume a chiral compound usually can metabolize only one of its enantiomers. For the same reason, the two enantiomers of a chiral pharmaceutical usually have vastly different potencies or effects.

Definition

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The chirality of a molecule is based on the molecular symmetry of its conformations. A conformation of a molecule is chiral if and only if it belongs to the Cn, Dn, T, O, or I point groups (the chiral point groups). However, whether the molecule itself is considered to be chiral depends on whether its chiral conformations are persistent isomers that could be isolated as separated enantiomers, at least in principle, or the enantiomeric conformers rapidly interconvert at a given temperature and timescale through low-energy conformational changes (rendering the molecule achiral). For example, despite having chiral gauche conformers that belong to the C2 point group, butane is considered achiral at room temperature because rotation about the central C–C bond rapidly interconverts the enantiomers (3.4 kcal/mol barrier). Similarly, cis-1,2-dichlorocyclohexane consists of chair conformers that are nonidentical mirror images, but the two can interconvert via the cyclohexane chair flip (~10 kcal/mol barrier). As another example, amines with three distinct substituents (R1R2R3N:) are also regarded as achiral molecules because their enantiomeric pyramidal conformers rapidly undergo pyramidal inversion.

However, if the temperature in question is low enough, the process that interconverts the enantiomeric chiral conformations becomes slow compared to a given timescale. The molecule would then be considered to be chiral at that temperature. The relevant timescale is, to some degree, arbitrarily defined: seconds is sometimes employed, as this is regarded as the lower limit for the amount of time required for chemical or chromatographic separation of enantiomers in a practical sense. Molecules that are chiral at room temperature due to restricted rotation about a single bond (barrier to rotation ≥ ca. 23 kcal/mol) are said to exhibit atropisomerism.

A chiral compound can contain no improper axis of rotation (Sn), which includes planes of symmetry and inversion center. Chiral molecules are always dissymmetric (lacking Sn) but not always asymmetric (lacking all symmetry elements except the trivial identity). Asymmetric molecules are always chiral.[6]

The following table shows some examples of chiral and achiral molecules, with the Schoenflies notation of the point group of the molecule. In the achiral molecules, X and Y (with no subscript) represent achiral groups, whereas XR and XS or YR and YS represent enantiomers. Note that there is no meaning to the orientation of an S2 axis, which is just an inversion. Any orientation will do, so long as it passes through the center of inversion. Also note that higher symmetries of chiral and achiral molecules also exist, and symmetries that do not include those in the table, such as the chiral C3 or the achiral S4.

Molecular symmetry and chirality Rotational
axis (Cn) Improper rotational elements (Sn) Chiral
no Sn Achiral
mirror plane
S1 = σ Achiral
inversion center
S2 = i C1
C1
Cs
Ci C2
C2
(Note: This molecule has only one C2 axis:
perpendicular to line of three C, but not in the plane of the figure.)
C2v
C2h
Note: This also has a mirror plane.

An example of a molecule that does not have a mirror plane or an inversion and yet would be considered achiral is 1,1-difluoro-2,2-dichlorocyclohexane (or 1,1-difluoro-3,3-dichlorocyclohexane). This may exist in many conformers (conformational isomers), but none of them has a mirror plane. In order to have a mirror plane, the cyclohexane ring would have to be flat, widening the bond angles and giving the conformation a very high energy. This compound would not be considered chiral because the chiral conformers interconvert easily.

An achiral molecule having chiral conformations could theoretically form a mixture of right-handed and left-handed crystals, as often happens with racemic mixtures of chiral molecules (see Chiral resolution#Spontaneous resolution and related specialized techniques), or as when achiral liquid silicon dioxide is cooled to the point of becoming chiral quartz.

Stereogenic centers

[edit] Main article: Stereogenic center

A stereogenic center (or stereocenter) is an atom such that swapping the positions of two ligands (connected groups) on that atom results in a molecule that is stereoisomeric to the original. For example, a common case is a tetrahedral carbon bonded to four distinct groups a, b, c, and d (Cabcd), where swapping any two groups (e.g., Cbacd) leads to a stereoisomer of the original, so the central C is a stereocenter. Many chiral molecules have point chirality, namely a single chiral stereogenic center that coincides with an atom. This stereogenic center usually has four or more bonds to different groups, and may be carbon (as in many biological molecules), phosphorus (as in many organophosphates), silicon, or a metal (as in many chiral coordination compounds). However, a stereogenic center can also be a trivalent atom whose bonds are not in the same plane, such as phosphorus in P-chiral phosphines (PRR′R″) and sulfur in S-chiral sulfoxides (OSRR′), because a lone-pair of electrons is present instead of a fourth bond.

Similarly, a stereogenic axis (or plane) is defined as an axis (or plane) in the molecule such that the swapping of any two ligands attached to the axis (or plane) gives rise to a stereoisomer. For instance, the C2-symmetric species 1,1′-bi-2-naphthol (BINOL) and 1,3-dichloroallene have stereogenic axes and exhibit axial chirality, while (E)-cyclooctene and many ferrocene derivatives bearing two or more substituents have stereogenic planes and exhibit planar chirality.

Chirality can also arise from isotopic differences between atoms, such as in the deuterated benzyl alcohol PhCHDOH; which is chiral and optically active ([α]D = 0.715°), even though the non-deuterated compound PhCH2OH is not.[7]

If two enantiomers easily interconvert, the pure enantiomers may be practically impossible to separate, and only the racemic mixture is observable. This is the case, for example, of most amines with three different substituents (NRR′R″), because of the low energy barrier for nitrogen inversion.

When the optical rotation for an enantiomer is too low for practical measurement, the species is said to exhibit cryptochirality.

Chirality is an intrinsic part of the identity of a molecule, so the systematic name includes details of the absolute configuration (R/S, D/L, or other designations).

Manifestations of chirality

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• Flavor: the artificial sweetener aspartame has two enantiomers. L-aspartame tastes sweet whereas D-aspartame is tasteless.[8]
• Odor: R-(–)-carvone smells like spearmint whereas S-(+)-carvone smells like caraway.[9]
• Drug effectiveness: the antidepressant drug citalopram is sold as a racemic mixture. However, studies have shown that only the (S)-(+) enantiomer (escitalopram) is responsible for the drug's beneficial effects.[10][11]
• Drug safety: D‑penicillamine is used in chelation therapy and for the treatment of rheumatoid arthritis whereas L‑penicillamine is toxic as it inhibits the action of pyridoxine, an essential B vitamin.[12]

In biochemistry

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Many biologically active molecules are chiral, including the naturally occurring amino acids (the building blocks of proteins) and sugars.

The origin of this homochirality in biology is the subject of much debate.[13] Most scientists believe that Earth life's "choice" of chirality was purely random, and that if carbon-based life forms exist elsewhere in the universe, their chemistry could theoretically have opposite chirality. However, there is some suggestion that early amino acids could have formed in comet dust. In this case, circularly polarised radiation (which makes up 17% of stellar radiation) could have caused the selective destruction of one chirality of amino acids, leading to a selection bias which ultimately resulted in all life on Earth being homochiral.[14][15]

Enzymes, which are chiral, often distinguish between the two enantiomers of a chiral substrate. One could imagine an enzyme as having a glove-like cavity that binds a substrate. If this glove is right-handed, then one enantiomer will fit inside and be bound, whereas the other enantiomer will have a poor fit and is unlikely to bind.

L-forms of amino acids tend to be tasteless, whereas D-forms tend to taste sweet.[13] Spearmint leaves contain the L-enantiomer of the chemical carvone or R-(−)-carvone and caraway seeds contain the D-enantiomer or S-(+)-carvone.[9] The two smell different to most people because our olfactory receptors are chiral.

Chirality is important in context of ordered phases as well, for example the addition of a small amount of an optically active molecule to a nematic phase (a phase that has long range orientational order of molecules) transforms that phase to a chiral nematic phase (or cholesteric phase). Chirality in context of such phases in polymeric fluids has also been studied in this context.[16]

In inorganic chemistry

[edit] Main article: Complex (chemistry): Isomerism

Chirality is a symmetry property, not a property of any part of the periodic table. Thus many inorganic materials, molecules, and ions are chiral. Quartz is an example from the mineral kingdom. Such noncentric materials are of interest for applications in nonlinear optics.

In the areas of coordination chemistry and organometallic chemistry, chirality is pervasive and of practical importance. A famous example is tris(bipyridine)ruthenium(II) complex in which the three bipyridine ligands adopt a chiral propeller-like arrangement.[17] The two enantiomers of complexes such as [Ru(2,2′-bipyridine)3]2+ may be designated as Λ (capital lambda, the Greek version of "L") for a left-handed twist of the propeller described by the ligands, and Δ (capital delta, Greek "D") for a right-handed twist (pictured). dextro- and levo-rotation (the clockwise and counterclockwise optical rotation of plane-polarized light) uses similar notation, but shouldn't be confused.

Chiral ligands confer chirality to a metal complex, as illustrated by metal-amino acid complexes. If the metal exhibits catalytic properties, its combination with a chiral ligand is the basis of asymmetric catalysis.[18]

Methods and practices

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The term optical activity is derived from the interaction of chiral materials with polarized light. In a solution, the (−)-form, or levorotatory form, of an optical isomer rotates the plane of a beam of linearly polarized light counterclockwise. The (+)-form, or dextrorotatory form, of an optical isomer does the opposite. The rotation of light is measured using a polarimeter and is expressed as the optical rotation.

Enantiomers can be separated by chiral resolution. This often involves forming crystals of a salt composed of one of the enantiomers and an acid or base from the so-called chiral pool of naturally occurring chiral compounds, such as malic acid or the amine brucine. Some racemic mixtures spontaneously crystallize into right-handed and left-handed crystals that can be separated by hand. Louis Pasteur used this method to separate left-handed and right-handed sodium ammonium tartrate crystals in . Sometimes it is possible to seed a racemic solution with a right-handed and a left-handed crystal so that each will grow into a large crystal.

Liquid chromatography (HPLC and TLC) may also be used as an analytical method for the direct separation of enantiomers and the control of enantiomeric purity, e.g. active pharmaceutical ingredients (APIs) which are chiral.[19][20]

Miscellaneous nomenclature

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• Any non-racemic chiral substance is called scalemic. Scalemic materials can be enantiopure or enantioenriched.[21]
• A chiral substance is enantiopure when only one of two possible enantiomers is present so that all molecules within a sample have the same chirality sense. Use of homochiral as a synonym is strongly discouraged.[22]
• A chiral substance is enantioenriched or heterochiral when its enantiomeric ratio is greater than 50:50 but less than 100:0.[23]
• Enantiomeric excess or e.e. is the difference between how much of one enantiomer is present compared to the other. For example, a sample with 40% e.e. of R contains 70% R and 30% S (70% − 30% = 40%).[24]

History

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The rotation of plane polarized light by chiral substances was first observed by Jean-Baptiste Biot in ,[25] and gained considerable importance in the sugar industry, analytical chemistry, and pharmaceuticals. Louis Pasteur deduced in that this phenomenon has a molecular basis.[26][27] The term chirality itself was coined by Lord Kelvin in .[28] Different enantiomers or diastereomers of a compound were formerly called optical isomers due to their different optical properties.[29] At one time, chirality was thought to be restricted to organic chemistry, but this misconception was overthrown by the resolution of a purely inorganic compound, a cobalt complex called hexol, by Alfred Werner in .[30]

In the early s, various groups established that the human olfactory organ is capable of distinguishing chiral compounds.[9][31][32]

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See also

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• Chirality (electromagnetism)
• Chirality (mathematics)
• Chirality (physics)
• Enantiopure drug
• Enantioselective synthesis
• Handedness
• Orientation (vector space)
• Pfeiffer effect
• Stereochemistry for overview of stereochemistry in general
• Stereoisomerism
• Supramolecular chirality

References

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Further reading

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• Clayden, Jonathan; Greeves, Nick; Warren, Stuart (). Organic Chemistry (2nd ed.). Oxford, UK: Oxford University Press. pp. 319f, 432, 604np, 653, 746int, 803ketals, 839, 846f. ISBN 978- .
• Eliel, Ernest Ludwig; Wilen, Samuel H.; Mander, Lewis N. (). "Chirality in Molecules Devoid of Chiral Centers (Chapter 14)". Stereochemistry of Organic Compounds. Vol. 9 (1st ed.). New York, NY, USA: Wiley & Sons. pp. 428–430. doi:10./(SICI)-636X()9:5/6<428::AID-CHIR5>3.0.CO;2-1. ISBN 978- .
• Eliel, E.L. (). "Infelicitous Stereochemical Nomenclatures". Chirality. 9 (5–6): 428–430. doi:10./(SICI)-636X()9:5/6<428::AID-CHIR5>3.0.CO;2-1. Archived from the original on 3 March .
• Gal, Joseph (). "Molecular Chirality: Language, History, and Significance". Chirality. Topics in Current Chemistry. 340: 1–20. doi:10./128__435. ISBN 978-3-319--2. PMID .