word chiral

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Introduction:

Chiral chromatography has recently become a

preferred method for rapidly separation of enantiopure

compounds in the pharmaceutical industry. Chiral

chromatographic enantioseparation has been practiced

for a decade by researchers.

Isomers: Compounds with the different chemical

structures and the same molecular formula

Stereoisomers: compounds made up of the same

atoms but have different arrangement of atoms in

space

Enantiomers are the 2 mirror image forms of a chiral

molecule can contain any number of chiral centers, as

long as each center is the exact mirror image of the

corresponding center in the other molecule

Identical physical and chemical properties, but may

have different biological profiles. Need chiral

recognition to be separated.

Different optical rotations (One enantiomer is (+) or

dextrorotatory (clockwise), while the other is (-) or

levorotatory (counter clockwise))

Racemate: a 1:1 mixture of enantiomers.

Separation of enantiomers occurs when mixture is

reacted with a chiral stationary phase to form 2

diastereomeric complexes that can be separated by

chromatographic techniques

Diastereomers: stereoisomers that are not enantiomers

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Have different chemical and physical characteristics,

and can be separated by non-chiral methods.Has at least 2 chiral centers; the number of potential

diastereomers for each chiral center is determined by

the equation 2n, where n=the number of chiral centers

Determination of Optical Activity

Each enantiomer has an equal but opposite optical

rotation; can be measured using optical rotation

polarimeter

One enantiomer rotates polarized light in a clockwise

direction and is then designed as (+), or dextrorotatory

The other enantiomer rotates polarized light incounter-clockwise direction and is the (-) enantiomer,

or levorotatory

Racemates (1:1 mixture of enantiomers) have no

observable optical rotation; they cancel each other out

where = observed rotation, l = cell length in dm,

c = concentration in g/mL, and D is the 589nm light

from a sodium lamp

WHY DO WE NEED CHIRAL SEPARATIONS.:

RACEMATE Vs SINGLE ENANTIOMER

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Single enantiomers of chiral active pharmaceutical

ingredients (APIs) may have different:Pharmacokinetic properties in animal models

Absorption, distribution, metabolism and

excretion

Pharmacological or toxicological effects

Biologically active isomer may have desirable

effects

Biologically inactive isomer may have undesirableside effects (increased toxicity)

Increased pressure by regulatory authorities to switch

from racemic to single enantiomer.

Development of chiral APIs raises issues regarding:

Acceptable manufacturing control of synthesis and

impurities Pharmacological and toxicological assessment of

both enantiomers

Proper assessment of metabolism and distribution

Proper clinical evaluation of these drugs.

Examples:

Albuterol (anti-asthmatic inhalant)

D-albuterol may actually cause airway

constriction

Levalbuterol (L-albuterol) avoids side effects

Allegra (allergy medication)

Single enantiomer of Seldane that avoids life-

threatening heart disorders of Seldane

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Fluoxetine (generic name for Prozac, depression

medication) R-Fluoxetine improved efficacy; minimizes

side effects, i.e. anxiety and sexual

dysfunction. Other indications (eating

disorders)

S-Fluoxetine use for treatment of migraines

Approaches to Pure Enantiomers:

Chiral synthetic approach

Steroselective or asymmetric synthesis

Biotransformation or enzymatic resolution

Catalytic enantioselective processes

Racemic approach

Crystallization Chiral salt resolution

CE(capillary electrophoresis)

SMB(simulated moving bed technology)

Chromatography

Chiral Chromatography.

Chiral Recognition: Ability of chiral stationary

phase, CSP, to interact differently with each

enantiomer to form transient-diastereomeric

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complexes; requires a minimum of 3 interactions

through: H-bonding

- interactions

Dipole stacking

Inclusion complexing

Steric bulk

Five general types of CSPs used inchromatography:

1. Polymer-based carbohydrates

2. Pirkle or brush-type phases

3.Cyclodextrins

4.Chirobiotic phases

5.Protein-based

Classification of Chiral Stationary Phases (CSP):1) Polymer-based Carbohydrates

Chiral polysaccharide derivatives, i.e. amylose

and cellulose, coated on a silica support

Enantiomers form H-bonds with carbamate links

between side chains and polysaccharide

backbone

Steric restrictions at polysaccharide backbone

may prevent access of one of enantiomers to H-

bonding site

Can be used with normal phase HPLC, SFC, RP-

HPLC

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Limitations : Not compatible with a wide range

of solvents other than alcohols Available columns:

i.e. Chiralpak AD, AD-RH, AS, AS-RH, and

Chiralcel OD, OD-RH, OJ, OJ-RH, etc. from Chiral

Technologies, Inc.

Chiralpak IA and IBsame chiral selectors as

AD and OD, respectively, but these are immobilized on

the silica; more robust and has much greater solventcompatibilities

2.Pirkle or Brush-type Phases: (Donor-Acceptor)

Small chiral molecules bonded to silica

More specific applications; strong 3-point

interactions through 3 classes:

-donor phases

-acceptor phases Mixed donor-acceptor phases

Binding sites are -basic or -acidic aromatic

rings (- interactions), acidic and basic sites

(H-bonding), and steric interaction

Separation occurs through preferential binding

of one enantiomer to CSP

Mostly used with normal phase HPLC, SFC.May get less resolution with RP-HPLC;

compatible with a broad range of solvents

L imitations : only works with aromatic

compounds .

.Available columns:

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Whelk-O 1, Whelk-O 2, ULMO, DACH-DNB (mixed

phases), - Burke 2, -Gem 1 (-acceptor phases),

Naphthylleucine (-donor phases), from Regis

Technologies, Inc.

Phenomenex Chirex phases

3.Cyclodextrin CSPs Alpha, beta and gamma-cyclodextrins bond to

silica and form chiral cavities

3-point interactions by:

Opening of cyclodextrin cavity contains

hydroxyls for H-bonding with polar groups

of analyte

Hydrophobic portion of analyte fits into

non-polar cavity (inclusion complexes)

One enantiomer will be able to better fit in the

cavity than the other

Used in RP-HPLC and polar organic mode

Limitations : analyte must have hydrophobic

or aromatic group to fit into cavity

Available columns:

Cyclobond ( -, -, and -cyclodextrins) from

Astec, Inc. ORpak CDA ( ), ORpak CDB ( ), ORpak CDC

( ) from JM Sciences .

4) Chirobiotic Phases

Macrocyclic glycopeptides linked to silica

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Contain a large number of chiral centers

together with cavities for analytes to enterand interact

Potential interactions:

- complexes, H-bonding, ionic

interactions

Inclusion complexation, steric interactions

Capable of running in RP-HPLC, normal phase,

polar organic, and polar ionic modes Available columns:

Chirobiotic V and V2 (Vancomycin), Chirobiotic

T and T2 (Teicoplanin), Chirobiotic R

(Ristocetin A) from Astec

5.Protein-based CSPs :

Natural proteins bonded to a silica matrix

Proteins contain large numbers of chiralcenters and interact strongly with small chiral

analytes through:

Hydrophobic and electrostatic interactions, H-

bonding

Limitations :

Requires aqueous based conditions in RP-

HPLC Analyte must have ionizable groups such as

amine or acid.

Not suited for preparative applications due to

low sample capacity

Available columns:

Chiral AGP ( -glycoprotein) from ChromTech

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HSA (human serum albumin) from ChromTech

BSA (bovine serum albumin) from RegisTechnologies

Selecting a CSP

General use column with no solubility issues

Polymer-based phases

Specific applications; solubility issuesPirkle-type

Chirobiotic phases

SFC only

Polymer-based, Pirkle-type, Chirobiotic

Biological Samples

Protein-based phases

Suggested applications of CSP:

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