RESOLUTION OF RACEMIC MIXTURE AND ROLE OF STEREOCHEMISTRY IN PHARMACOKINETICS AND PHARMACODYNAMICS

The optical isomers are called enantiomers These are distinguished by 1)+/- 2)D/L 3)R/S

A 50/50 mixture of the two enantiomers is called a racemic mixture or a racemate. Enantiomers have identical chemical and physical properties, except:Their effect on plane polarised light.

A B C D E F A Light source produces light vibrating in all directions B Polarising filter only allows light vibrating in one direction C Plane polarised light passes through sample D If substance is optically active it rotates the plane polarised light E Analysing filter is used so light reaches a maximum F Direction of rotation is measured coming towards the observer If the light appears to have turned to the right turned to the left DEXTROROTATORY LAEVOROTATORY

Optical isomers rotate the plane of plane polarised light.

RESOLUTION OF RACEMIC MIXTURES: RACEMISATION: racemisation is the formation of racemic modification(mixture). RACEMIC MODIFICATION:equimolar mixture of pair of enantiomers is called as racemic modification. RESOLUTION:the process of seperation of pure enantiomer from their racemic modification is called resolution.

NEED FOR RESOLUTION OF RACEMIC MIXTURE: CETRIZINE  levocetirizine has been found to be less sedating than cetirizine.

FIG:Levodopa levodopa (L-dopa) is used in treatment of Parkinson’s disease, its D-form causes serious side effects,such as granulocytopenia.

THALIDOMIDE (R)-Thalidomide (S)-Thalidomide Thalidomide, as a racemic mixture, was the active ingredient in a treatment to relieve the symptoms of morning sickness in pregnant women. (R) enantiomer is effective against morning sickness, but the (S) isomer causes birth defects.

METHODS FOR RESOLUTION OF RACEMIC MIXTURES: BY DIASTEREOMERS PREFRENTIAL CRYSTALLIZATION BY INNOCULATION BIOCHEMICAL SEPERATION CHROMATOGRAPHIC SEPERATION KINETIC METHOD PRECIPITATION 7) BY MECHANICAL SEPERATION

1) BY DIASTEREOMERS: When racemic mixture is allowed to interact with optically active material, it give a diastereomeric derivatives.

Fig: Seperation of enantiomers of 2-hydroxylpropionic acid Fig: Seperation of enantiomers of 2-hydroxylpropionic acid. The two enantiomers interact with (R)-2-phenyl-ethylamine to form two distinct salt species that are diastereomers of each other. The diastereomers can then be crystallized separately.

2) PREFERENTIAL CRYSTALLIZATION BY INOCULLATION: It was discovered by GRENEZ in 1866. This method involves seeding of saturated solution of the racemic mixture with pure crystals of one of the two enantiomers. Example: crystals of aspargine crystallises out (+) sodium ammonium tartarate from solution of racemic mixture.

3) BIOCHEMICAL METHOD: It was introduced by PASTEUR in 1858. This method is based on fact that when certain micro organisms like bacteria,fungi,yeast,moulds,etc are grown in dilute solution of racemic mixture,they eat up one enantiomer rapidly than other. Example: the mould penicillium glaucum preferentially destroys the (+) isomer of racemic ammonium tartarate leaving (-) ammonium tartarate in solution.

4) CHROMATOGRAPHIC SEPERATION: The racemic mixture can be separated by chromatography on an optically active support. The diastereomeric adsorbates which are formed have different stabilities. Thus one enantiomer will be held more tightly than the other and would be eluted first.

5) KINETIC METHOD : This method is based on the fact that one of the enantiomer of racemic mixture reacts faster than other with optically active compound. menthol reacts faster with (+) mandelic acid than with (-) mandelic acid. Thus with difference in kinetics of reaction,racemic mixture can be seperated.

6) PRECIPITATION: This method is based on formation of precipitate by reaction between any reagent and racemic mixture. Example: (+) & (-) narcotine when dissolved in hcl,precipitates (+) narcotine.

7) MECHANICAL SEPERATION: This method was introduced by LOUIS PASTEUR (1848). It is also known as spontaneous resolution by crystallisation. (+) and (-) forms of compounds have opposite crystalline shapes. PASTEUR used this process to separate (+) & (-) tartaric acid from mixture of tartaric acid.

Fig: MECHANICAL SEPERATION

ROLE OF STEREOCHEMISTRY IN PHARMACOKINETICS: The study of absorption, distribution, metabolisum and excretion (ADME) of drug are called as pharmacokinetics.

CHIRAL BIOLOGIOCAL MACROMOLECULES ARE: 1. Chiral biopolymers proteins glycoprotein 2. Chiral building blocks L- amino acids D- carbohydrates 3. Many of natural ligands at target site neurotransmitters autocoids hormones etc..

STEREOCHEMICAL ASPECTS IN ABSORPTION

ABSORPTION: “The process of movement of unchanged drug from the site of administration to systemic circulation is called as absorption” MECHANISM: 1) passive diffusion. 2) active transport.

1) PASSIVE DIFFUSSION: Also called as non-ionic diffusion. It is major process of absorption of more than 90% of the drugs. The driving force for this process is concentration gradient. It is defined as the difference in drug concentration on either side of membrame.

The aqs solubility of ampicillin with [D-epimer] configuration is greater than configuration [L-epimer] * 2R [D-epimer] * 2S [L-epimer]

2) ACTIVE TRANSPORT: The drug is transported from a region of lower to higher concentration i.e against the concentration gradient. The process is faster than passive diffusion. This process is uphill process and requires expenditure of energy.

STEREOCHEMICAL ASPECTS IN DISTRIBUTION

DISTRIBUTION: Distribution of a drug is defined as the reversible transfer of a drug between one compartment and another. One of compartment is always the blood or plasma & other represents extra vascular fluid & other body tissues.

PROTEIN BINDING: The phenomenon of complex formation with proteins is called as protein binding of drugs. Protein binding may be divided into: 1) Intracellular binding:where drug is bound to cell protein. 2) Extracellular binding:where drug is bound to extracellular protein.

STEREOCHEMICAL ASPECTS IN METABOLISM

Metabolism of drug is defined as the conversion of one chemical form to another. The decreasing order of drug metabolising ability of various organs is: liver > lungs > kidneys > intestine >skin. The pathways of drug metabolism is divided into two categories: Phase 1 reactions. Phase 2 reactions

STEREOCHEMICAL ASPECTS IN EXCREATION

Excreation is defined as the process where by drugs or their metabolites are irreversibly transferred from internal to external environment. Renal excretion is the net result of : glomerular filtration Active tubular secretion Active tubular reabsorption.

Eg.The renal clearance of quinidine has been reported to be four times greater than that of its diastereoisomer quinine. In oral administration of racemaic pindolol,its renal clearance of the S-enantiomer was 1.2-folds greater than that of R-enantiomer

ROLE OF STEREOCHEMISTRY IN PHARMACODYNAMIC

PHARMACODYNAMIC: it is study of action of drug on living organism. RECEPTORS: A macromolecular component of a cell with which a drug interacts to produce a pharmacologic response. A molecule which binds to a receptor is called a ligand, and may be a peptide or other small molecule, such as a neurotransmitter, a hormone, a pharmaceutical drug, or a toxin.

Receptor Drug interaction Pharmacologic effect

Morphine is an asymmetric molecule containing several asymmetric centers, and exist naturally as (-) morphine Epimerization of single asymmetric center can result in a drastic change of shape, making it difficult for the binding of molecule with receptors.

ADVANTAGES OF SINGLE ENANTIOMERIC PRODUCTS: Improved therapeutic index. Improved duration of effect. Increased potency. Less complex and more selective pharmacological profile. Less complex pharmacokinetic profile.

REFERENCES: Wilson & gisvold’s textbook of organic medicinal & pharmaceutical chemistry. eleventh edition ,lippioncott,williams & wilkins publication. Biopharmaceutics & pharmacokinetics by D.M. BRAHMANKAR, S.J. JAISWAL. Stereochemistry of organic compounds ,by D.NASIPURI Smith & william’s introduction to principle of drug design & action. Essentials of medical pharmacology by KD Tripathi.

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