ラセミ混合物

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(chemistry) a substance consisting of two or more substances mixed together (not in fixed proportions and not with chemical bonding)

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〈U〉(…を)『混ぜ合わせること』,(…の)茶合《+『of』+『名』》 / 〈C〉『混合した物』,混合薬

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/07/07 00:05:19」(JST)

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In chemistry, a racemic mixture, or racemate /reɪˈsimeɪt/, is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid. A mixture with only a single enantiomer is an enantiomerically pure or enantiopure mixture.^[1]

Nomenclature

A racemic mixture is denoted by the prefix (±)- or dl- (for sugars the prefix dl- may be used), indicating an equal (1:1) mixture of dextro and levo isomers. Also the prefix rac- (or racem-) or the symbols RS and SR (all in italic letters) are used.

If the ratio is not 1:1 (or is not known), the prefix (+)/(−), d/l- or d/l- (with a slash) is used instead.

The usage of d and l is strongly discouraged by IUPAC. ^[2]^[3]

Properties

A racemate is optically inactive, meaning that there is no net rotation of plane-polarized light. Although the two enantiomers rotate plane-polarized light in opposite directions, the rotations cancel because they are present in equal amounts.

In contrast to the two pure enantiomers, which have identical physical properties except for the direction of rotation of plane-polarized light, a racemate sometimes has different properties from either of the pure enantiomers. Different melting points are most common, but different solubilities and boiling points are also possible.

Pharmaceuticals may be available as a racemate or as the pure enantiomer, which might have different potencies.

Crystallization

There are four ways in which a racemate can crystallize, three of which H. W. B. Roozeboom had distinguished by 1899:

Conglomerate (sometimes racemic conglomerate)

A mechanical mixture of enantiomerically pure crystals of one enantiomer and its opposite. Molecules in the crystal structure have a greater affinity for the same enantiomer than for the opposite enantiomer. The melting point of the racemic conglomerate is always lower than that of the pure enantiomer. Addition of a small amount of one enantiomer to the conglomerate increases the melting point.

Racemic compound (sometimes true racemate)

Molecules have a greater affinity for the opposite enantiomer than for the same enantiomer; the substance forms a single crystalline phase in which the two enantiomers are present in an ordered 1:1 ratio in the elementary cell. Adding a small amount of one enantiomer to the racemic compound decreases the melting point. But the pure enantiomer can have a higher or lower melting point than the compound. A special case of racemates are kryptoracemates, in which the enantiomers are not related by improper rotations. The crystals are enantiomorphic, despite containing both enantiomorphs in a 1:1 ratio.^[4]

Pseudoracemate (sometimes racemic solid solution)

In contrast to the racemic compound or conglomerate, there is no big difference in affinity between the same and opposite enantiomers. Overall, both enantiomers occur in equal proportions in the crystal, but they coexist in an unordered manner in the crystal lattice. Addition of a small amount of one enantiomer changes the melting point just little bit or not at all.

Quasiracemate

A quasiracemate is a mixture of two similar but distinct compounds, one of which is left-handed and the other right-handed. Although chemically different, they are sterically similar (isosteric) and are still able to form a racemic crystalline phase. One of the first such racemates studied, by Pasteur in 1853, forms from a 1:2 mixture of the bis ammonium salt of (+)-tartaric acid and the bis ammonium salt of (−)-malic acid in water. Re-investigated in 2008,^[5] the crystals formed are dumbbell-shape with the central part consisting of ammonium (+)-bitartrate, whereas the outer parts are a quasiracemic mixture of ammonium (+)-bitartrate and ammonium (−)-bimalate.

Resolution

The separation of a racemate into its components, the pure enantiomers, is called a chiral resolution. There are various methods, including crystallization, chromatography, and the use of enzymes. The first successful resolution of a racemate was performed by Louis Pasteur, who manually separated the crystals of a conglomerate.

Synthesis

Without a chiral influence (for example a chiral catalyst, solvent or starting material), a chemical reaction that makes a chiral product will always yield a racemate. That can make the synthesis of a racemate cheaper and easier than making the pure enantiomer, because it does not require special conditions. This fact also leads to the question of how biological homochirality evolved on what is presumed to be a racemic primordial earth.

The reagents of, and the reactions that produce, racemic mixtures are said to be "not stereospecific" or "not stereoselective," for their indecision in a particular stereoisomerism.

Racemic pharmaceuticals

Some drug molecules are chiral, and the enantiomers have different effects on biological entities. They can be sold as one enantiomer or as a racemic mixture. Examples include thalidomide, ibuprofen, and salbutamol. Adderall is an unequal mixture of both amphetamine enantiomers. A single amphetamine dose combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and D/L-amphetamine aspartate monohydrate. The prescription analgesic tramadol is also a racemate.

In some cases (e.g., ibuprofen and thalidomide), the enantiomers interconvert or racemize in vivo. This means that preparing a pure enantiomer for medication is largely pointless. However, sometimes samples containing pure enantiomers may be made and sold at a higher cost in cases where the use requires specifically one isomer (e.g., for a stereospecific reagent); compare omeprazole and esomeprazole.

While often only one enantiomer of the drug may be active, in cases like salbutamol^[6] and thalidomide, the other enantiomer may be harmful. The (R) enantiomer of thalidomide is effective against morning sickness, while the (S) enantiomer is teratogenic, causing birth defects. Since the drug racemizes, the drug cannot be considered safe for use by women of child-bearing age,^[7] and its use is tightly controlled when used for treating other illness.^[8]

Methamphetamine is available by prescription under the brand name Desoxyn. The active component of Desoxyn is dextromethamphetamine hydrochloride. This is the right-hand isomer of methamphetamine. The left-handed isomer of methamphetamine, levomethamphetamine, is an OTC drug that is less centrally-acting and more peripherally-acting.

In the development of manufacturing chemical process for a chiral drug, some intermediates and the final active have to be purified by crystallization. Only compounds which crystallized as conglomerates must be selected for crystallization to get enantiomeric quality (see for more complete explanation: Impact Racemate and Conglomerate on purification)

Wallach's rule

Wallach's rule (first proposed by Otto Wallach) states that racemic crystals tend to be more dense than their chiral counterparts.^[9] This rule has been substantiated by crystallographic database analysis ^[10]

References

^ Moss, Gerry P. (1996). Basic terminology of stereochemistry (IUPAC Recommendations 1996). Department of Chemistry, Queen Mary University of London: Blackwell Scientific Publications. pp. 8,11.
^ G.P. Moss: Basic terminology of stereochemistry ( Recommendations 1996); Pure Appl. Chem., 1996, Vol. 68, No. 12, p. 2205-2216; doi:10.1351/pac199668122193
^ Nomenclature of Carbohydrates (Recommendations 1996), 2-Carb-4. - Configurational symbols and prefixes
^ L. Fábián and C. P. Brock (2010). "A list of organic kryptoracemates". Acta Crystallogr. B66 (1): 94–103. doi:10.1107/S0108768109053610.
^ Rediscovering Pasteur's Quasiracemates Kraig A. Wheeler, Rebecca C. Grove, Raymond E. Davis, and W. Scott Kassel Angew. Chem. Int. Ed. 2008, 47, 78 –81 doi:10.1002/anie.200704007
^ (R)-Albuterol for Asthma: Pro, Bill T. Ameredes and William J. Calhoun
^ "Use of thalidomide in leprosy". WHO:leprosy elimination. WHO. Retrieved 22 April 2010.
^ Sheryl Gay Stolberg (17 July 1998). "Thalidomide Approved to Treat Leprosy, With Other Uses Seen". New York Times. Retrieved 8 January 2012.
^ (Wallach, O. (1895). Liebigs Ann. Chem. 286, 90-143.)
^ Carolyn Pratt Brock, W. Bernd Schweizer, and Jack D. Dunitz (1991). "On the validity of Wallach's rule: on the density and stability of racemic crystals compared with their chiral counterparts". J. Am. Chem. Soc. 113 (26): 9811. doi:10.1021/ja00026a015.

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Profiling of enantiopure drugs towards aryl hydrocarbon (AhR), glucocorticoid (GR) and pregnane X (PXR) receptors in human reporter cell lines.

Novotna A1, Kamenickova A1, Pecova M1, Korhonova M1, Bartonkova I1, Dvorak Z2.Author information 1Department of Cell Biology and Genetics, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, Šlechtitelů 11, 783 71 Olomouc, Czech Republic.2Department of Cell Biology and Genetics, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, Šlechtitelů 11, 783 71 Olomouc, Czech Republic. Electronic address: moulin@email.cz.AbstractIn the past decade, a large number of enantiopure drugs were introduced to clinical practice, since improved therapeutic effects were demonstrated for one of the enantiomers from originally racemic drug. While the therapeutic effects and safety of enantiopure drugs were tested prior to their approval, various biological enantiospecific activities of these, often "old" drugs, remain to be elucidated. In the current paper, we examined enantiospecific effects of clinically used enantiopure drugs containing one chiral center in the structure (i.e. zopiclone, tamsulosin, tolterodine, modafinil, citalopram) towards aryl hydrocarbon (AhR), glucocorticoid (GR) and pregnane X (PXR) receptors in human reporter cell lines. The cytotoxicity (IC50), agonist (EC50) and antagonist effects (IC50) of R-form, S-form and racemic mixture for each tested drugs were determined and compared in AhR-, GR- and PXR-gene reporter cell lines. Since AhR, GR and PXR are key regulators of drug metabolism, energy metabolism, immunity and play many other physiological functions, the data presented here might be of toxicological significance.
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In the past decade, a large number of enantiopure drugs were introduced to clinical practice, since improved therapeutic effects were demonstrated for one of the enantiomers from originally racemic drug. While the therapeutic effects and safety of enantiopure drugs were tested prior to their approva
PMID 24316275

Amlodipine Metabolism in Human Liver Microsomes and Roles of CYP3A4/5 in the Dihydropyridine Dehydrogenation.

Zhu Y, Wang F, Li Q, Zhu M, Du A, Tang W, Chen W.Author information DMPK Department, Shanghai ChemPartner, Shanghai, People's Republic of China (Y.Z., F.W., Q.L., A.D., W.T., W.C.) and Department of Biotransformation, Bristol-Myers Squibb, Princeton, New Jersey (M.Z.).AbstractAmlodipine is a commonly prescribed calcium channel blocker for the treatment of hypertension and ischemic heart disease. The drug is slowly cleared in humans primarily via dehydrogenation of its dihydropyridine moiety to a pyridine derivative (M9). Results from clinical drug-drug interaction studies suggest that CYP3A4/5 mediate metabolism of amlodipine. However, attempts to identify a role of CYP3A5 in amlodipine metabolism in humans based on its pharmacokinetic differences between CYP3A5 expressers and nonexpressers failed. Objectives of this study were to determine the metabolite profile of amlodipine (a racemic mixture and S-isomer) in human liver microsomes (HLM), and to identify the cytochrome P450 (P450) enzyme(s) involved in the M9 formation. Liquid chromatography/mass spectrometry analysis showed that amlodipine was mainly converted to M9 in HLM incubation. M9 underwent further O-demethylation, O-dealkylation, and oxidative deamination to various pyridine derivatives. This observation is consistent with amlodipine metabolism in humans. Incubations of amlodipine with HLM in the presence of selective P450 inhibitors showed that both ketoconazole (an inhibitor of CYP3A4/5) and CYP3cide (an inhibitor of CYP3A4) completely blocked the M9 formation, whereas chemical inhibitors of other P450 enzymes had little effect. Furthermore, metabolism of amlodipine in expressed human P450 enzymes showed that only CYP3A4 had significant activity in amlodipine dehydrogenation. Metabolite profiles and P450 reaction phenotyping data of a racemic mixture and S-isomer of amlodipine were very similar. The results from this study suggest that CYP3A4, rather than CYP3A5, plays a key role in metabolic clearance of amlodipine in humans.
Drug metabolism and disposition: the biological fate of chemicals.Drug Metab Dispos.2014 Feb;42(2):245-9. doi: 10.1124/dmd.113.055400. Epub 2013 Dec 3.
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PMID 24301608

Parallel achiral-chiral determination of oxybutynin, N-desethyl oxybutynin and their enantiomers in human plasma by LC-MS/MS to support a bioequivalence trial.

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A parallel achiral and chiral determination of oxybutynin, its pharmacologically active metabolite N-desethyl oxybutynin and their enantiomers in human plasma is described using LC-MS/MS. Both the methods were developed and validated using deuterated analogues as internal standards. Achiral analysis
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Japanese Journal

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Mutual Inhibition between Carvedilol Enantiomers during Racemate Glucuronidation Mediated by Human Liver and Intestinal Microsomes

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NAID 130001872288

ハロアルカン脱ハロゲン酵素DbjAの鏡像異性体選択性機構の解明

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日本結晶学会誌 53(2), 124-129, 2011-04-30
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NAID 10028253974