Title of the topic:
“ RESOLUTION AND CHARACTERIZATION OF
RACEMIC MIXTURE OF CARBINOXAMINE
USING TARTARIC ACID ”
Brief resume of the intended work:
Need for the study: Carbinoxamine is an anti-histaminic drug that antagonises the H-1 receptors1. The most frequent adverse reactions are urticaria, anaphylactic shock, photosensitivity, agranulocytosis, sedation, diplopia and epigastric distress. Many drugs are marketed as mixtures of the isomers that often differ in the pharmacological, toxicological and pharmacokinetic properties2.
Pharmaceutical industries need to consider that how they propose a drug that shows chiral potential. Increasingly, designer drugs are developed that target the active site of receptor or enzymes are stereoselective. Based on structure-activity relationships, a pharmacologist can devise synthetic or semi synthetic drugs that target the enzyme or receptor, thus reducing the risk that the drug may cause side effects. Using a single enantiomer further improves the benefits-risk profile. Recently there has been considerable interest in preparing and testing Enantiomers of drugs that exert their pharmaceutical action via specific receptor or enzymes in many instances. This has been shown to result in enhanced activity, greater potency and fewer side effects. Specifically in case of certain drugs like an anti-histamine Terfenadine caused QT- prolongation, while its chiral metabolite did not3. In case of Ofloxacins, ex: Ofloxacin, optical active isomers were separated and isolated by HPLC. (-) Ofloxacin is about 8-128 times more active as the racemate against both gram-positive and gram-negative bacteria4. In case of Penicillamine, its enantiomers show different pharmacological effects. The (d) form of Penicillamine is widely used for treatment of Rheumatoid arthritis and Wilson’s diseases. The (l) Enantiomer is highly toxic5. Budesonide is an Anti-inflammatory drug; (R) isomer is nearly three times as strong as of (S) isomer6. Betaxolol is a cardio selective beta-adrenergic blocking agent with high bioavailability having a long half life, and is used in hypertension and the studies have shown that the cardiovascular activity of Betaxolol resides mainly in its (S) isomer, and the (R) isomer is usually responsible for the side effects. In case of Propranolol the levo isomer is responsible for the beta-receptor antagonist. The dextro isomer do not possess beta-receptor antagonistic activity7.In case of Carbinoxamine the Levo form is more active than Dextro form1.
Review of Literature:
Tang Kewen, Zhou Chunshan and Jiang Xinyu4 have studied the chemical thermodynamic theory; racemic Ofloxacin is separated in chiral systems by hollow Fiber Liquid Supported Membrane Technology combining with Counter Current Fractional Extraction. The fairly polar Ofloxacin can cross the membrane back and forth. According to Fractional Chiral Extraction theory, mass transfer performance of hollow fiber membrane and enantio-selectivity are investigated. The optical purity for Ofloxacin enantiomers is upto 90% when 11 hollow fiber membrane modules of 22cm in length series are used.
Bamman et al. Huppe Seyler’s8 demonstrated an Enzymatic method for resolution of a racemic mixture of hydroxy compound. A, D, L mixture of the hydroxy compound is phosphorylated to form the D, L-mono ortho phosphate esters of the hydroxy compound. The D, L mixture obtained is treated with a stereospecific phosphatase, which causes the hydrolysis of substantially only one optical isomer of the mono ortho phosphate ester. The resulting hydrolysed isomer of the hydroxy compound is then separated.
Karen W. Phinney and Lane C. Sander 9 evaluated Dextran sulphate a poly anionic poly saccharide as a chiral additive in Capillary Electrophoresis. The effects of pH chiral selector concentration and composition on resolution were also studied. At low pH the reversal polarity mode was employed to achieve separation of the probe compounds. The electrophoretic results provided insight into the chiral recognition of dextran sulphate in Capillary Electrophoresis.
H.Blanco and I.Valverde10 demonstrated that Capillary Electrophoresis is an effective tool for the resolution of enantiomers, which is accomplished by supplying the background electrolyte, which is a chiral selector capable of discriminating between the enantiomers. A large number of chiral selectors are currently available; especially prominent among those are cyclodextrins, chiral crown ethers, chiral surfactants, ligand exchange complexes and linear polysaccharides. The most suitable chiral selector for each specific purpose is usually elected by trial and error, which is expensive and time consuming.
Seog Beom Song, II Hawn Cho, Yong Sik Youn and Dong Kwon Lim 11 have studied a method for the separation of S (-) Amlodipine from a racemic Amlodipine. They used L-tartaric acid as an optical resolution agent and DMAC as a solvent. The separation method allows the resolution of S (-) Amlodipine from racemic Amlodipine at high yield and to a satisfactory enantiomeric excess and thus is economically favourable and applicable to the mass production of the optical isomer.
R. Herráez-Hernández, P. Campíns-Falcó and L. A. Tortajada-Genaro12 have demonstrated that the High Performance Liquid Chromatography (HPLC) is the method of choice for the enatiomeric determination of Amphetamine and Amphetamine-type compounds and a number of Chromatographic procedures have been proposed using both direct and indirect methods.
Objectives of the study:
The primary objective of the study is an attempt to:
1)Preparation of corresponding optical active salts from the racemic mixture.
2)Crystallization of the racemic mixture to pure Enantiomer isomers.
3)Characterization of isomers.
Resolution methodology:
Carbinoxamine will be resolved by the formation of distereo isomeric salts with L-Tartaric acid13 followed by crystallisation of salt and characterisation by using NMR Spectroscopy. The traditional acid base resolution method is simple and economic for the preparation of large quantity of enantiomers of Carbinoxamine.
Source of data:
Data on drugs will be collected from Drug Information Center, standard books, physicochemical database and literature search from
Indian Institute of Sciences, Bangalore.
Scientific journals and related articles.
Internet facilities.
Krupanidhi College of pharmacy library.
Library of R.L. Fine Chem. Ltd.
Publication and Journals of Medicinal Chemistry.
Does the study require any Investigations and Interventions to be conducted on patients or other humans or animals?
Not applicable.
Has ethical clearance been obtained from your institute in case of above ?
Not applicable.
List of references:
  1. Manfred E Wolff. Burger’s medicinal chemistry and drug discovery. 5th ed. A Wiley-International Publication: 1997; p. 518,532. (Therapeutic agents; vol 5).
  2. Lein Ainguyene, Hus Heb, Chuong Pharm-Huys. Chiral drugs. International Journal of Biomedical Science. 2006;( 2):85-100
  3. Sean P. Pinney, Bettina S. Koller, Michael R.Franz, Raymond L. Woosley. Terfenadine increases the qt interval in isolated guinea pig heart. J Cardiovasc PharmacolTM [25:30-34] 1994 Aug 9 1995]: 25(1).
  4. Tang Kewen, Zhou Chunshan, Jiang Xinyu. Racemic ofloxacin separation by supported liquid membrane extraction with two organic phases. Science in China (series B) 2003 Feb; 46(1):96-103.
  5. Katilin. Kovics-hadady, et, al, attempts for the separation of D- and L- Penicillamine, chromatographia, 1987; (4): 677-679.
  6. J Krzek, U Hubicka, M Dabrowska-Tylka, E Leciejewicz-Ziemecka. Determination of Budesonide R (+) and S (–) isomers in pharmaceuticals by Thin Layer Chromatography with UV Densitometric detection. Chromatographia 2002; 56.759-762.
  7. Hong-Hao Zhou, Alastair J.J.Wood. Differences in stereoselective disposition of propranolol do not explain sensitivity differences between white and Chinese subjects: correlation between the clearance of (-) and (+) propranolol. Clin pharmacol ther [serial online] 1990 Jun; 47(6).

  1. Bamman et al. Huppe Seyler’s. Enzymatic separation of racemic mixtures of hydroxy compounds. United states patent, patent no.4,659,671. 2 physical chem. Bd. 349, 1988:192-196.
  2. Karen W. Phinney, Lane C. Sander. Enantioselective separations in capillary electrophoresis with dextran sulfate as the chiral selector. Anal Bionannal Chem. [DOI 10.1007/s00216-003-1808-2] 2003 [2003 Mar 7]; 763-768.
  3. M. Blanco, I. Valverde. Election of the chiral selection for enatioseperations by capillary electrophoresis: 1-23.
  4. Seog Beom Song, II Hawn Cho, Yong Sik Youn, Dong Kwon Lim. Method for the separation of S (-) amlodipine from racemic amlodipine. United States Patent Application Publication [Pub no.: US 2010/0069445A1] 2010 Mar 18 [cited 2009 Apr 27]; 1-4.
  5. R. Herráez-Hernández, P. Campíns-Falcó, L. A. Tortajada-Genaro. Chiral determination of amphetamine and related compounds using chloroformates for derivation and high-performance liquid chromatography. The analyst 1998 July 21st; (123): 2131-2137.
  6. Jack. Gawronski, Krystyna Gawronska. Tartaric and Malic acids in synthesis.