Current regulatory (draft) guidance on chiral medicinal products: Canada, EEC, Japan, United States

Rauws, A. G.; Groen, K.

doi:10.1002/chir.530060206

Cited by 75 publications

(24 citation statements)

References 5 publications

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“…In the mid 1980s, apparently suddenly, the composite character of racemic therapeutics was highlighted [1]. In awareness that usually only one of the isomers fully contributes to the desired therapeutic acitvity and the other must be classified as an unwanted byproduct, the current regulatory guidelines on chiral drugs were formulated [2,3]. The importance of investigating drug enantiomers in pharmacokinetic and pharmacodynamic studies is emphasized and justification of the choice of a racemate on a scientific basis is required.…”

Section: Introductionmentioning

confidence: 99%

Enantiomeric separation of dihydroxyphenyl-alanine (DOPA), methyldihydroxyphenylalanine (MDOPA) and hydrazinomethyldihydroxyphenyl-alanine (CDOPA) by using capillary electrophoresis with sulfobutyl ether-β-cyclodextrin as a chiral selector

Doležalová

Fanali

2000

Electrophoresis

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Capillary electrophoresis (CE) was successfully applied to the enantiomer resolution of racemic structurally related compounds, namely dihydroxyphenylalanine (DOPA), methyldihydroxyphenylalanine (MDOPA) and hydrazinomethyldihydroxyphenylalanine (CDOPA). The chiral resolution was performed in an untreated fused-silica capillary by using a phosphate buffer at pH 2.5 or 3.0 supplemented with sulfobutylated beta-cyclodextrin (SBE-CD). Resolution was strongly influenced by the concentration of the chiral selector added to the background electrolyte. In fact, 2-5 mM of SBE-CD enabled the resolution of DOPA and MDOPA enantiomers, while CDOPA optical isomers were resolved by using either 0.5 mM or 6-20 mM of SBE-CD. The latter separation conditions (reversed polarity mode) made it possible to obtain inversion of migration order.

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Section: Introductionmentioning

confidence: 99%

Enantiomeric separation of dihydroxyphenyl-alanine (DOPA), methyldihydroxyphenylalanine (MDOPA) and hydrazinomethyldihydroxyphenyl-alanine (CDOPA) by using capillary electrophoresis with sulfobutyl ether-β-cyclodextrin as a chiral selector

Doležalová

Fanali

2000

Electrophoresis

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“…The issue of chirality to avoid unnecessary drug burden on the body has also emerged as a factor in decision making for the selection of lead compound for further studies in drug discovery process, as enantiomers often differ in their pharmacological activity, toxicity and pharmacokinetic characteristics [25][26][27] . This prompted us to undertake pharmacokinetic study of racemic compound along with resolved individual optical isomers in laboratory animals.…”

Section: Preclinical Pharmacokinetic Studiesmentioning

confidence: 99%

Chalcone-Based Aryloxypropanolamine as a Potential Antidiabetic and Antidyslipidaemic Agent

Shukla¹,

Satyanarayana²,

Verma³

et al. 2017

Current Science

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The hybrid congener 3 derived from hydroxychalcone and pharmacophore oxypropanolamine for adrenergic receptor, along with its enantiomers 9a and 9b were selected from a series of compounds for detailed studies of their antidiabetic profile in sucrose-challenged, low-dosed, streptozotocin-induced diabetic rats and in db/db mice, and antidyslipidaemic profile in high fat diet-induced dyslipidaemic hamsters. The test compounds exhibited significant and consistent antidiabetic and antidyslipidaemic activities in the above models. The pharmacodynamic studies of two metabolites, 10 and 11, were undertaken. Metabolite 10 having greater bioavailability in plasma was synthesized and found to exhibit significant antidiabetic activity. The parent compound together with its active metabolites exhibited significant oral bioavailability, thus establishing compound 3 as a potential lead molecule for further studies.

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“…3 The United States Food and Drug Administration (US FDA) and other regulatory agencies have made it mandatory for the manufacturers to investigate each enantiomer of the chiral drug individually. 4 According to the International Conference on Harmonization (ICH) guidelines, chiral identity, enantiomeric impurity and chiral assay tests are required for product specifications. 5 Chromatographic techniques, especially by HPLC have been given priority for the separation of enantiomers during the past several decades.…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of a Chiral HPLC Method for Quantitative Analysis of Enantiomeric Escitalopram

Rahman

Haque

Rahman

et al. 2018

Dhaka Univ. J. Pharm. Sci

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ABSTRACT:In the present study a rapid, accurate and precise chiral HPLC method was developed and validated for enantiomeric separation of racemate citalopram and escitalopram according to the guidelines of United States of Pharmacopeia (USP) and International Conference on Harmonization (ICH). The chiral chromatographic separation was achieved with ammonium acetate/ ethanol/ 2-propanol/ methylene dichloride (100 : 150 : 70 : 30, v/v) at a flow rate of 0.5 ml/min using a chiral CD-PH column. The HPLC analyses were monitored at 254 nm. The method showed a good linearity with regression coefficient (r 2 ) of 0.998 in the range of 20.0-70.0 µg/ml for escitalopram. The detection limit (LOD), quantitation limit (LOQ) and average percentage of recovery for escitalopram were found to be 2.54, 7.68 µg/ml and 100.28% to 102.86%, respectively. The percentage of relative standard deviation (%RSD) for intra-and inter-day precision were found as 0.16% and 0.09%, respectively. The established method proved as reproducible with a %RSD value of less than 2 and having the robustness within specified limit. The present study also showed the enantiomeric purity or excess (%ee) of seven pharmaceutical preparations of escitalopram. Thus the proposed chiral method can be applied for the enantiomeric purity determination of escitalopram formulations.

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Current regulatory (draft) guidance on chiral medicinal products: Canada, EEC, Japan, United States

Cited by 75 publications

References 5 publications

Enantiomeric separation of dihydroxyphenyl-alanine (DOPA), methyldihydroxyphenylalanine (MDOPA) and hydrazinomethyldihydroxyphenyl-alanine (CDOPA) by using capillary electrophoresis with sulfobutyl ether-β-cyclodextrin as a chiral selector

Enantiomeric separation of dihydroxyphenyl-alanine (DOPA), methyldihydroxyphenylalanine (MDOPA) and hydrazinomethyldihydroxyphenyl-alanine (CDOPA) by using capillary electrophoresis with sulfobutyl ether-β-cyclodextrin as a chiral selector

Chalcone-Based Aryloxypropanolamine as a Potential Antidiabetic and Antidyslipidaemic Agent

Development and Validation of a Chiral HPLC Method for Quantitative Analysis of Enantiomeric Escitalopram

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