title: Generic, highly selective and robust capillary electrophoresis method for separation of a racemic mixture of glitazone compounds.
abstract: A generic, highly selective, and robust capillary electrophoresis (CE) method was developed for separation of a racemic mixture of three available glitazone compounds (also known as thiazolidinediones) in active pharmaceutical ingredients (API) and tablets. The method separated the R and S enantiomers of balaglitazone, pioglitazone and rosiglitazone, and showed that the samples contained an equal (50:50) quantity of the enantiomers as a mixture. After a simple extraction of samples with acetonitrile:water (80:20), separation was performed using a combination of two cyclodextrins: sulfobuthylether-beta-cyclodextrin (SB-beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD) in the electrolyte at pH 8.0. The method showed a very good specificity, and all separations were achieved with a resolution (Rs) over 3.0. The developed CE method was then validated. The Rs for the separations were 3.5 for balaglitazone enantiomers, 3.5 for pioglitazone enantiomers, and 3.7 for rosiglitazone. The squared correlation coefficients (r2) were found to be 0.999 for all three compounds. The range of the CE method (injection volume was approximately 4 nl) was demonstrated to be from 1.0 to 2.4 ng. The R.S.D. in the repeatability study was found to be less than 0.5 for area/area ratio (and 3.0% for area) for all three compounds. The R.S.D. in the intermediate precision study was found to be less than 0.7 for area/area ratio (and 4.5% for area) for all three compounds. Generally, the method showed good robustness. Resolution between the enantiomers peak was maintained acceptable throughout the small variations around the pH value of the buffer, different capillary, CE instrument and electrolytes ion strength capacity, but changes in concentration of cyclodextrins and acetonitrile showed significant effects on separations and affected the resolution. The validation results showed that the CE method was suitable for separation of the racemic mixtures of the three glitazone drugs. The CE method was then applied for routine test during the drug and formulation development work of balaglitazone. Due to the achieved results from this work, it is the authors' belief that this method can easily separate other glitazone racemic mixtures.
authors.affiliation: Department of Analytical Development, CMC Development, Global Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark. bjam@novonordisk.com
authors.forename: Babak
authors.initials: B
authors.lastname: Jamali
authors.forename: Gitte Cargen
authors.initials: GC
authors.lastname: Theill
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Sørensen
mesh_terms: D003505:Cyclodextrins / Q000737:chemistry; D004573:Electrolytes / Q000737:chemistry; D019075:Electrophoresis, Capillary; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000302:isolation & purification*; D007202:Indicators and Reagents; D000077205:Pioglitazone; D011799:Quinazolines / Q000737:chemistry*; D015203:Reproducibility of Results; D000077154:Rosiglitazone; D012996:Solutions; D013237:Stereoisomerism; D013607:Tablets; D045162:Thiazolidinediones / Q000737:chemistry* / Q000302:isolation & purification*
chemical_list: D003505:Cyclodextrins; D004573:Electrolytes; D007004:Hypoglycemic Agents; D007202:Indicators and Reagents; D011799:Quinazolines; D012996:Solutions; D013607:Tablets; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C497232:balaglitazone; D000077205:Pioglitazone