TY - JOUR

T1 - Investigation of racemisation of the enantiomers of glitazone drug compounds at different pH using chiral HPLC and chiral CE

AU - Jamali, Babak

AU - Bjørnsdottir, Inga

AU - Nordfang, Ole

AU - Hansen, Steen Honore'

PY - 2008

Y1 - 2008

N2 - Drug enantiomers can have biologically distinct interactions within the biological system and consequently different pharmacological or toxicological effects. Development of a better and safer drug product may be considered if one of the enantiomers has a significantly better effect/side effect ratio than the other. Investigation of the single enantiomers in a racemic mixture could be valuable in order to investigate whether the single enantiomers demonstrate difference in pharmacological effect and/or fewer side effects versus the racemic mixture. In this context investigation of a possible racemisation of the pure enantiomers is very important.In order to obtain the enantiomers of the racemic pioglitazone and the racemic rosiglitazone an HPLC method for chiral separation was developed. Using this method the R and S enantiomers were separated and the method was used to collect each enantiomer for investigation of racemisation process. The racemisation of the enantiomers of pioglitazone and rosiglitazone was investigated at pH 2.5, 7.4 and 9.3 using a chiral CE system. At pH 2.5 all enantiomers showed a slow racemisation. After 192 h (8 days) at 37 °C the ratio of the enantiomers in the mixture for all four isolated enantiomers was approximately 2 to 1 and after 1440 h (30 days) full racemisation was observed. The racemisation speed increased with increasing pH. At pH 7.4 the ratio of the enantiomers in the mixtures was approximately 2 to 1 already after 10 h. Full racemisation was observed within 48 h (2 days) at pH 7.4 and within 24 h at pH 9.3. These investigations have shown that it is possible to separate and isolate the enantiomers from a racemic mixture of glitazone drug substance and perform racemisation studies on each enantiomer.

AB - Drug enantiomers can have biologically distinct interactions within the biological system and consequently different pharmacological or toxicological effects. Development of a better and safer drug product may be considered if one of the enantiomers has a significantly better effect/side effect ratio than the other. Investigation of the single enantiomers in a racemic mixture could be valuable in order to investigate whether the single enantiomers demonstrate difference in pharmacological effect and/or fewer side effects versus the racemic mixture. In this context investigation of a possible racemisation of the pure enantiomers is very important.In order to obtain the enantiomers of the racemic pioglitazone and the racemic rosiglitazone an HPLC method for chiral separation was developed. Using this method the R and S enantiomers were separated and the method was used to collect each enantiomer for investigation of racemisation process. The racemisation of the enantiomers of pioglitazone and rosiglitazone was investigated at pH 2.5, 7.4 and 9.3 using a chiral CE system. At pH 2.5 all enantiomers showed a slow racemisation. After 192 h (8 days) at 37 °C the ratio of the enantiomers in the mixture for all four isolated enantiomers was approximately 2 to 1 and after 1440 h (30 days) full racemisation was observed. The racemisation speed increased with increasing pH. At pH 7.4 the ratio of the enantiomers in the mixtures was approximately 2 to 1 already after 10 h. Full racemisation was observed within 48 h (2 days) at pH 7.4 and within 24 h at pH 9.3. These investigations have shown that it is possible to separate and isolate the enantiomers from a racemic mixture of glitazone drug substance and perform racemisation studies on each enantiomer.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1016/j.jpba.2007.09.004

DO - 10.1016/j.jpba.2007.09.004

M3 - Journal article

C2 - 17942259

VL - 46

SP - 82

EP - 87

JO - Journal of Pharmaceutical and Biomedical Analysis

JF - Journal of Pharmaceutical and Biomedical Analysis

SN - 0731-7085

IS - 1

ER -