Pharmaceutical impurity identification: a case study using a multidisciplinary approach.
A multidisciplinary team approach to identify pharmaceutical impurities is presented in this article. It includes a representative example of the methodology. The first step is to analyze the sample by LC-MS. If the structure of the unknown impurity cannot be conclusively determined by LC-MS, LC-NMR is employed. If the sample is unsuitable for LC-NMR, the impurity needs to be isolated for conventional NMR characterization. Although the technique of choice for isolation is preparative HPLC, enrichment is often necessary to improve preparative efficiency. One such technique is solid-phase extraction. For complete verification, synthesis may be necessary to compare spectroscopic characteristics to those observed in the original sample. Although not widely practiced, an effective means of getting valuable structural information is to conduct a degradation study on the purified impurity itself. This systematic strategy was successfully applied to the identification of an impurity in the active pharmaceutical ingredient 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulphonylurea. Identification required the use of all of the previously mentioned techniques. The instability of the impurity under acidic chromatographic conditions presented an additional challenge to purification and identification. However, we turned this acidic instability to an advantage, conducting a degradation study of the impurity, which provided extensive and useful information about its structure. The following discussion describes how the information gained from each analytical technique was brought together in a complementary fashion to elucidate a final structure.
Analytical Research & Development Department, Pharmaceutical Sciences, Pfizer Global Research & Development, Pfizer Inc., Groton, Connecticut 06340, USA.
Karen M
KM
Alsante
Peter
P
Boutros
Michel A
MA
Couturier
Robert C
RC
Friedmann
Jeffrey W
JW
Harwood
George J
GJ
Horan
Andrew J
AJ
Jensen
Qicai
Q
Liu
Linda L
LL
Lohr
Ronald
R
Morris
Jeffrey W
JW
Raggon
George L
GL
Reid
Dinos P
DP
Santafianos
Thomas R
TR
Sharp
John L
JL
Tucker
Glenn E
GE
Wilcox
D004340:Drug Contamination; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods*
D004364:Pharmaceutical Preparations