ABSTRACT
L-pidolic acid is being used as a coformer for ertugliflozin, a sodium-glucose cotransport 2 inhibitor. A sensitive and rapid two-step achiral derivatization combined with gas chromatography with flame ionization detection or gas chromatography with mass spectroscopic detection was developed and validated for the enantiomeric purity determination of L-pidolic acid in the drug substance and drug product, respectively. The method was used to analyze ertugliflozin drug substance forced degradation samples and showed no racemization of pidolic acid in any of the solid or solution stress samples. Analysis of ertugliflozin drug product stability samples showed no significant levels of D-pidolic acid in the drug product indicating that no significant racemization of pidolic acid occurs in the drug product under normal storage conditions. Based on the data generated, a chiral control for pidolic acid is not necessary for drug substance or drug product, but rather can be controlled in the purchase of L-pidolic acid.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/analysis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Gas Chromatography-Mass Spectrometry/methods , Pyrrolidonecarboxylic Acid/analysis , Pyrrolidonecarboxylic Acid/chemistry , Chromatography, Gas/methods , StereoisomerismABSTRACT
A dissolution test for a once daily combination tablet containing 10 mg of cetirizine dihydrochloride (cetirizine HCl) for immediate release and 240 mg of pseudoephedrine hydrochloride (pseudoephedrine HCl) for extended release was developed and validated according to current ICH and FDA guidelines. The cetirizine HCl is contained within an outer layer of the tablet while a semipermeable membrane of cellulose acetate and polyethylene glycol controls the rate at which pseudoephedrine HCl is released from the tablet core. The dissolution method, which uses USP apparatus 2 with paddles rotating at 50 rpm, 1000 ml of deaerated water as the dissolution medium, and reversed-phased HPLC for quantitation, was demonstrated to be robust, discriminating, and transferable. These test conditions were selected after it was demonstrated that the cetirizine HCl portion of the tablet rapidly dissolved in aqueous media over the physiologically relevant pH range of 1.1-7.5, and that the extended-release profile of pseudoephedrine HCl was independent of dissolution conditions (i.e., apparatus, pH, and agitation).
Subject(s)
Cetirizine/analysis , Chemistry, Pharmaceutical/methods , Delayed-Action Preparations/chemistry , Drug Combinations , Drug Industry/methods , Ephedrine/analysis , Pharmaceutical Preparations/chemistry , Biological Availability , Cetirizine/chemistry , Chromatography, High Pressure Liquid , Ephedrine/chemistry , Linear Models , Methanol/chemistry , Models, Chemical , Models, Statistical , Osmosis , Sensitivity and Specificity , Solubility , Tablets , Therapeutic Equivalency , Time Factors , WaterABSTRACT
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.
