title: Determination of apomorphine freebase in sublingual tablets by proton nuclear magnetic resonance spectroscopy.
abstract: An apomorphine sublingual tablet formulation under development contains mixtures of apomorphine freebase (FB) and apomorphine hydrochloride salt. It is important to have a reliable analytical method to determine the ratio of the base and salt forms to ensure accuracy, reproducibility and robustness of the manufacturing processes as well as to meet the requirements of the quality target product profile. A Proton Nuclear Magnetic Resonance ((1)H NMR) spectroscopy method based on the proton shift of the amine methyl group (N-CH3) in apomorphine has been developed to determine the mole percentage of freebase to the total mole of freebase and hydrochloride salt in the drug product. The method was evaluated in terms of specificity, linearity, and variability. The presence of excipients does not interfere with the analysis. A standard calibration curve of the chemical shift as a function of the proportion of freebase forms of apomorphine was established, covering the range of 100% apomorphine freebase to 100% apomorhine hydrochloride. The correlation coefficient (r(2)), slope, and Y-intercept of the regression line are 0.998, -0.00596, and 3.191, respectively. The day-to-day variability of the (1)H shift in two instruments in the standard is less than 1% RSD. Three lots of the sublingual tablet drug product were examined and quantified by the standard. The mole percent apomorphine freebase was determined to be 73.8%, 75.2%, and 76.2%, respectively, within 100.0%±2.0% of the target value of 75.0%. The method is a new avenue to use the (1)H NMR technique for determination of apomorphine freebase and salt ratio in a solid drug product dosage form for release testing and in-process control.
authors.affiliation: Impax Inc., 31047 Genstar Road, Hayward, CA 94544, USA. Electronic address: tan.acwli@gmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.affiliation: Impax Inc., 31047 Genstar Road, Hayward, CA 94544, USA.
authors.forename: Shook F
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Acorn NMR Inc., 7670 Las Positas Road, Livermore, CA 94551, USA.
authors.forename: Virginia W
authors.initials: VW
authors.lastname: Miner
authors.affiliation: Impax Inc., 31047 Genstar Road, Hayward, CA 94544, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
authors.affiliation: Impax Inc., 31047 Genstar Road, Hayward, CA 94544, USA.
authors.forename: Suneel
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Impax Inc., 31047 Genstar Road, Hayward, CA 94544, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Fields
mesh_terms: D000286:Administration, Sublingual; D001058:Apomorphine / Q000737:chemistry*; D002138:Calibration; D002626:Chemistry, Pharmaceutical / Q000379:methods; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods; D011522:Protons; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013607:Tablets / Q000737:chemistry*
chemical_list: D011522:Protons; D013607:Tablets; D001058:Apomorphine
keywords: (1)H NMR; Amine methyl group proton shift; Apomorphine freebase; Apomorphine hydrochloride; Sublingual tablets