title: Real-time endpoint monitoring and determination for a pharmaceutical salt formation process with in-line FT-IR spectroscopy.
abstract: An application of Fourier transform infrared (FT-IR) spectroscopy equipped with an attenuated total reflectance (ATR) probe for in-line monitoring of a hydrochloride (HCl) salt formation process of 4-{1-methyl-2-piperidin-4-yl-4-[3-(trifluorometryl)phenyl]-1H-imidazol-5-yl}-N-[(1S)-1-phenylethyl]pyridine-2-amine (freebase), an active pharmaceutical ingredient as a P38 MAP kinase inhibitor, is described. The freebase forms both mono- and bis-HCl salts due to its structural features. The mono-HCl salt is the desired product but the bis-salt is an impurity. The key to maximizing the product yield and minimizing the impurity level is to monitor the salt-forming reaction and to terminate it at the correct HCl charge amount. The process analytical technology (PAT) provided real-time data for process control and overcame the limitations that had been previously encountered by other analytical instrumentations, such as high-performance liquid chromatography and titration. Two qualitative approaches for reaction endpoint determination were employed. In the first approach, changes in the concentration of the freebase and bis-salt were monitored via the first derivative concentration profiles. The flat point in the freebase profile and the rise in the bis-salt profile were used as a detection bracket for the endpoint of HCl charging. In the second approach, principal component analysis (PCA) was used to classify the status of the process based on a spectral library consisting of spectra collected around the endpoint. Results indicated that both methods provided adequate accuracy for endpoint control in a small window between 1.0 and 1.05 HCl to freebase mole ratio. Both methods were used to support a scaled up process. Three batches of MAP mono-HCl salt formation were successfully controlled and prepared.
authors.affiliation: Merck Research Laboratories, Merck and Co. Inc., P.O. Box 2000, RY818-C306, Rahway, NJ 07065, USA. Zhihao_lin@merck.com
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Lin
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.forename: Amar
authors.initials: A
authors.lastname: Mahajan
authors.forename: Sherry
authors.initials: S
authors.lastname: Song
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Ge
authors.forename: Dean
authors.initials: D
authors.lastname: Ellison
mesh_terms: D002138:Calibration; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000032:analysis*; D025341:Principal Component Analysis; D012492:Salts / Q000032:analysis / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods*; D013678:Technology, Pharmaceutical / Q000379:methods*; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis
chemical_list: D004364:Pharmaceutical Preparations; D012492:Salts; D048051:p38 Mitogen-Activated Protein Kinases