George X. Zhou

A simple quantitative FT-IR approach for the study of a polymorphic transformation under crystallization slurry conditions

The pharmaceutical compound (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine hydrochloride (denoted here as Compound X), has been found to crystallize in at least two polymorphic forms. Using only two frequencies (1009 and 1058 cm(-1)) in the infrared, a linear (R=0.998) calibration plot, consisting of the ratio of the peak absorbances plotted against polymorph concentration, was constructed. This plot allowed the quantification of binary mixtures of polymorphs ranging from <3 to approximately 100 wt% Form II in Form I. Spectra were acquired in transmission mode using mineral oil (Nujol) mull sample preparation, for reasons of compatibility with wet cake and slurry samples. The transformation of the less thermodynamically stable polymorph (Form II) to the more stable form (Form I), in stirred methyl isobutyl ketone (MIBK) slurries, was monitored spectroscopically as a function of time. Performing the experiment at various temperatures allowed the energy of activation for the process to be estimated (42 kJ/mol).

Employment of on-line FT-IR spectroscopy to monitor the deprotection of a 9-fluorenylmethyl protected carboxylic acid peptide conjugate of doxorubicin

A method for accurately determining the end-point, >98% conversion, of the deprotection reaction of a highly toxic 9-fluorenylmethyl (Fm) ester 1b to its corresponding carboxylate 1d in real time by FT-IR spectroscopy is reported. Advantages of this method over analysis by conventional chromatographic means include real time determination of the end-point of a reaction that is time sensitive to by-product formation, and elimination of sampling a highly toxic reaction mixture. The FT-IR method is based on monitoring, in real time, the disappearance of the Fm ester carbonyl band for 1b at 1737 cm(-1), during deprotection by piperidine, and calibration models were established by Partial Least Squares (PLS) regression analysis with high performance liquid chromatography (HPLC) as reference. The best calibration model was built with 5 PLS factors in the spectral range of 1780-1730 and 1551-1441 cm(-1) and resulted in a standard error of cross validation (SECV) of 0.63 mM 1b and a standard error of prediction (SEP) of 0.51 mM 1b in the range of 0-25 mM. This error of prediction is approximately 0.8% of the initial concentration of 1b and is well within our specifications of <2% initial concentration.

Concentration determination of methyl magnesium chloride and other Grignard reagents by potentiometric titration with in-line characterization of reaction species by FTIR spectroscopy.

A potentiometric titration method for methyl magnesium chloride and other Grignard reagents based on the reaction with 2-butanol in THF has been developed and validated. The method employs a commercially available platinum electrode, using an electrolyte compatible with non-aqueous solvents. Well-defined titration curves were obtained, along with excellent method precision. The endpoint was precisely determined based on the first derivative of the titration curve. Different solvents such as THF, diethyl ether and methylene chloride provided similar results with regard to sharpness of the endpoint and method precision. The method was applied to a wide array of Grignard reagents including methyl magnesium bromide, ethyl magnesium chloride, propyl magnesium chloride, vinyl magnesium chloride, phenyl magnesium chloride, and benzyl magnesium chloride with similar precision and accuracy. Application of in-line FTIR was demonstrated for in situ monitoring of the titration reaction, allowing characterization of the reaction species. An authentic spectrum of the MeMgCl-THF complex was obtained using spectral subtraction and the vibrational absorbance bands were identified. FTIR also provided an alternative for detecting the titration endpoint, and the titration results so obtained, provided a cross-validation of the accuracy of the potentiometric titration.

Application of Online NIR for Process Understanding of Spray-Drying Solution Preparation

Solution preparation is the first unit operation of the manufacturing process for spray-dried solid dispersions. Visual inspection and offline high-performance liquid chromatography analysis are routinely used to assess the solution preparation end point as well as the final solution composition. However, the accuracy and appropriateness of these approaches are challenged by the scale of production and solvent evaporation during sample handling. Thus an appropriate online process analytical tool is needed to improve process and quality control for the solution preparation process. The objective of this report is to develop near infrared (NIR) models for real-time monitoring of the spray solution preparation process. These models were built and refined via 2 different experiments designs with different production scale. The potency of spray-dried intermediate was analyzed by high-performance liquid chromatography and used to verify the quantitative model. The results indicated that the quantitative NIR models can be used to predict the active pharmaceutical ingredient concentration of the final spray solution accurately with a standard error of prediction of 2.4 wt%. Based on this investigation, online NIR was deemed to be a suitable analytical tool on process and quality control for spray solution preparation.

Near infrared spectroscopy for the accurate measurement of crystallisation seeding point

T his article is condensed from the research paper by Zhou et al. which describes the use of near infrared (NIR) spectroscopy as an in-line method for measuring the concentration of Etoricoxib, a polymorphic drug compound, as well as detecting the presence of solids produced by premature crystallisation prior to seeding in the crystallisation process. In this NIR spectroscopic method, a spectrum was fi rst qualifi ed as that of clear solution and then the concentration of Etoricoxib was predicted by a NIR spectroscopy calibration model built with partial least squares (PLS) regression using off-line high-performance liquid chromatography (HPLC) analysis as the reference method.