Critical investigation of the substituent distribution in the polymer chains of hydroxypropyl methylcelluloses by (LC-)ESI-MS

Three hydroxypropyl methylcellulose samples (HPMC1-3, DSMe = 1.45, 1.29, and 1.36; MSHP = 0.28, 0.46, and 0.84) were analyzed with respect to their methyl and hydroxypropyl substitution pattern in the polymer chains. Ionization yield of HPMC oligomers in electrospray ionization ion trap mass spectrometry (ESI-IT-MS) is strongly influenced by the hydroxypropyl pattern. Therefore, a sample derivatization procedure, as well as suitable measurement conditions that enable relative quantification were elaborated. Analysis was performed by negative ESI-IT-MS after per(deutero)methylation, partial depolymerization, and reductive amination with m-aminobenzoic acid. Measurement parameters like solvent, trap drive, and voltages of the ion transportation unit were studied with regard to the suitability for quantitative evaluation. Using direct infusion of the samples, strong influence of trap drive and octopole settings was observed. Optimized measurement conditions were used for the determination of the HP pattern of the permethylated samples by direct infusion. The methyl pattern was determined from the perdeuteromethylated samples by high-performance liquid chromatography-electrospray tandem mass spectrometry. For HPMC1, substituents were both found to fit the random distribution model. The other two samples showed pronounced heterogeneity which could be interpreted in more detail by extracting methyl subpatterns depending on the number of HP groups.