Determination of the weight average molecular weight of methacrylic acid copolymers by diffusion-ordered NMR spectroscopy

Introduction. Methacrylic acid copolymers are synthetic anionic copolymers that are used as the main component of enteric-soluble coatings that provide controlled drug release in the small intestine. The molecular weight of these copolymers is a critical parameter affecting their solubility in the gastrointestinal tract, therefore it is among the normalized parameters that determine the quality of copolymers.

Aim. Development of a method for determining the weight average molecular weight of methacrylic acid copolymers by diffusion-ordered NMR spectroscopy, which does not involve the stage of converting the molecular weight of derivatives into the molecular weights of the initial methacrylic acid copolymers.

Materials and methods. A solution of the sodium salt of polymethacrylic acid, copolymers of methacrylic acid from various manufacturers, as well as copolymers of methacrylic acid isolated from pharmaceutical film coatings were used as objects of research. The DOSY experiments were performed on an Agilent DD2 600 NMR spectrometer.

Results and discussion. Using a set of comparison samples, a calibration graph of the dependence of the logarithm of the weight average molecular weight of the comparison samples on the logarithm of their adjusted average value of the self-diffusion coefficient was constructed and a correlation equation with a coefficient of determination R² = 0.9992 was derived. The values of the molecular weights of the tested samples calculated using this correlation equation agreed within the confidence intervals with the values measured by the coating manufacturers using the GPC method. The relative measurement error of the DOSY method (5.6 %) does not exceed the relative error of the determination of molecular weights by the GPC method (5–10 %).

Conclusion. In the course of the study, a method was developed for determining the weight average molecular weight of methacrylic acid copolymers by diffusion-ordered NMR spectroscopy. When implementing this technique, the possibility of formation of methacrylic acid copolymers conglomerates due to their derivatization into the corresponding sodium salts is excluded; recalculation of the weight average molecular weight of the derivatized methacrylic acid copolymers into the weight average molecular weight of the initial methacrylic acid copolymers is excluded; different mobility of individual macromolecule segments is taken into account; the effect of the viscosity of the analyzed solutions on the measured value of the self-diffusion coefficient has been reduced. The relative error in measuring the weight average molecular weight of methacrylic acid copolymers using the developed technique does not exceed the relative error in measuring the molecular weights of substances by the GPC method.

1. Giordanengo R., Viel S., Hidalgo M., Allard-Breton B., Thévand A., Charles L. Analytical strategy for the molecular weight determination of random copolymers of poly(methyl methacrylate) and poly(methacrylic acid). Journal of the American Society for Mass Spectrometry. 2010;21(6):1075–1085. https://doi.org/10.1016/j.jasms.2010.02.007

2. Yessine M.-A., Lafleur M., Meier C., Petereit H.-U., Leroux J.-C. Characterization of the membrane-destabilizing properties of different pH-sensitive methacrylic acid copolymers. Biochimica et Biophysica Acta (BBA) – Biomembranes. 2003;1613(1–2):28–38. https://doi.org/10.1016/S0005-2736(03)00137-8

3. Maklakov A. I., Skirda V. D., Fatkullin N. F.Self-diffusion in solutions and melts of polymers. Kazan: Kazan State University Press; 1987. 224 р. (In Russ.)

4. Kuz’mina N. E., Moiseev S. V., Severinova E. Yu., Luttseva A. I. Diffusion-ordered NMR spectroscopy application for analysis of polysaccharides. Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. Regulatory Research and Medicine Evaluation. 2022;12(1):24–40 (In Russ.) https://doi.org/10.30895/1991-2919-2022-12-1-24-40

5. Kasprzak A., Poplawska M., Krawczyk H., Molchanov S., Kozlowski M., Bystrzejewski M. Novel non-covalent stable supramolecular ternary system comprising of cyclodextrin and branched polyethylenimine. Journal of Inclusion Phenomena and Macrocyclic Chemistry. 2017;87(1):53–65. https://doi.org/10.1007/s10847-016-0677-1