NMR spectroscopy study of the structure of hypromellose phthalate, a component of enteric coatings of medicinal products

Scientific relevance. Hypromellose phthalate is a component of enteric coatings used to modify active substance release from oral medicinal products in the small intestine. The release rate directly depends on the non-stoichiometric composition of the polymer, first of all, on the proportion of phthalate groups in the macromolecule. It is therefore necessary to develop reliable analytical procedures for determining the structure of hypromellose phthalate to evaluate the dissolution rate of medicinal products containing the polymer.

Aim. The study aimed to develop an analytical procedure for quantifying the proportion of phthalate groups in hypromellose phthalate samples using NMR spectroscopy and to determine the relationship between the polymer dissolution rate in aqueous buffer solutions and its structural features (degree of molar substitution and molecular mass).

Materials and methods. The study examined hypromellose phthalate samples isolated from enteric coatings of proton-pump inhibitors and used the reference standard for hypromellose phthalate. The non-stoichiometric composition of the polymer was determined by 13C NMR spectroscopy.

Results. The authors established the conditions required to separate hypromellose phthalate from the other coating components and identified the characteristic 13C NMR signals that may be used to differentiate between the structural fragments of hypromellose phthalate. The study demonstrated the relationship between the dissolution rate and the structure of the polymer. Commercial grades of hypromellose phthalate were shown to differ in composition and, as a result, in their dissolution kinetics (in particular, the threshold pH for the onset of dissolution (5.0–5.5), as well as the dissolution rates at the same pH).

Conclusions. The authors developed NMR-based procedures to determine the proportion of phthalate groups on the basis of their mass fraction in a weighted hypromellose phthalate sample and the degree of molar substitution of the polymer. The results support the applicability of these analytical procedures to the characterisation of sample composition in polymer dissolution rate studies. In principle, it is possible to derive a multiple linear regression equation that describes the dissolution rate of hypromellose phthalate as a function of the molecular mass and the molar substitution with phthalate groups. Further investigation of a larger number of polymer samples with different compositions is needed to improve the regression model and demonstrate its statistical significance. In addition to the proportion of phthalate groups, the pharmacopoeial analysis of hypromellose phthalate should also control the molecular mass of the polymer.

1. Kalmer RR, Haddadan MM, Azizi М, Ghanbari М, Samandarian В, Sadjadinia A, et al. Industrial manufacture of enteric hard capsules using novel formulations based on hypromellose phthalate/gelatin and investigation of pantoprazole release. ACS Omega. 2023;8(12):11293–303. https://doi.org/10.1021/acsomega.2c08290

2. Chung JH, Lee SJ, Chung JO, Oh YJ, Hwang JA, Kim YK, et al. Effect of hydroxypropyl methyl cellulose phthalate coating on digestive stability and intestinal transport of green tea catechins. Integr Med Res. 2014;3(1):34–7. https://doi.org/10.1016/j.imr.2013.11.001

3. Fu M, Blechar JA, Sauer A, Al-Gousous J, Langguth P. In vitro evaluation of enteric-coated HPMC capsules— effect of formulation factors on product performance. Pharmaceutics. 2020;12(8):696–712. https://doi.org/10.3390/pharmaceutics12080696

4. Moiseev SV, Kuz’mina NE, Severinova EYu, Bunyatyan ND, Evteev VA. NMR spectroscopy study of the effect of the molecular mass of hypromellose phthalate on Its solubility. Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. Regulatory Research and Medicine Evaluation. 2023;13(4):385–93 (In Russ.). https://doi.org/10.30895/1991-2919-2023-541

5. Moiseev SV, Kuz’mina NE, Luttseva AI. NMR as used in the Russian and foreign pharmacopoeias for quality control of medicinal products. Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. Regulatory Research and Medicine Evaluation. 2022;12(1):8–24 (In Russ.). https://doi.org/10.30895/1991-2919-2022-12-1-8-23

6. Rodionova OY, Pomerantsev AL. Chemometrics: achievements and prospects. Russian Chemical Reviews. 2006;75(4):302–21 (In Russ.). https://doi.org/10.1070/RC2006v075n04ABEH003599