Klimashevich V.B.1, Kazyuchits O.A.1, Zhebentyaev A.I.2, Gudovich V.V.1, Nasennikova E.E.1
Technological aspects of the pharmaceutical development of the ranolazine-based drug
1Republican Unitary Enterprise «ACADEMPHARM», Minsk, Republic of Belarus
2Vitebsk State Order of Peoples’ Friendship Medical University, Vitebsk, Republic of Belarus
Vestnik VGMU. 2019;18(4):98-112.
Objectives. To develop a generic drug, identify the main risks to the quality of the target product at the stage of the development of its composition and technology for the production of the finished dosage form, taking the results of the study of the regularities of the ranolazine release from matrix tablets as the basis.
Material and methods. The equivalence assessment in the test of the comparative kinetics of in vitro dissolution of the tablets of the studied variants and tablets of the original drug was carried out in the following pharmacopoeial dissolution media: 0.1 M HCl solution with pH 1.2, acetate buffer with pH 4.5, phosphate buffer with pH 6.8, 0.1 M HCl solution (pH 1.2) with a change in 2 hours to phosphate buffer solution (pH 6.8). In the medium with a pH change from 1.2 to 6.8, two-factor dispersion analysis was performed. The final optimization of the composition of the drug based on ranolazine was carried out as a result of the full factorial experiment 23.
Results. The release of ranolazine from prolonged action tablets, obtained on the basis of a combined matrix system from pH-independent and pH-dependent polymers, was studied in pharmacopoeial media with pH 1.2, 4.5 and 6.8. In the medium with pH change from 1.2 to 6.8, as a result of the made two-factor analysis of variance, factors (type of pH-dependent and pH-independent polymer) were identified that significantly affect the release of ranolazine at the time points studied. The following polymers were used as pH-independent: Methocel E10M Premium CR, Methocel K100M Premium CR; the following polymers were used as pH-dependent: Eudragit L 100-55, Kollicoat MAE 100P, Carbopol 974 P. The composition of the hydrophilic matrix was developed, that provides dissolution profiles equivalent to the original drug in the test of comparative in vitro dissolution kinetics in all media studied. The composition of nonfunctional excipients was optimized using the full factorial experiment 23.
Conclusions. During the pharmaceutical development of the composition and production technology, the following risks to the quality of ranolazine-based generic product were revealed: the type and brand of pH-dependent and pH-independent polymer matrix, the number of non-matrix-forming substances in the tablet, the type of equipment and pressing force, as well as geometric characteristics of the tablet.
Key words: ranolazine, prolonged action, matrix tablets, pH-dependent polymer, pH-independent polymer.
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Information about authors:
Klimashevich V.B. – main technologist of the laboratory of finished dosage forms technology of the scientific research and development department, Republican Unitary Enterprise «ACADEMPHARM»;
Kazyuchits O.A. – Candidate of Biological Sciences, deputy director for scientific work, Republican Unitary Enterprise «ACADEMPHARM»;
Zhebentyaev A.I. – Doctor of Pharmaceutical Sciences, professor, head of the Chair of Toxicological & Analytic Chemistry, Vitebsk State Order of Peoples’ Friendship Medical University;
Gudovich V.V. – deputy head of the laboratory of pharmaceutical & pharmacologic researches, Republican Unitary Enterprise «ACADEMPHARM»;
Nasennikova E.E. – head of the laboratory of finished dosage forms technology, Republican Unitary Enterprise «ACADEMPHARM».