Application of multivariate anova and generalized desirability to optimize the composition and technology of tablets containing N-benzyl-N-methyl-1-phenylpyrrolo [1,2-a] pyrazine-3-carboxamide

The creation of drugs with an anxiolytic activity, which do not have the main side effects characteristic of drugs of this group, is an important and socially significant task. For its implementation, within the framework of the development of an original drug with an anxiolytic activity, the composition and manufacturing of GML-1 tablets (N-benzyl-N-methyl-1-phenylpyrrolo [1,2-a] pyrazine-3-carboxamide) are being developed.

The aim of this article is to study, using a four-factor analysis of variance, the influence of composition factors on the manufacturing properties of GML-1 tablets and the selection of the type, the amount, stage of the disintegrant addition and the type of lubricating excipients used in the technology of wet granulation of GML-1 tablets.

Materials and methods. The materials used are: the substance – GML-1 (N-benzyl-N-methyl-1-phenylpyrrolo [1,2-a] pyrazine-3-carboxamide). Excipients: microcrystalline cellulose 101 (MCC 101); polyvinylpyrrolidone (PVP); crospovidone, croscarmellose sodium (CCS), sodium starch glycolate (SSG); magnesium stearate (MS), sodium stearyl fumarate (SSF). To obtain tablet mixtures, wet granulation and tableting with the study of their main pharmaceutical and technological properties was used.

Results. Model compositions were developed and their pharmaceutical and technological properties were studied. These results have been analyzed, the degree of these factors’ influence and their interactions have been determined. In most of the cases considered, the interactions of the factors did not cause a significant change in the optimization criteria. With an increase in the amount of a disintegrant, the disintegration time decreased unevenly, so an increase in the amount of these excipients from 4 to 6 mg had a stronger effect than from 2 to 4 mg. Factor B affected the release degree non-linearly. Factor A influenced all the optimization criteria considered, especially a PS release. The best release and disintegration were observed with crospovidone, which was of a particular importance when processing the test results using a generalized desirability method.

Conclusion. In view of the conflicting variance analysis results, for particular factors, the resulting values were additionally analyzed using the generalized desirability function. The use of this method made it possible to reduce the conflicting variance analysis results to the most optimal composition.

Abbreviations: MP – medicinal product; DP – drug product; DF – dosage form; PS – pharmaceutical substance; API – active pharmaceutical ingredient; PVP – polyvinylpyrrolidone; MCC – microcrystalline cellulose; SCC – sodium croscarmellose; SSG – sodium starch glycolate; MS – magnesium stearate; SSF – sodium stearyl fumarate; GPM – General Pharmacopoeia Monograph.