Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer
N-butyl-N-methyl-1-phenylpyrrole[1,2-a] pyrazine-3-carboxamide (GML-3) is a potential candidate for combination drug therapy due to its anxiolytic and antidepressant activity. The anxiolytic activity of GML-3 is comparable to diazepam. The antidepressant activity of GML-3 is comparable to amitriptyl...
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| Format: | Article |
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MDPI AG
2023-10-01
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| Series: | Polymers |
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| Online Access: | https://www.mdpi.com/2073-4360/15/20/4136 |
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| author | Vladimir B. Markeev Sergey V. Tishkov Anton M. Vorobei Olga O. Parenago Evgenia V. Blynskaya Konstantin V. Alekseev Anna I. Marakhova Alexandre A. Vetcher |
| author_facet | Vladimir B. Markeev Sergey V. Tishkov Anton M. Vorobei Olga O. Parenago Evgenia V. Blynskaya Konstantin V. Alekseev Anna I. Marakhova Alexandre A. Vetcher |
| author_sort | Vladimir B. Markeev |
| collection | DOAJ |
| description | N-butyl-N-methyl-1-phenylpyrrole[1,2-a] pyrazine-3-carboxamide (GML-3) is a potential candidate for combination drug therapy due to its anxiolytic and antidepressant activity. The anxiolytic activity of GML-3 is comparable to diazepam. The antidepressant activity of GML-3 is comparable to amitriptyline. GML-3 is an 18 kDa mitochondrial translocator protein (TSPO) ligand and is devoid of most of the side effects of diazepam, which makes the research on the creation of drugs based on it promising. However, its low water solubility and tendency to agglomerate prevented its release. This research aimed to study the effect of dry grinding, the rapid expansion of a supercritical solution (RESS), and the eutectic mixture (composite) of GML-3 with polyvinylpyrrolidone (PVP) on the particle size, dissolution rate, and lattice retention of GML-3. The use of supercritical CO<sub>2</sub> in the RESS method was promising in terms of particle size reduction, resulting in a reduction in the particle size of GML-3 to 20–40 nm with a 430-fold increase in dissolution rate. However, in addition to particle size reduction after RESS, GML-3 began to show signs of a polymorphism phenomenon, which was also studied in this article. It was found that coarse grinding reduced particle size by a factor of 2 but did not significantly affect solubility or crystal structure. Co-milling with the polymer made it possible to level the effect of the appearance of a residual electrostatic charge on the particles, as in the case of grinding, and the increased solubility in the resulting mechanical mixtures of GML-3 with the polymer may also indicate the dissolving properties of polymers (an increase in 400–800 times). The best result in terms of GML-3 solubility was demonstrated by the resulting GML-3:PVP composite at a ratio of 1:4, which made it possible to achieve a solubility of about 80% active pharmaceutical ingredient (API) within an hour with an increase in the dissolution rate by 1600 times. Thus, the creation of composites is the most effective method for improving the solubility of GML-3, superior to micronization. |
| first_indexed | 2024-03-10T20:56:39Z |
| format | Article |
| id | doaj.art-6d52e5f192f241c49feb56e530576885 |
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| issn | 2073-4360 |
| language | English |
| last_indexed | 2024-03-10T20:56:39Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Polymers |
| spelling | doaj.art-6d52e5f192f241c49feb56e5305768852023-11-19T17:51:43ZengMDPI AGPolymers2073-43602023-10-011520413610.3390/polym15204136Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a PolymerVladimir B. Markeev0Sergey V. Tishkov1Anton M. Vorobei2Olga O. Parenago3Evgenia V. Blynskaya4Konstantin V. Alekseev5Anna I. Marakhova6Alexandre A. Vetcher7V.V. Zakusov Research Institute of Pharmacology, 8 Baltiyskaya St., 125315 Moscow, RussiaV.V. Zakusov Research Institute of Pharmacology, 8 Baltiyskaya St., 125315 Moscow, RussiaKurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31Leninsky Pr., 119071 Moscow, RussiaKurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31Leninsky Pr., 119071 Moscow, RussiaV.V. Zakusov Research Institute of Pharmacology, 8 Baltiyskaya St., 125315 Moscow, RussiaV.V. Zakusov Research Institute of Pharmacology, 8 Baltiyskaya St., 125315 Moscow, RussiaInstitute of Biochemical Technology and Nanotechnology, Peoples’ Friendship University of Russia n.a. P. Lumumba (RUDN), 6 Miklukho-Maklaya St., 117198 Moscow, RussiaInstitute of Biochemical Technology and Nanotechnology, Peoples’ Friendship University of Russia n.a. P. Lumumba (RUDN), 6 Miklukho-Maklaya St., 117198 Moscow, RussiaN-butyl-N-methyl-1-phenylpyrrole[1,2-a] pyrazine-3-carboxamide (GML-3) is a potential candidate for combination drug therapy due to its anxiolytic and antidepressant activity. The anxiolytic activity of GML-3 is comparable to diazepam. The antidepressant activity of GML-3 is comparable to amitriptyline. GML-3 is an 18 kDa mitochondrial translocator protein (TSPO) ligand and is devoid of most of the side effects of diazepam, which makes the research on the creation of drugs based on it promising. However, its low water solubility and tendency to agglomerate prevented its release. This research aimed to study the effect of dry grinding, the rapid expansion of a supercritical solution (RESS), and the eutectic mixture (composite) of GML-3 with polyvinylpyrrolidone (PVP) on the particle size, dissolution rate, and lattice retention of GML-3. The use of supercritical CO<sub>2</sub> in the RESS method was promising in terms of particle size reduction, resulting in a reduction in the particle size of GML-3 to 20–40 nm with a 430-fold increase in dissolution rate. However, in addition to particle size reduction after RESS, GML-3 began to show signs of a polymorphism phenomenon, which was also studied in this article. It was found that coarse grinding reduced particle size by a factor of 2 but did not significantly affect solubility or crystal structure. Co-milling with the polymer made it possible to level the effect of the appearance of a residual electrostatic charge on the particles, as in the case of grinding, and the increased solubility in the resulting mechanical mixtures of GML-3 with the polymer may also indicate the dissolving properties of polymers (an increase in 400–800 times). The best result in terms of GML-3 solubility was demonstrated by the resulting GML-3:PVP composite at a ratio of 1:4, which made it possible to achieve a solubility of about 80% active pharmaceutical ingredient (API) within an hour with an increase in the dissolution rate by 1600 times. Thus, the creation of composites is the most effective method for improving the solubility of GML-3, superior to micronization.https://www.mdpi.com/2073-4360/15/20/4136polymorphismmicronizationsolubilitypolyvinylpyrrolidoneanxiolyticsantidepressants |
| spellingShingle | Vladimir B. Markeev Sergey V. Tishkov Anton M. Vorobei Olga O. Parenago Evgenia V. Blynskaya Konstantin V. Alekseev Anna I. Marakhova Alexandre A. Vetcher Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer Polymers polymorphism micronization solubility polyvinylpyrrolidone anxiolytics antidepressants |
| title | Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer |
| title_full | Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer |
| title_fullStr | Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer |
| title_full_unstemmed | Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer |
| title_short | Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer |
| title_sort | modeling of the aqueous solubility of n butyl n methyl 1 phenylpyrrolo 1 2 a pyrazine 3 carboxamide from micronization to creation of amorphous crystalline composites with a polymer |
| topic | polymorphism micronization solubility polyvinylpyrrolidone anxiolytics antidepressants |
| url | https://www.mdpi.com/2073-4360/15/20/4136 |
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