Selective formation of coamorphous systems with enzalutamide: Benzene rings as key structural features

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22340%2F25%3A43932416" target="_blank" >RIV/60461373:22340/25:43932416 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1016/j.ejps.2025.107281" target="_blank" >https://doi.org/10.1016/j.ejps.2025.107281</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejps.2025.107281" target="_blank" >10.1016/j.ejps.2025.107281</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Selective formation of coamorphous systems with enzalutamide: Benzene rings as key structural features

Popis výsledku v původním jazyce

Enzalutamide (ENZ), a non-steroidal antiandrogen used in the treatment of metastatic castration-resistant prostate cancer, exhibits poor aqueous solubility and bioavailability. Coamorphous systems, formed between an active pharmaceutical ingredient (API) and a low-molecular-weight coformer, offer a promising strategy to enhance solubility and dissolution. Here, we systematically screened a range of small organic acids and amino acids as coformers for coamorphous system formation with ENZ. Interestingly, full coamorphous systems formed exclusively with coformers containing a benzene ring, including benzoic acid, salicylic acid, 2-aminobenzoic acid, 2,5-dihydroxybenzoic acid (25H), L-phenylalanine, and L-tryptophan. Crystal structure analysis revealed that ENZ is stabilized in its crystalline state through strong pi-pi stacking, but these interactions are weakened or disrupted upon amorphization. Coamorphization is facilitated by coformers that can stabilize the amorphous phase through molecular complementarity and favorable packing. FTIR indicated limited new strong interactions, suggesting stabilization mainly via molecular mixing and weak pi-pi contacts. Thermal analysis confirmed single-phase systems with distinct Tg values, and stability studies revealed that the ENZ-25H system remained amorphous for nearly four months, outperforming others. Dissolution testing demonstrated up to a 3.6fold increase in intrinsic dissolution rate compared with crystalline ENZ. These results identify aromaticity as a critical structural feature for coamorphous formation with ENZ and provide a rational basis for coformer selection for this drug and, by extension, other aromatic-rich, poorly soluble APIs.

Název v anglickém jazyce

Selective formation of coamorphous systems with enzalutamide: Benzene rings as key structural features

Popis výsledku anglicky

Enzalutamide (ENZ), a non-steroidal antiandrogen used in the treatment of metastatic castration-resistant prostate cancer, exhibits poor aqueous solubility and bioavailability. Coamorphous systems, formed between an active pharmaceutical ingredient (API) and a low-molecular-weight coformer, offer a promising strategy to enhance solubility and dissolution. Here, we systematically screened a range of small organic acids and amino acids as coformers for coamorphous system formation with ENZ. Interestingly, full coamorphous systems formed exclusively with coformers containing a benzene ring, including benzoic acid, salicylic acid, 2-aminobenzoic acid, 2,5-dihydroxybenzoic acid (25H), L-phenylalanine, and L-tryptophan. Crystal structure analysis revealed that ENZ is stabilized in its crystalline state through strong pi-pi stacking, but these interactions are weakened or disrupted upon amorphization. Coamorphization is facilitated by coformers that can stabilize the amorphous phase through molecular complementarity and favorable packing. FTIR indicated limited new strong interactions, suggesting stabilization mainly via molecular mixing and weak pi-pi contacts. Thermal analysis confirmed single-phase systems with distinct Tg values, and stability studies revealed that the ENZ-25H system remained amorphous for nearly four months, outperforming others. Dissolution testing demonstrated up to a 3.6fold increase in intrinsic dissolution rate compared with crystalline ENZ. These results identify aromaticity as a critical structural feature for coamorphous formation with ENZ and provide a rational basis for coformer selection for this drug and, by extension, other aromatic-rich, poorly soluble APIs.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/EH22_008%2F0004607" target="_blank" >EH22_008/0004607: Nové technologie pro translační výzkum ve farmaceutických vědách /NETPHARM</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES

ISSN

0928-0987

e-ISSN

1879-0720

Svazek periodika

214

Číslo periodika v rámci svazku

214

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

9

Strana od-do

nestránkováno

Kód UT WoS článku

001586706800004

EID výsledku v databázi Scopus

2-s2.0-105017170012