Increase in Solubility of Poorly-Ionizable Pharmaceuticals by Salt Formation: A Case of Agomelatine Sulfonates

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00480929" target="_blank" >RIV/61388963:_____/17:00480929 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60461373:22310/17:43914798 RIV/60461373:22340/17:43914798 RIV/00216208:11320/17:10370291

Výsledek na webu

<a href="http://dx.doi.org/10.1021/acs.cgd.7b00805" target="_blank" >http://dx.doi.org/10.1021/acs.cgd.7b00805</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.cgd.7b00805" target="_blank" >10.1021/acs.cgd.7b00805</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Increase in Solubility of Poorly-Ionizable Pharmaceuticals by Salt Formation: A Case of Agomelatine Sulfonates

Popis výsledku v původním jazyce

The search for new solid forms of an active pharmaceutical ingredient (API) is an important step in drug development. Often, an API has a low water solubility, which then leads to low oral bioavailability. For basic or acidic APIs, the rational solution is the preparation of salts. For neutral, poorly ionizable, compounds, the cocrystallization is often the only choice. Agomelatine, a poorly soluble ”nonionizable” amide acting as a melatonergic antidepressant is a typical representative of such class of compounds. Until recently, the only multicomponent forms of agomelatine were cocrystals. In this work, we report the preparation of three salts of agomelatine (hydrogensulfate, mesylate, and besylate) and their solvated forms, along with their crystallographic characterization. Interestingly, the crystal structures of the solvated and nonsolvated hydrogensulfates were determined from the same crystal via a topotactic transformation. In all of the structures, the agomelatine molecule was positively charged with the amide oxygen being protonated. The salt formation was also confirmed by solid state nuclear magnetic resonance measurements and density functional theory calculations. By sulfonate salt formation, up to similar to 200-times faster dissolution of agomelatine was achieved, which proves that salts might be an attractive alternative even for the poorly ionizable compounds.

Název v anglickém jazyce

Increase in Solubility of Poorly-Ionizable Pharmaceuticals by Salt Formation: A Case of Agomelatine Sulfonates

Popis výsledku anglicky

The search for new solid forms of an active pharmaceutical ingredient (API) is an important step in drug development. Often, an API has a low water solubility, which then leads to low oral bioavailability. For basic or acidic APIs, the rational solution is the preparation of salts. For neutral, poorly ionizable, compounds, the cocrystallization is often the only choice. Agomelatine, a poorly soluble ”nonionizable” amide acting as a melatonergic antidepressant is a typical representative of such class of compounds. Until recently, the only multicomponent forms of agomelatine were cocrystals. In this work, we report the preparation of three salts of agomelatine (hydrogensulfate, mesylate, and besylate) and their solvated forms, along with their crystallographic characterization. Interestingly, the crystal structures of the solvated and nonsolvated hydrogensulfates were determined from the same crystal via a topotactic transformation. In all of the structures, the agomelatine molecule was positively charged with the amide oxygen being protonated. The salt formation was also confirmed by solid state nuclear magnetic resonance measurements and density functional theory calculations. By sulfonate salt formation, up to similar to 200-times faster dissolution of agomelatine was achieved, which proves that salts might be an attractive alternative even for the poorly ionizable compounds.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2017

Kód důvěrnosti údajů

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

Název periodika

Crystal Growth & Design

ISSN

1528-7483

e-ISSN

—

Svazek periodika

17

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

5283-5294

Kód UT WoS článku

000412718100035

EID výsledku v databázi Scopus

2-s2.0-85042508930