The impact of ionic excipients on stabilization of enalapril
tablets by the formation of alkaline salt

J 2025

The impact of ionic excipients on stabilization of enalapril tablets by the formation of alkaline salt "in situ"

FRANC, Aleš; Bořek ŽALUDEK; Petr SOVA; Roman GONĚC; Jan MUSELÍK et al.

Základní údaje

Originální název

The impact of ionic excipients on stabilization of enalapril tablets by the formation of alkaline salt "in situ"

Autoři

FRANC, Aleš; Bořek ŽALUDEK; Petr SOVA; Roman GONĚC a Jan MUSELÍK

Vydání

European Journal of Pharmaceutics and Biopharmaceutics, AMSTERDAM, Elsevier, 2025, 0939-6411

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30104 Pharmacology and pharmacy

Stát vydavatele

Nizozemské království

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.300 v roce 2024

Organizační jednotka

Farmaceutická fakulta

DOI

https://doi.org/10.1016/j.ejpb.2025.114790

UT WoS

001521573800002

EID Scopus

2-s2.0-105009019492

Klíčová slova anglicky

Enalapril maleate; Tablets; Alkaline excipients; Sodium salt; Diacid; Diketopiperazine; Neutralization; Stability

Štítky

rivok, ÚFT

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 23. 7. 2025 10:37, Mgr. Irena Doubková

Anotace

V originále

The formation of salts is one of the possibilities of stabilizing medicinal substances. Salts can be prepared during the manufacture of the dosage form, saving time, reducing cost and environmental impact. Several studies have documented significant enalapril maleate (EM) instability. EM decomposes into diketopiperazine (DKP) and diacid (DA) impurities at elevated temperature and humidity. Notably, toxic DKP is preferentially formed at pH 2 - 3, and DA formation dominates at pH values above 5. This instability raises concerns about the therapeutic efficacy and safety of the drug. The proposed stabilization strategy involves the "in situ" conversion of EM into a stable sodium salt. This is achieved by incorporating suitable ionic excipients, specifically alkali metal salts and an ethanol-based hydrolysis inhibitor, into the granulation solution. This method effectively inhibits the deethylation to DA and provides uniform tablets with minimal DKP content to ensure long-term five-year stability. In general, these tablets show a lower content of degradation products compared to the stability results reported so far in various generics, and the amount of impurities meets the ICH Q3B (R2) requirements.

Citovat

FRANC, Aleš; Bořek ŽALUDEK; Petr SOVA; Roman GONĚC a Jan MUSELÍK. The impact of ionic excipients on stabilization of enalapril tablets by the formation of alkaline salt "in situ". European Journal of Pharmaceutics and Biopharmaceutics. AMSTERDAM: Elsevier, 2025, roč. 214, September, s. 1-9. ISSN 0939-6411. Dostupné z: https://doi.org/10.1016/j.ejpb.2025.114790.

@article{2509497,
   author = {Franc, Aleš and Žaludek, Bořek and Sova, Petr and Goněc, Roman and Muselík, Jan},
   article_location = {AMSTERDAM},
   article_number = {September},
   doi = {https://doi.org/10.1016/j.ejpb.2025.114790},
   keywords = {Enalapril maleate; Tablets; Alkaline excipients; Sodium salt; Diacid; Diketopiperazine; Neutralization; Stability},
   language = {eng},
   issn = {0939-6411},
   journal = {European Journal of Pharmaceutics and Biopharmaceutics},
   title = {The impact of ionic excipients on stabilization of enalapril tablets by the formation of alkaline salt "in situ"},
   url = {https://www.sciencedirect.com/science/article/pii/S0939641125001675?via%3Dihub},
   volume = {214},
   year = {2025}
}

TY  - JOUR
ID  - 2509497
AU  - Franc, Aleš - Žaludek, Bořek - Sova, Petr - Goněc, Roman - Muselík, Jan
PY  - 2025
TI  - The impact of ionic excipients on stabilization of enalapril tablets by the formation of alkaline salt "in situ"
JF  - European Journal of Pharmaceutics and Biopharmaceutics
VL  - 214
IS  - September
SP  - 1-9
EP  - 1-9
PB  - Elsevier
SN  - 09396411
KW  - Enalapril maleate
KW  - Tablets
KW  - Alkaline excipients
KW  - Sodium salt
KW  - Diacid
KW  - Diketopiperazine
KW  - Neutralization
KW  - Stability
UR  - https://www.sciencedirect.com/science/article/pii/S0939641125001675?via%3Dihub
N2  - The formation of salts is one of the possibilities of stabilizing medicinal substances. Salts can be prepared during the manufacture of the dosage form, saving time, reducing cost and environmental impact. Several studies have documented significant enalapril maleate (EM) instability. EM decomposes into diketopiperazine (DKP) and diacid (DA) impurities at elevated temperature and humidity. Notably, toxic DKP is preferentially formed at pH 2 - 3, and DA formation dominates at pH values above 5. This instability raises concerns about the therapeutic efficacy and safety of the drug. The proposed stabilization strategy involves the "in situ" conversion of EM into a stable sodium salt. This is achieved by incorporating suitable ionic excipients, specifically alkali metal salts and an ethanol-based hydrolysis inhibitor, into the granulation solution. This method effectively inhibits the deethylation to DA and provides uniform tablets with minimal DKP content to ensure long-term five-year stability. In general, these tablets show a lower content of degradation products compared to the stability results reported so far in various generics, and the amount of impurities meets the ICH Q3B (R2) requirements.
ER  -

FRANC, Aleš; Bořek ŽALUDEK; Petr SOVA; Roman GONĚC a Jan MUSELÍK. The impact of ionic excipients on stabilization of enalapril tablets by the formation of alkaline salt ''in situ''. \textit{European Journal of Pharmaceutics and Biopharmaceutics}. AMSTERDAM: Elsevier, 2025, roč.~214, September, s.~1-9. ISSN~0939-6411. Dostupné z: https://doi.org/10.1016/j.ejpb.2025.114790.

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