In situ co-amorphisation of arginine with indomethacin or furosemide during immersion in an acidic medium – A proof of concept study

TY - JOUR

T1 - In situ co-amorphisation of arginine with indomethacin or furosemide during immersion in an acidic medium – A proof of concept study

AU - Petry, Ina

AU - Löbmann, Korbinian

AU - Grohganz, Holger

AU - Rades, Thomas

AU - Leopold, Claudia S.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The concept of controlled in situ amorphisation of drug/polymer mixtures has been introduced previously with indomethacin-Eudragit® E and naproxen-Eudragit® E compacts. In the present study, the feasibility of in situ amorphisation of a crystalline API with the low molecular weight coformer arginine was investigated. This research was based on a previous study, which showed that a high relative humidity (75% RH) may induce co-amorphisation of indomethacin with arginine. It was assumed that an in situ co-amorphisation may be achieved, if a tablet containing a crystalline acidic API and the basic amino acid arginine, coated with a gastro-resistant but water-permeable coating, is exposed to an acidic medium. To investigate this hypothesis, tablets containing arginine and either indomethacin or furosemide were coated with Eudragit® L. After different time periods of immersion (10, 20, 30, 60, 120 min) in 0.1 M HCl, samples were analysed with respect to their solid state properties by XRPD, FTIR spectroscopy and modulated temperature DSC. In both formulations co-amorphous API-arginine was already detected after 10 min of immersion. The maximum of co-amorphous content was reached after 20 min with both formulations, while longer immersion time periods than 60 min revealed a partial API recrystallisation. In addition, during immersion of the indomethacin-arginine formulation, basic hydrolysis of indomethacin was observed, which could be prevented by addition of citric acid to the tablet formulation. However, this addition also inhibited the co-amorphisation of indomethacin. In this proof-of-principle study it was shown that the concept of in situ co-amorphisation of APIs with arginine might be a feasible formulation approach for those poorly water-soluble drugs, which are not susceptible to basic hydrolysis.

AB - The concept of controlled in situ amorphisation of drug/polymer mixtures has been introduced previously with indomethacin-Eudragit® E and naproxen-Eudragit® E compacts. In the present study, the feasibility of in situ amorphisation of a crystalline API with the low molecular weight coformer arginine was investigated. This research was based on a previous study, which showed that a high relative humidity (75% RH) may induce co-amorphisation of indomethacin with arginine. It was assumed that an in situ co-amorphisation may be achieved, if a tablet containing a crystalline acidic API and the basic amino acid arginine, coated with a gastro-resistant but water-permeable coating, is exposed to an acidic medium. To investigate this hypothesis, tablets containing arginine and either indomethacin or furosemide were coated with Eudragit® L. After different time periods of immersion (10, 20, 30, 60, 120 min) in 0.1 M HCl, samples were analysed with respect to their solid state properties by XRPD, FTIR spectroscopy and modulated temperature DSC. In both formulations co-amorphous API-arginine was already detected after 10 min of immersion. The maximum of co-amorphous content was reached after 20 min with both formulations, while longer immersion time periods than 60 min revealed a partial API recrystallisation. In addition, during immersion of the indomethacin-arginine formulation, basic hydrolysis of indomethacin was observed, which could be prevented by addition of citric acid to the tablet formulation. However, this addition also inhibited the co-amorphisation of indomethacin. In this proof-of-principle study it was shown that the concept of in situ co-amorphisation of APIs with arginine might be a feasible formulation approach for those poorly water-soluble drugs, which are not susceptible to basic hydrolysis.

KW - Arginine

KW - Co-amorphous

KW - Eudragit®

KW - Furosemide

KW - In situ amorphisation

KW - Indomethacin

U2 - 10.1016/j.ejpb.2018.10.011

DO - 10.1016/j.ejpb.2018.10.011

M3 - Journal article

C2 - 30339888

AN - SCOPUS:85055117583

SN - 0939-6411

VL - 133

SP - 151

EP - 160

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

ER -