Undesired co-amorphisation of indomethacin and arginine during combined storage at high humidity conditions

Ina Petry; Korbinian Löbmann; Holger Grohganz; Thomas Rades; Claudia S. Leopold

doi:10.1016/j.ijpharm.2018.04.026

Undesired co-amorphisation of indomethacin and arginine during combined storage at high humidity conditions

Ina Petry, Korbinian Löbmann, Holger Grohganz, Thomas Rades, Claudia S. Leopold^*

^*Corresponding author af dette arbejde

8 Citationer (Scopus)

Abstract

The use of co-amorphous systems for solubility enhancement of poorly water-soluble drugs has recently gained interest in the field of pharmaceutical technology. However, undesired co-amorphisation of a drug may lead to an alteration of the performance of the drug product, e.g. the previously observed co-amorphisation of indomethacin and arginine upon storage of tablets containing both components in an initially crystalline form at room temperature (RT) and 75% relative humidity (RH). Therefore, the aim of the present study was to further investigate this unintended co-amorphisation by storing plain crystalline γ-indomethacin and arginine as well as physical mixtures of both components at RT and three different RH levels (28, 58, and 75% RH). After storage for up to 101 days, their properties were analysed by X-ray powder diffraction, infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and HPLC. Results showed that the solid state of plain γ-indomethacin did not change during storage at all three storage conditions. In contrast, arginine was found to form a dihydrate upon storage at RT/58% RH and RT/75% RH. The physical mixtures, stored at RT/28% RH and RT/58% RH, remained crystalline and were chemically stable, while the formation of a co-amorphous salt between indomethacin and arginine as well as basic hydrolysis of indomethacin started already 1 day after exposure to RT/75% RH. Moreover, formation of a crystalline salt of indomethacin and arginine upon storage at RT/75% RH was observed. As neither of these instabilities occurred, if indomethacin was stored separately, the simultaneous effects of arginine and moisture on the solid state properties and chemical stability of indomethacin should be taken into account, if selecting arginine as excipient.

Originalsprog	Engelsk
Tidsskrift	International Journal of Pharmaceutics
Vol/bind	544
Udgave nummer	1
Sider (fra-til)	172-180
Antal sider	9
ISSN	0378-5173
DOI	https://doi.org/10.1016/j.ijpharm.2018.04.026
Status	Udgivet - 2018

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10.1016/j.ijpharm.2018.04.026

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title = "Undesired co-amorphisation of indomethacin and arginine during combined storage at high humidity conditions",

abstract = "The use of co-amorphous systems for solubility enhancement of poorly water-soluble drugs has recently gained interest in the field of pharmaceutical technology. However, undesired co-amorphisation of a drug may lead to an alteration of the performance of the drug product, e.g. the previously observed co-amorphisation of indomethacin and arginine upon storage of tablets containing both components in an initially crystalline form at room temperature (RT) and 75% relative humidity (RH). Therefore, the aim of the present study was to further investigate this unintended co-amorphisation by storing plain crystalline γ-indomethacin and arginine as well as physical mixtures of both components at RT and three different RH levels (28, 58, and 75% RH). After storage for up to 101 days, their properties were analysed by X-ray powder diffraction, infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and HPLC. Results showed that the solid state of plain γ-indomethacin did not change during storage at all three storage conditions. In contrast, arginine was found to form a dihydrate upon storage at RT/58% RH and RT/75% RH. The physical mixtures, stored at RT/28% RH and RT/58% RH, remained crystalline and were chemically stable, while the formation of a co-amorphous salt between indomethacin and arginine as well as basic hydrolysis of indomethacin started already 1 day after exposure to RT/75% RH. Moreover, formation of a crystalline salt of indomethacin and arginine upon storage at RT/75% RH was observed. As neither of these instabilities occurred, if indomethacin was stored separately, the simultaneous effects of arginine and moisture on the solid state properties and chemical stability of indomethacin should be taken into account, if selecting arginine as excipient.",

keywords = "Arginine, Co-amorphous, Hydrate, In situ amorphisation, Indomethacin, Physicochemical stability",

author = "Ina Petry and Korbinian L{\"o}bmann and Holger Grohganz and Thomas Rades and Leopold, {Claudia S.}",

year = "2018",

doi = "10.1016/j.ijpharm.2018.04.026",

language = "English",

volume = "544",

pages = "172--180",

journal = "International Journal of Pharmaceutics",

issn = "0378-5173",

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TY - JOUR

T1 - Undesired co-amorphisation of indomethacin and arginine during combined storage at high humidity conditions

AU - Petry, Ina

AU - Löbmann, Korbinian

AU - Grohganz, Holger

AU - Rades, Thomas

AU - Leopold, Claudia S.

PY - 2018

Y1 - 2018

N2 - The use of co-amorphous systems for solubility enhancement of poorly water-soluble drugs has recently gained interest in the field of pharmaceutical technology. However, undesired co-amorphisation of a drug may lead to an alteration of the performance of the drug product, e.g. the previously observed co-amorphisation of indomethacin and arginine upon storage of tablets containing both components in an initially crystalline form at room temperature (RT) and 75% relative humidity (RH). Therefore, the aim of the present study was to further investigate this unintended co-amorphisation by storing plain crystalline γ-indomethacin and arginine as well as physical mixtures of both components at RT and three different RH levels (28, 58, and 75% RH). After storage for up to 101 days, their properties were analysed by X-ray powder diffraction, infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and HPLC. Results showed that the solid state of plain γ-indomethacin did not change during storage at all three storage conditions. In contrast, arginine was found to form a dihydrate upon storage at RT/58% RH and RT/75% RH. The physical mixtures, stored at RT/28% RH and RT/58% RH, remained crystalline and were chemically stable, while the formation of a co-amorphous salt between indomethacin and arginine as well as basic hydrolysis of indomethacin started already 1 day after exposure to RT/75% RH. Moreover, formation of a crystalline salt of indomethacin and arginine upon storage at RT/75% RH was observed. As neither of these instabilities occurred, if indomethacin was stored separately, the simultaneous effects of arginine and moisture on the solid state properties and chemical stability of indomethacin should be taken into account, if selecting arginine as excipient.

AB - The use of co-amorphous systems for solubility enhancement of poorly water-soluble drugs has recently gained interest in the field of pharmaceutical technology. However, undesired co-amorphisation of a drug may lead to an alteration of the performance of the drug product, e.g. the previously observed co-amorphisation of indomethacin and arginine upon storage of tablets containing both components in an initially crystalline form at room temperature (RT) and 75% relative humidity (RH). Therefore, the aim of the present study was to further investigate this unintended co-amorphisation by storing plain crystalline γ-indomethacin and arginine as well as physical mixtures of both components at RT and three different RH levels (28, 58, and 75% RH). After storage for up to 101 days, their properties were analysed by X-ray powder diffraction, infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and HPLC. Results showed that the solid state of plain γ-indomethacin did not change during storage at all three storage conditions. In contrast, arginine was found to form a dihydrate upon storage at RT/58% RH and RT/75% RH. The physical mixtures, stored at RT/28% RH and RT/58% RH, remained crystalline and were chemically stable, while the formation of a co-amorphous salt between indomethacin and arginine as well as basic hydrolysis of indomethacin started already 1 day after exposure to RT/75% RH. Moreover, formation of a crystalline salt of indomethacin and arginine upon storage at RT/75% RH was observed. As neither of these instabilities occurred, if indomethacin was stored separately, the simultaneous effects of arginine and moisture on the solid state properties and chemical stability of indomethacin should be taken into account, if selecting arginine as excipient.

KW - Arginine

KW - Co-amorphous

KW - Hydrate

KW - In situ amorphisation

KW - Indomethacin

KW - Physicochemical stability

U2 - 10.1016/j.ijpharm.2018.04.026

DO - 10.1016/j.ijpharm.2018.04.026

M3 - Journal article

C2 - 29669257

AN - SCOPUS:85046030652

SN - 0378-5173

VL - 544

SP - 172

EP - 180

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

IS - 1

ER -

Undesired co-amorphisation of indomethacin and arginine during combined storage at high humidity conditions

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