A slow cooling rate of indomethacin melt spatially confined in microcontainers increases the physical stability of the amorphous drug without influencing its biorelevant dissolution behaviour

TY - JOUR

T1 - A slow cooling rate of indomethacin melt spatially confined in microcontainers increases the physical stability of the amorphous drug without influencing its biorelevant dissolution behaviour

AU - Nielsen, Line Hagner

AU - Keller, Stephan Sylvest

AU - Boisen, Anja

AU - Müllertz, Anette

AU - Rades, Thomas

PY - 2014/6

Y1 - 2014/6

N2 - Amorphous indomethacin was prepared by melting the γ-form of indomethacin, spatially confined within microcontainers (inner diameter of 223 μm), followed by cooling of the melt at a rate of 14, 23 or 36 K/min. The physical stability of the amorphous indomethacin within microcontainers was investigated using Raman microscopy. Furthermore, the dissolution behaviour of confined amorphous indomethacin was evaluated in biorelevant intestinal media at pH 6.5. After 30 days of storage, 10.3 ± 1.2 % of the amorphous indomethacin cooled at 14 K/min and confined within microcontainers was found to be crystalline. When the melt of indomethacin was cooled at 23 or 36 K/min, 20.7 ± 1.5 and 31.0 ± 2.6 % of the indomethacin were found to be crystalline after storage for 30 days. Scanning electron microscopy showed a smooth surface of amorphous indomethacin within the microcontainers when cooling the melt at 14 K/min, whereas cracks and an uneven surface were observed when cooling at rates of 23 and 36 K/min. The uneven surface is hypothesised to be the main reason for the lower physical stability, as the cracks could act as nucleation sites for crystal growth. The rate of cooling was not seen to have any effect on the dissolution of amorphous indomethacin from the microcontainers.

AB - Amorphous indomethacin was prepared by melting the γ-form of indomethacin, spatially confined within microcontainers (inner diameter of 223 μm), followed by cooling of the melt at a rate of 14, 23 or 36 K/min. The physical stability of the amorphous indomethacin within microcontainers was investigated using Raman microscopy. Furthermore, the dissolution behaviour of confined amorphous indomethacin was evaluated in biorelevant intestinal media at pH 6.5. After 30 days of storage, 10.3 ± 1.2 % of the amorphous indomethacin cooled at 14 K/min and confined within microcontainers was found to be crystalline. When the melt of indomethacin was cooled at 23 or 36 K/min, 20.7 ± 1.5 and 31.0 ± 2.6 % of the indomethacin were found to be crystalline after storage for 30 days. Scanning electron microscopy showed a smooth surface of amorphous indomethacin within the microcontainers when cooling the melt at 14 K/min, whereas cracks and an uneven surface were observed when cooling at rates of 23 and 36 K/min. The uneven surface is hypothesised to be the main reason for the lower physical stability, as the cracks could act as nucleation sites for crystal growth. The rate of cooling was not seen to have any effect on the dissolution of amorphous indomethacin from the microcontainers.

U2 - 10.1007/s13346-013-0166-7

DO - 10.1007/s13346-013-0166-7

M3 - Journal article

C2 - 25786881

SN - 2190-393X

VL - 4

SP - 268

EP - 274

JO - Drug Delivery and Translational Research

JF - Drug Delivery and Translational Research

IS - 3

ER -