TY - JOUR
T1 - Root cause evaluation of particulates in the lyophilized indomethacin sodium trihydrate plug for parenteral administration
AU - Siddiqui, Akhtar
AU - Rahman, Ziyaur
AU - Khan, Saeed R.
AU - Awotwe-Otoo, David
AU - Khan, Mansoor A.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - Particulate growth in parenteral product frequently results in product recalls causing drug shortages. While this is mostly attributed to quality issues in a firm, particulates growth could also be due to inadequate product, process, or environmental understanding. Therefore, the objective of this study was to use indomethacin sodium trihydrate (drug) as a model drug for lyophilization and evaluates short-term stability with respect to particulate growth at different storage temperatures. Under aseptic condition, each vial filled with filtered drug solution was lyophilized, and stoppered in LyoStar3. Crimped vials were kept at 5 °C, 15 °C, 25 °C, 25 °C/60%RH, and 40 °C/75%RH. At predefined time interval, samples were characterized using X-ray powder diffraction (XRPD), thermal, and spectroscopic method. Lyophilized formulation showed four thermal events: 60-90 °C demonstrating glass transition, 110-160 °C showing recrystallization exotherm,170-220 °C exhibiting endotherm of potential polymorph, and 250 °C showing melting endotherm. XRPD of the lyophilized powder demonstrated peak at 2θ 11.10. Spectroscopic studies of lyophilized powder indicated alteration in symmetric and asymmetric carboxylate peaks over time indicating initiation of crystallization and crystal growth. Reconstitution studies indicated higher reconstitution time after six weeks for sample stored at 40 °C/75%RH. Furthermore, reconstituted solution showed presence of particulates after 8 weeks storage. These studies suggest that particulate growth can stem from poorly developed formulation and not necessarily due to frequently ascribed filtration issues.
AB - Particulate growth in parenteral product frequently results in product recalls causing drug shortages. While this is mostly attributed to quality issues in a firm, particulates growth could also be due to inadequate product, process, or environmental understanding. Therefore, the objective of this study was to use indomethacin sodium trihydrate (drug) as a model drug for lyophilization and evaluates short-term stability with respect to particulate growth at different storage temperatures. Under aseptic condition, each vial filled with filtered drug solution was lyophilized, and stoppered in LyoStar3. Crimped vials were kept at 5 °C, 15 °C, 25 °C, 25 °C/60%RH, and 40 °C/75%RH. At predefined time interval, samples were characterized using X-ray powder diffraction (XRPD), thermal, and spectroscopic method. Lyophilized formulation showed four thermal events: 60-90 °C demonstrating glass transition, 110-160 °C showing recrystallization exotherm,170-220 °C exhibiting endotherm of potential polymorph, and 250 °C showing melting endotherm. XRPD of the lyophilized powder demonstrated peak at 2θ 11.10. Spectroscopic studies of lyophilized powder indicated alteration in symmetric and asymmetric carboxylate peaks over time indicating initiation of crystallization and crystal growth. Reconstitution studies indicated higher reconstitution time after six weeks for sample stored at 40 °C/75%RH. Furthermore, reconstituted solution showed presence of particulates after 8 weeks storage. These studies suggest that particulate growth can stem from poorly developed formulation and not necessarily due to frequently ascribed filtration issues.
KW - Indomethacin
KW - Lyophilization
KW - NIR
KW - Spectroscopy
KW - Stability
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U2 - 10.1016/j.ijpharm.2014.07.035
DO - 10.1016/j.ijpharm.2014.07.035
M3 - Article
C2 - 25089509
AN - SCOPUS:84905837220
SN - 0378-5173
VL - 473
SP - 545
EP - 551
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
IS - 1-2
ER -