Scientific Publications by FDA Staff

Int J Pharm 2014 Oct 1;473(1-2):545-51

Root cause evaluation of particulates in the lyophilized indomethacin sodium trihydrate plug for parenteral administration.

Siddiqui A, Rahman Z, Khan SR, Awotwe-Otoo D, Khan MA

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 degrees C, 15 degrees C, 25 degrees C, 25 degrees C/60%RH, and 40 degrees 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 degrees C demonstrating glass transition, 110-160 degrees C showing recrystallization exotherm,170-220 degrees C exhibiting endotherm of potential polymorph, and 250 degrees C showing melting endotherm. XRPD of the lyophilized powder demonstrated peak at 2theta 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 degrees 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.