Polymorphism of Triamcinolone Acetonide Acetate and Its Implication for the Morphology Stability of the Finished Drug Product

Abstract

Triamcinolone acetonide acetate (TAA) is a widely applied drug for rheumatoid arthritis and for the treatment of chronic inflammatory diseases. The drug was marketed as an injectable suspension with very low aqueous solubility. It was found that significant changes in crystal form, particle size, and morphology were observed during the shelf life period, which resulted in product lot failure and recall. TAA was thus an interesting subject for polymorphism screening and led to the discovery of multiple solid modifications, including three polymorphs (A, B, and C) and a monohydrate. These forms were fully characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy, dynamic vapor sorption, and zeta potential. Single-crystal structures of four different forms and the transformation pathways among different modifications were discussed in detail. Single-crystal-to-single-crystal transformation behaviors were also analyzed and monitored by variable temperature-powder X-ray diffraction and hot stage microscopy. Morphological stability, form change, and particle size in suspension were also closely monitored, and the data were compared with the marketed product. It was found that crystal form selection plays a critical role in the stability of the injectable suspension products. The results indicate that form B has better physical stability in 0.5% NaCMC aqueous suspension compared to that of the currently marketed form.

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“…30 A less common example is the triamcinolone acetonide acetate injectable formulation, for which crystallization of a polymorph resulted in product lot failure and recall, due to differences in the morphological stability of the two polymorphs. 41 In the case of transdermal delivery, polymorphism can also influence the rate and extent of transdermal penetration of a drug if the active substance crystallizes as a less soluble solid form from a drug product, usually a patch. For example, a more thermodynamically stable polymorph of the drug rotigotine for treatment of the symptoms of Parkinson's disease, crystallized from the rotigotine transdermal system Neupro Transdermal Patch, resulting in significantly reduced drug release and, hence, lower amount of free drug being available for absorption.…”

“…Later, three other polymorphs of ritonavir were discovered by high-throughput screening . A less common example is the triamcinolone acetonide acetate injectable formulation, for which crystallization of a polymorph resulted in product lot failure and recall, due to differences in the morphological stability of the two polymorphs …”