Abstract:
The main objective of this work was to understand particle formation pathways and polymorphism of curcumin. Curcumin is a poorly water soluble ingredient found in turmeric (Curcumin longa). In this ork, curcumin was precipitated by liquid antisolvent (LAS) technique in presence of ultrasound and additives. The curcumin particles precipitated in presence of ultrasound and with (or without) additives were found to be in orthorhombic forms (Forms 2 or 3), whereas raw curcumin and curcumin particles precipitated without ultrasound and without additives were found to be in monoclinic form (Form 1). Solid-state characterization studies of these particles revealed that the orthorhombic forms (Forms 2 and 3) undergo polymorphic transformation to monoclinic form (Form 1) during differential scanning Calorimetry (DSC) heating studies. These polymorphic transformations were found to occur below the melting points of all three curcumin forms, hence polymorphs could be enantiotropically related to each other. However, further research is required to establish relationship between the curcumin polymorphs. Curcumin particles precipitated with ultrasound and bovine serum albumin (BSA), hydroxyl propyl methylcellulose (HPMC), and polyvinyl pyrrolidone (PVP) were found to follow non-classical particle formation pathways. These particles precipitated as micron sized superstructures formed by aggregation of several primary curcumin nanoparticles. The particles appeared to be the loose aggregates (of ~1–5 μm in size) composed of several curcumin nanoparticles (~50–200 nm in size). Curcumin particles precipitated with ultrasound and other additives such as, SDS (at concentration below and above critical micelle concentration (CMC)), Tween 80 (at concentration below, and above CMC), Sodium Alginate (Na-Alg), Polymer JR 400, and Pluronic F68 (PF68) however, appeared to be completely fused particles. Hence, hypothesizing particle formation pathways in these cases was difficult. Curcumin particles precipitated in presence of ultrasound and additives such as, Tween 80 (at concentration below CMC), Sodium Alginate (Na-Alg), and Pluronic F68 (PF68) were found to be mixture of both Form 3 and Form 1. This concomitant behavior of polymorphs could be the result of the nucleation of Form 3 and Form 1, when precipitated in presence of these additives and ultrasound. The morphology of curcumin particles was found to be dependent on the polymorphic form of the precipitated curcumin particles. Rice seed like morphology was found to be indicative of orthorhombic form whereas rectangular plate-like morphology was the indication of monoclinic form. The long term stability of precipitated curcumin particles in terms of polymorphic as well as morphological transformations was also studied. Curcumin particles precipitated with higher ultrasound energy (105W) were stable in terms of particle size and size distribution for nearly 2 years. However, the particles precipitated with lower ultrasound energy (13W) or without ultrasound (0W) were found to grow to larger particles. Similarly, the precipitated curcumin particles stored in aqueous suspensions at room temperature (25°C) were found to remain stable in the same polymorphic form as that of freshly precipitated particles with no significant change in particle morphology even after 3 years.
The results presented in this work demonstrate that the particle formation pathways of curcumin could be manipulated to obtain desired polymorphic and morphological characteristics through a judicious choice of additives and vii mixing techniques (ultrasound vs. stirring). Moreover, the methodology developed could be applied to other poorly water-soluble drugs as well as other organic and inorganic materials.