Polymorphism of Indomethacin in Semicrystalline Dispersions: Formation, Transformation, and Segregation

Abstract

The crystallization of metastable crystal polymorphs in polymer matrices has been extensively reported in literature as a possible approach to enhance the solubility of poorly water-soluble drug compounds, yet no clarification of the mechanism of the polymorph formation has been proposed. The current work aims to elucidate the polymorphism behavior of the model compound indomethacin as well as the mechanism of polymorph selection of drugs in semicrystalline systems. Indomethacin crystallized as either the α- or τ-form, a new metastable form, or a mixture of the two polymorphs in dispersions containing different drug loadings in polyethylene glycol, poloxamer, or Gelucire as the result of the variation in the mobility of drug molecules. As a general rule, low molecular mobility of the amorphous drug favors the crystallization into thermodynamically stable forms whereas metastable crystalline polymorphs are preferred when the molecular mobility of the drug is sufficiently high. This rule provides insight into the polymorph selection of numerous active pharmaceutical ingredients in semicrystalline dispersions and can be used as a guide for polymorphic screening from melt crystallization by tuning the mobility of drug molecules. In addition, the drug crystallized faster while the polymer crystallized slower as the drug-loading increased with the maxima of drug crystallization rate in 70% indomethacin dispersion. Increasing the drug content in solid dispersions reduced the τ to α polymorphic transition rate, except for when the more stable form was initially dominant. The segregation of τ and α polymorphs as well as the polymorphic transformation during storage led to the inherent inhomogeneity of the semicrystalline dispersions. This study highlights and expands our understanding about the complex crystallization behavior of semicrystalline systems and is crucial for preparation of solid dispersions with reproducible and consistent physicochemical properties and pharmaceutical performance.

Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances

“…The majority of studies on semicrystalline dispersions employed PEG as a carrier. Multiple aspects about drug-PEG dispersions, including their microstructure [ 3 , 5 ], crystallinity [ 2 , 6 ], interactions [ 7 , 8 ], stability [ 9 ], and dissolution performances [ 10 , 11 ] have been described. Alternatively to PEG, a class of hydrophilic surface-active PEG derivatives called Gelucires ® has been proposed as a carrier for the production of semicrystalline solid dispersions [ 12 ].…”

Spray Congealing: An Emerging Technology to Prepare Solid Dispersions with Enhanced Oral Bioavailability of Poorly Water Soluble Drugs

“…This tendency results in the progressive crystallization of both components: the API will be excluded from the carrier-rich crystalline phase and, conversely, the drug segregation and crystallization will favor the carrier crystallization. This process has been very clearly explained by Van Duong and co-workers by studying the indomethacin PEG-based SD [58,59].…”

Evaluation of the Solid Dispersion System Engineered from Mesoporous Silica and Polymers for the Poorly Water Soluble Drug Indomethacin: In Vitro and In Vivo

“…This interaction between the carriers and IMC can be analyzed by the shift of the carbonyl peak and the hydrogen and oxygen peaks. Figure 4C shows the IR spectra of IMC and SDs, in which IMC exhibited rather broad OH vibration bands from 3400 to 2500 cm −1 [28]. The bands at 1692 cm −1 , 1685 cm −1 , and 1680 cm −1 originated from the stretching vibration of benzoyl ν C=O of IMC, IMC-MSNs@Kollicoat IR (F6), and IMC-MSNs@HPMC (F9), respectively.…”