Crystal engineering of salts and cyclodextrin inclusion complexes of selected medicinal agents

Pietrobelli, Erica

Crystal engineering of salts and cyclodextrin inclusion complexes of selected medicinal agents

Thesis / Dissertation

2026

Publisher

University of Cape Town

Department

Department of Chemistry

Faculty

Faculty of Science

Abstract

The objective of this study was to improve the aqueous solubility of four active pharmaceutical ingredients (APIs), namely droperidol, tolfenamic acid, loratadine and 5methoxy-1H-indole-2-carboxylic acid via supramolecular derivatization. The main techniques employed were co-crystallization and cyclodextrin inclusion complexation. All isolated products were characterised using powder X-ray diffraction (PXRD), hot stage microscopy (HSM), Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). When a single crystal was obtained, it was characterized with single-crystal X-ray diffraction (SCXRD). Co-crystallization was attempted for each API in combination with different “generally recognized as safe” (GRAS) coformers to form co-crystals. Liquid-assisted grinding (LAG) and co-precipitation experiments involving droperidol and loratadine were generally unproductive due to their intractable nature, while tolfenamic acid was tractable but showed no affinity for co-crystallization. On the other hand, the experiments with MICA (5-methoxy-1H-indole-2-carboxylic acid) resulted in the successful synthesis and characterisation of salts with isonicotinamide and piperazine, with a MICA:coformer 2:1 molar ratio in both cases. Cyclodextrin (CD) inclusion complexation of the APIs was studied with β-CD, γ-CD and dimethylated β-CD (DIMEB). The complexation attempts yielded an inclusion complex between DIMEB and loratadine. A single crystal was isolated, and its crystal structure was determined. The general structural features of a new β-CD inclusion complex of MICA were deduced using PXRD in the absence of suitable crystals for SCXRD by establishing isostructurality of its host assembly with that of a series of known CD complexes. Phase solubility studies of MICA were carried out in aqueous medium using β-CD, γ-CD, hydroxypropyl-β-cyclodextrin (HPβCD), randomly methylated β-cyclodextrin (RAMEB) and sulfobutyl ether β-cyclodextrin sodium salt (SeβCD). The stability constants of the resulting complexes were estimated, and solubility improvement of MICA was recorded. RAMEB produced the greatest solubility enhancement of MICA by a factor of ~11 at the highest CD concentration employed.

Keywords

aqueous solubility

pharmaceutical ingredients

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