Spray Encapsulation as a Formulation Strategy for Drug-Based Room Temperature Ionic Liquids: Exploiting Drug-Polymer Immiscibility to Enable Processing for Solid Dosage Forms

Michael W Stocker; Anne Marie Healy; Steven Ferguson

doi:10.1021/acs.molpharmaceut.0c00467

Spray Encapsulation as a Formulation Strategy for Drug-Based Room Temperature Ionic Liquids: Exploiting Drug-Polymer Immiscibility to Enable Processing for Solid Dosage Forms

Mol Pharm. 2020 Sep 8;17(9):3412-3424. doi: 10.1021/acs.molpharmaceut.0c00467. Epub 2020 Aug 27.

Authors

Michael W Stocker¹, Anne Marie Healy², Steven Ferguson^{1

3

4}

Affiliations

¹ School of Chemical and Bioprocess Engineering, University College Dublin, Dublin 4, Ireland.
² SSPC, The SFI Research Centre for Pharmaceuticals, School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, Dublin 2, Ireland.
³ SSPC, The SFI Research Centre for Pharmaceuticals, School of Chemical and Bioprocess Engineering, University College Dublin, Dublin 4, Ireland.
⁴ I-form, The SFI Research Centre for Advanced Manufacturing, School of Chemical and Bioprocess Engineering, University College Dublin, Dublin 4, Ireland.

PMID: 32852215
DOI: 10.1021/acs.molpharmaceut.0c00467

Abstract

Active pharmaceutical ingredient (API)-based ionic liquids (API-ILs) present an exciting new paradigm for the formulation of poorly water-soluble drugs. In this study, a model room temperature API-IL (1-butyl-3-methyl imidazolium ibuprofenate) was demonstrated to be not just highly soluble but fully miscible and hence have effectively unlimited solubility in water, compared to 0.021 mg mL^-1 solubility for the ibuprofen API. Solutions of the API-IL were found to be stable for up to 2 years, indicating that they have the potential to offer thermodynamic stability upon release, avoiding in vivo recrystallization issues that can limit the bioavailability of amorphous solid dispersions (ASDs) and some high-energy crystalline forms. The ibuprofen API-IL was successfully spray-dried into a polymer carrier in loadings of up to 75% w/w in order to transform it into a solid powder suitable for oral solid dosage (OSD) formulation. From modulated differential scanning calorimetry, hot-stage microscopy, powder X-ray diffraction, and attenuated total reflectance Fourier transform infrared spectroscopy measurements, the mechanism by which this high loading was achieved is based on the immiscibility between the polymer and API-IL, with the polymer encapsulating the phase-separated API-IL. Dissolution studies showed that solidification of the API-IL into microcapsules by spray drying in this manner had no detrimental effect on release characteristics. Failure to dissolve crystalline API forms into the polymer matrix eliminates the solubility enhancement of ASDs but not for highly soluble or fully miscible API-ILs. Furthermore, miscible API-IL/polymer dispersions at high loadings were found to possess less-favorable physical properties because of melting point depression, resulting, in some cases, in a failure to form a viable powder. As such, microencapsulated API-ILs at high loadings in immiscible or low-miscibility polymers that have solubility enhancement of the API-IL form, while providing solid powders for processing, represent a promising new platform for the formulation of poorly soluble compounds as OSDs.

Keywords: amorphous; formulation; ionic liquid API; manufacturing; oral solid dosage forms; spray drying.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chemistry, Pharmaceutical / methods
Crystallization / methods
Drug Carriers / chemistry
Drug Liberation / drug effects
Ionic Liquids / chemistry*
Pharmaceutical Preparations / chemistry*
Polymers / chemistry*
Powders / chemistry
Solubility / drug effects
Temperature
Water / chemistry

Substances

Drug Carriers
Ionic Liquids
Pharmaceutical Preparations
Polymers
Powders
Water