Solubility parameter-based screening methods for early-stage formulation development of itraconazole amorphous solid dispersions

Piccinni, Piero; Tian, Yiwei; McNaughton, Alyn; Fraser, Jane; Brown, Stephen; Shu, Li; Andrews, Gavin

doi:10.1111/jphp.12491

Cited by 33 publications

(18 citation statements)

References 34 publications

(105 reference statements)

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“…In addition, compounds are deemed immiscible if the difference in their Hansen's solubility parameters is greater than 7 MPa 1/2 (Greenhalgh et al, 1999). The previously reported solubility parameters for Soluplus ® and HPMCP are 23.4 and 22.4 MPa 1/2 , respectively, which are very similar to that of ITZ; 22.6 MPa 1/2 (Piccinni et al, 2016), supporting the suggestion that the ITZ, HPMCP and Soluplus ® are miscible.…”

Section: Rationale For Polymers Selectionmentioning

confidence: 52%

Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus® processed by hot melt extrusion

Albadarin

Potter

Davis

et al. 2017

International Journal of Pharmaceutics

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The aim of this study was to evaluate a novel combination of hydroxypropyl methylcellulose phthalate (HPMCP-HP-50) and Soluplus polymers for enhanced physicochemical stability and solubility of the produced amorphous solid dispersions (ASDs). This was achieved using hot melt extrusion (HME) to convert the crystalline active pharmaceutical ingredient (API) into a more soluble amorphous form within the ternary systems. Itraconazole (ITZ), a Biopharmaceutics Classification System class II (BCS II) API, was selected as the model drug. The ASDs were characterized by Powder X-Ray diffraction (PXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared (FTIR) spectroscopy, Solid State Nuclear Magnetic Resonance (ssNMR) and dissolution studies. The data showed that the ASDs were physically and chemically stable at 20°C and 50% RH over 12 months. PXRD results indicated that the ITZ in the ASDs was in the amorphous state and no recrystallization occurred. DSC scans confirmed that each formulation exhibited a single intermediate glass transition (T), around 96.4°C, indicating that ITZ was completely miscible in the polymeric blends of HPMCP and Soluplus at up to 30% (w/w) drug loading and that the two polymers were miscible with each other in the presence of ITZ. The FTIR analysis indicated the formation of strong hydrogen bonding between ITZ, HPMCP and Soluplus. The dissolution end-point of the ASDs was determined to be approximately 10 times greater than that of the crystalline ITZ.

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Section: Rationale For Polymers Selectionmentioning

confidence: 52%

Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus® processed by hot melt extrusion

Albadarin

Potter

Davis

et al. 2017

International Journal of Pharmaceutics

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“…polymer typically seen as a single Tg [21], [32] and the presence of crystalline material seen as melting endotherms. Additionally, PCM is a glass forming ability, GFA class 2 system, i.e.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Development of a hot-melt extrusion (HME) process to produce drug loaded Affinisol™ 15LV filaments for fused filament fabrication (FFF) 3D printing

Prasad

Islam

Goodwin

et al. 2019

Additive Manufacturing

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The aim of the present work was to develop a pilot scale process to produce drug-loaded filaments for 3D printing of oral solid dose forms by fused filament fabrication (FFF). Using hot melt extrusion, a viable operating space and understanding of processing limits were established using a hydrophilic polymer (hydroxypropyl methylcellulose (HPMC)-Affinisol™ LV15). This was then extended to formulate paracetamol (PCM) loaded Affinisol™ 15LV filaments across a wide range of compositions (5-50 wt% drug). From the process development work, challenges in achieving a pilot scale process for filament production for pharmaceutical applications have been highlighted. 3D printing trials across the range of compositions demonstrated limitations concerning the ability to print successfully across all compositions. Results from characterisation techniques including thermal and mechanical testing when applied to the formulated filaments indicated that these techniques are a useful predictive measure for assessing the ability to print a given formulation via filament methods. Oral solid dosage forms of variable surface area to mass ratios printed from suitable filament 2 compositions demonstrated the ability to modify the release rates of drug for fixed formulations across substantial timescales.

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“…PLM-HS and PXRD studies clearly indicate that ITZ forms an ordered, anisotropic structure at 25 °C on cooling from its melt and that the molecular organisation of this phase is of a smectic and not a fully disordered, amorphous phase, as sometimes misinterpreted and referred to in many publications 30,35,36. DSC thermogram, however, displays a Tg transition on cooling at 56 °C and therefore, consistent with the accepted nomenclature37 , this phase should be referred to as a vitrified smectic phase.…”

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confidence: 99%

Phase Diagrams of Polymer-Dispersed Liquid Crystal Systems of Itraconazole/Component Immiscibility Induced by Molecular Anisotropy

et al. 2018

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Liquid crystalline (LC) materials and their nonmedical applications have been known for decades, especially in the production of displays; however, the pharmaceutical implications of the LC state are inadequately appreciated, and the misunderstanding of experimental data is leading to possible errors, especially in relation to the physical stability of medicines. The aim of this work was to study LC phases of itraconazole (ITZ), an azole antifungal active molecule, and for the first time, to generate full thermodynamic phase diagrams for ITZ/polymer systems, taking into account isotropic and anisotropic phases that this drug can form. It was found that supercooled ITZ does not form an amorphous but a vitrified smectic (vSm) phase with a glass transition temperature of 59.35 °C (determined using a 10 °C/min heating rate), as is evident from X-ray diffraction and thermomicroscopic (PLM) experiments. Two endothermic LC events with the onset temperature values for a smectic to nematic transition of 73.2 ± 0.4 °C and a nematic to isotropic transformation at 90.4 ± 0.35 °C and enthalpies of transition of 416 ± 34 J/mol and 842 ± 10 J/mol, respectively, were recorded. For the binary supercooled mixtures, PLM and differential scanning calorimetry showed a phase separation with birefringent vSm persistent over a wide polymer range, as noticed especially for the hypromellose acetate succinate (HAS) systems. Both, smectic and nematic, phases were detected for the supercooled ITZ/HAS and ITZ/methacrylic acid–ethyl acrylate copolymer (EUD) mixtures, while geometric restrictions inhibited the smectic formation in the ITZ/poly(acrylic acid) (CAR) systems. The Flory–Huggins lattice theory coupled with the Maier–Saupe–McMillan approach to model anisotropic ordering of molecules was successfully utilized to create phase diagrams for all ITZ/polymer mixtures. It was concluded that in a supercooled ITR/polymer mix, if ITZ is present in a LC phase, immiscibility as a result of molecule anisotropy is afforded. This study shows that the LC nature of ITZ cannot be disregarded when designing stable formulations containing this molecule.

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Solubility parameter-based screening methods for early-stage formulation development of itraconazole amorphous solid dispersions

Cited by 33 publications

References 34 publications

Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus® processed by hot melt extrusion

Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus® processed by hot melt extrusion

Development of a hot-melt extrusion (HME) process to produce drug loaded Affinisol™ 15LV filaments for fused filament fabrication (FFF) 3D printing

Phase Diagrams of Polymer-Dispersed Liquid Crystal Systems of Itraconazole/Component Immiscibility Induced by Molecular Anisotropy

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