Using Flory–Huggins phase diagrams as a pre-formulation tool for the production of amorphous solid dispersions: a comparison between hot-melt extrusion and spray drying

Tian, Yiwei; Caron, Vincent; Healy, Anne Marie; Andrews, Gavin

doi:10.1111/jphp.12141

Cited by 59 publications

(53 citation statements)

References 39 publications

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“…Hence, there is a need to identify and implement material-sparing methodologies to enable development of bioavailable ASD and successful scale up of process for manufacture of ASD using minimal API. Currently, only few studies in literature have studied and discussed material-sparing methodologies to develop ASD (13)(14)(15)(16)(17). These literature reports are very informative but describe only some of the aspects of ASD development.…”

Section: Introductionmentioning

confidence: 99%

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

2015

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Abstract. The objective of the study was to develop an amorphous solid dispersion (ASD) for an insoluble compound X by hot melt extrusion (HME) process. The focus was to identify material-sparing approaches to develop bioavailable and stable ASD including scale up of HME process using minimal drug. Mixtures of compound X and polymers with and without surfactants or pH modifiers were evaluated by hot stage microscopy (HSM), polarized light microscopy (PLM), and modulated differential scanning calorimetry (mDSC), which enabled systematic selection of ASD components. Formulation blends of compound X with PVP K12 and PVP VA64 polymers were extruded through a 9-mm twin screw mini-extruder. Physical characterization of extrudates by PLM, XRPD, and mDSC indicated formation of single-phase ASD's. Accelerated stability testing was performed that allowed rapid selection of stable ASD's and suitable packaging configurations. Dissolution testing by a discriminating two-step non-sink dissolution method showed 70-80% drug release from prototype ASD's, which was around twofold higher compared to crystalline tablet formulations. The in vivo pharmacokinetic study in dogs showed that bioavailability from ASD of compound X with PVP VA64 was four times higher compared to crystalline tablet formulations. The HME process was scaled up from lab scale to clinical scale using volumetric scale up approach and scale-independent-specific energy parameter. The present study demonstrated systematic development of ASD dosage form and scale up of HME process to clinical scale using minimal drug (∼500 g), which allowed successful clinical batch manufacture of enabled formulation within 7 months.

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Section: Introductionmentioning

confidence: 99%

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

2015

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“…The use of Flory-Huggins lattice theory to construct a T-ϕ phase diagram thus determining drug-polymer solubility as a function of temperature has been well established in the current literature (13)(14)(15)(16)(17)(18)20,21). Accordingly, Gibb's free energy of mixing ΔG mix can be expressed as (22):…”

Section: Treatment Of Data and Construction Of Phase Diagrammentioning

confidence: 99%

“…A number of recent publications have successfully defined the mixing behaviour of drug-polymer binary mixtures from a thermodynamic perspective (12)(13)(14)(15). Our group has also published a series of articles, utilising Flory-Huggins (F-H) theory in combination with the measurement of melting temperature depression to understand drug-polymer phase behaviour (16)(17)(18). In doing so, thermodynamic miscibility is expressed as a temperature/composition phase diagram, whilst Gibb's free energy of mixing may be expressed as a function of both temperature and composition.…”

Section: Introductionmentioning

confidence: 99%

Optimising Drug Solubilisation in Amorphous Polymer Dispersions: Rational Selection of Hot-melt Extrusion Processing Parameters

et al. 2016

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Abstract. The aim of this article was to construct a T-ϕ phase diagram for a model drug (FD) and amorphous polymer (Eudragit® EPO) and to use this information to understand the impact of how temperature-composition coordinates influenced the final properties of the extrudate. Defining process boundaries and understanding drug solubility in polymeric carriers is of utmost importance and will help in the successful manufacture of new delivery platforms for BCS class II drugs. Physically mixed felodipine (FD)-Eudragit ® EPO (EPO) binary mixtures with pre-determined weight fractions were analysed using DSC to measure the endset of melting and glass transition temperature. Extrudates of 10 wt% FD-EPO were processed using temperatures (110°C, 126°C, 140°C and 150°C) selected from the temperaturecomposition (T-ϕ) phase diagrams and processing screw speed of 20, 100 and 200rpm. Extrudates were characterised using powder X-ray diffraction (PXRD), optical, polarised light and Raman microscopy. To ensure formation of a binary amorphous drug dispersion (ADD) at a specific composition, HME processing temperatures should at least be equal to, or exceed, the corresponding temperature value on the liquid-solid curve in a F-H T-ϕ phase diagram. If extruded between the spinodal and liquid-solid curve, the lack of thermodynamic forces to attain complete drug amorphisation may be compensated for through the use of an increased screw speed. Constructing F-H T-ϕ phase diagrams are valuable not only in the understanding drug-polymer miscibility behaviour but also in rationalising the selection of important processing parameters for HME to ensure miscibility of drug and polymer.

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Section: Introductionmentioning

confidence: 99%

“…toxicity, safety hazards and solvent residuals make melting the method of choice despite of the potential problem of thermal degradation of drugs and carriers. Over the last decade, hot-melt extrusion (HME) has gathered renewed interest, particularly with regard to production of solid dispersions (Albers et al, 2009;Lakshman et al, 2008;Miller et al, 2008, Tian et al, 2014.Polyethylene oxide (PEO) is a semicrystalline non-ionic thermoplastic polymer exhibiting a low melting point, rapid solidification rate and low toxicity making it ideal for HME and formation of amorphous solid dispersion (Zhang and McGinity, 1999).Due to their hydrophilic character and ability to form solid dispersions, lower molecular weight PEOs have been widely used as carriers to enhance the solubility/dissolution properties of poorly soluble drugs (Li et al, 2006;Ozeki et al, 1997;Schachter et al, 2004). Melting of PEO followed by solidification upon cooling may decrease PEO crystallinity, and hence increase the amorphous PEO fraction (Prodduturi et al, 2005).…”

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confidence: 99%

The Use of Binary Polymeric Networks in Stabilizing Polyethylene Oxide Solid Dispersions

Jones

Tian

Shu

et al. 2016

Journal of Pharmaceutical Sciences

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The objective of this study was to investigate the role of amorphous domain of polyethylene oxide (PEO), a semicrystalline polymer, on the stability of drug/PEO solid dispersion. Molecular dispersion of drugs within hydrophilic low molecular weights PEOs (solid solution) has been demonstrated as a viable approach to enhance the dissolution properties and hence the oral bioavailability of poorly soluble drugs. In this system, the drug molecules are dissolved within the amorphous domain of the polymer and a miscible amorphous drug/polymer combination can result in a decrease of the polymer crystallinity, and hence increasing its amorphous fraction. This may result in increasing the drug solubility in the polymer hence affecting the stability of drug/polymer solid dispersion system. PEO is a highly crystallisable semi-crystalline polymer in natural and a rapid decrease in the amorphous fraction of the polymer may occur immediately after hot-melt extrusion resulting a forced migration of amorphous drug into nearby amorphous region. Thus, the actual concentrations of the drug within PEO solid dispersion were much higher than the concentration that we intended. Therefore, we are proposing a novel method of stabilising the amorphous drug/PEO solid dispersion by stabilising the amorphous region of PEO using another amorphous polymer. Inclusion of a miscible polymer that can increase the glass transition (Tg) of PEO (antiplasticization) or/and form strong inter-polymer interactions was used to enhance the stability of the amorphous PEO. In this study, the effects of inter-polymer interactions and miscibility between PEO and an amorphous polymer of high Tg, Eudragit ® S100, on the stability of the amorphous PEO and consequently the PEO/drug celecoxib (CX) solid dispersion was studied. Hot-melt extrusion (HME) was used to prepare different ratios of binary polymer blends of PEO/S100 (70/30, 50/50 and 30/70 w/w) and ternary solid dispersion systems containing pre-defined drug loading within the PEO/S100 polymer blends. Results from differential scanning calorimetry (DSC) and dynamic mechanical thermal analysis (DMTA) suggested a great miscibility between PEO and S100 polymer blends particularly in the 50/50 ratio. After immediately HME, single Tg was observed in all ternary systems that increase with increasing S100 amount (antiplasticization). The completely absence of PXRD crystalline Bragg's peaks also suggested the full amorphous CX/polymer solid dispersion has been produced. Upon storage, CX crystallized rapidly from the CX/PEO (30/70) system within 3 days at 40°C and 75% RH, whereas it remained stable without crystallization up to 4 weeks within CX/(PEO/S100) 30/(50/50) system. Interestingly, both the stability of the amorphous PEO and CX were greater in the ternary system containing the polymer blend at 50/50 ratio than other systems. Despite of the lower Tg of 30/(50/50) system than 30/(30/70) one, the former was more stable. This indicates that the antiplasticization effects by Eudragit ® S100 were not the ...

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Using Flory–Huggins phase diagrams as a pre-formulation tool for the production of amorphous solid dispersions: a comparison between hot-melt extrusion and spray drying

Abstract: Using temperature-composition phase diagrams to probe the relevance of temperature and drug composition in specific polymer candidates facilitates polymer screening for the purpose of formulating solid dispersions.

Cited by 59 publications

References 39 publications

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

Optimising Drug Solubilisation in Amorphous Polymer Dispersions: Rational Selection of Hot-melt Extrusion Processing Parameters

The Use of Binary Polymeric Networks in Stabilizing Polyethylene Oxide Solid Dispersions

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