Qualitative and quantitative methods to determine miscibility in amorphous drug–polymer systems

Meng, Fan; Dave, Vivek S; Chauhan, Harsh

doi:10.1016/j.ejps.2015.05.018

Cited by 94 publications

(60 citation statements)

References 59 publications

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“…The phase behavior of a drug and polymer system can be very complicated, as the drug can be present in a crystalline form (i.e., as one or more polymorphic forms), or partially or completely amorphous forms (Vasconcelos et al, 2007). The degree of miscibility between drug and polymer in a blended system is extremely important for stabilization of the amorphous drug-polymer system, as it is generally believed that miscibility at the molecular level is necessary to achieve maximum physical stabilization, as well as enhanced solubility (Marsac et al, 2006;Djuris et al, 2013;Meng et al, 2015). One of the methods for miscibility evaluation is based on determination of the Flory-Huggins interaction parameter, χ.…”

Section: Introductionmentioning

confidence: 99%

“…This can be achieved through a description of the mixing thermodynamics in drug and excipient systems using Flory-Huggins lattice theory and the melting point depression method. Another approach for miscibility evaluation is based on the group contribution method, as modified by Hansen, and this is based on determination of the difference in the total solubility parameter, Δδt, between the two components (Meng et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Application of miscibility analysis and determination of Soluplus solubility map for development of carvedilol-loaded nanofibers

Kaljević

Djuriš

Čalija

et al. 2017

International Journal of Pharmaceutics

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Electrospinning was used to produce carvedilol-loaded Soluplus polymer nanofibers using a systematic approach. Miscibility between drug and polymer was determined through calculation of the interaction parameter, χ, and the difference between the total solubility parameters, Δd. A solubility map for Soluplus was obtained by examining different solvent systems, carrying out electrospinning, and characterizing the nanofibers formed. Miscibility studies showed that carvedilol and Soluplus can form a miscible system (χ=-2.3054; Δδ<7.0MPa). Based on the Soluplus solubility map, acetone: chloroform (90:10; w/w) represents a suitable solvent system for electrospinning of carvedilol-loaded Soluplus nanofibers. Scanning electron microscopy of these nanofiber samples showed smooth surface morphology. The nanofibers had a regular cylindrical morphology. Beads appeared along the nanofibers more frequently in formulations with lower percentages of carvedilol. Differential scanning calorimetry showed no melting endothermic peak for carvedilol, which suggests its complete conversion from the crystalline to the amorphous form (at polymer: carvedilol 1:1). The infrared spectrum of the carvedilol-loaded Soluplus nanofibers showed no characteristic carvedilol peak at 3344.5cm, which suggests interactions between carvedilol and Soluplus. Dissolution studies of these nanofibers showed improved pure carvedilol dissolution properties, with >85% of the carvedilol released in the first 15min, versus 20% for pure carvedilol. The use of miscibility analysis and polymer solubility studies demonstrate great technological potential to tackle the challenge for inadequate dissolution of poorly water-soluble drugs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Application of miscibility analysis and determination of Soluplus solubility map for development of carvedilol-loaded nanofibers

Kaljević

Djuriš

Čalija

et al. 2017

International Journal of Pharmaceutics

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“…Due to the advancement in basic physicochemical understanding of amorphous systems, the utilization of this techniques has immensely increased in enabling the delivery of the difficult to solubilize compounds. Traditional binary solid dispersions contain a drug dispersed in a single polymer matrix, whereas in recently developed ternary solid dispersions three components i.e., API, polymer, and an additive are present [1][2][3][4][5][6][7].…”

Section: Editorialmentioning

confidence: 99%

Ternary Amorphous Solid Dispersions

Prasad¹,

Lande²,

Chauhan³

et al. 2017

J Dev Drugs

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EditorialAmorphous solid dispersion is one of the techniques used in the formulation development of poorly soluble compounds. Due to the advancement in basic physicochemical understanding of amorphous systems, the utilization of this techniques has immensely increased in enabling the delivery of the difficult to solubilize compounds. Traditional binary solid dispersions contain a drug dispersed in a single polymer matrix, whereas in recently developed ternary solid dispersions three components i.e., API, polymer, and an additive are present [1][2][3][4][5][6][7].In both the systems, API is present in amorphous form and polymer is used for the stabilization of this amorphous form via decrease in molecular mobility or via drug-polymer molecular interactions. The third component is usually a surface-active agent or another polymer depending on the desired dissolution/stability profiles of the drug. For example, if the faster dissolution is desired then surfactant would be a better choice and if the prevention of re-crystallization is needed then another polymer with higher Tg may be used in developing the ternary solid dispersions.One of the challenges associated with developing ternary dispersion is the selection of appropriate polymers/surfactant and their combinations. In those cases, solution studies can be successfully used to distinguish the ability of individual polymer vs. combined polymers for synergistic effect in terms of dissolution enhancement or amorphous stabilization or both [2]. The parameters studied in such solution state screening studies usually are the ability of polymers or their combinations to inhibit precipitation and maintaining supersaturation (Figure 1). The prepared ternary solid dispersions can be characterized by technique such as DSC/MDSC, PXRD, and FTIR. These techniques are used to determine important parameters such as the glass-transition temperature of amorphous components, the crystallinity of the drug and the molecular interaction between drug and excipients.The future research focusing on the 1) combination of polymers to tailor the release profile and stability, 2) advance characterization techniques such as small angle X-ray scattering and solid-state NMR and 3) improvement in manufacturing of amorphous solid dispersions will progress the application of ternary solid dispersions strategy in resolving the challenges of current drug development program. The advancement of dedicated CROs for amorphous dispersions development and recent success of drugs such as Telaprevir (Incivek®) and Ivacaftor (Kalydeco®) suggests that this technique is capable of providing the desired approach for the development of poorly soluble compounds.Finally, the fact that almost 40% of the new chemical entities are poorly water soluble in nature implies that studies with ternary solid dispersions will continue, and with increase understanding of these systems, more drug compounds formulated as solid dispersions will reach the market in the future.

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“…Some of the disadvantages especially for HME, are the time-and material-consuming trials that have to be conducted to set the manufacturing process variables [10]. Furthermore, predictive micro-scale assays are needed to determine if an ASD is mandatory to overcome solubility issues [11,12]. For this purpose, differential scanning calorimetry (DSC) is often used to evaluate the API solubility in polymers and their respective physical stability [13].…”

Section: Introductionmentioning

confidence: 99%

“…For this purpose, differential scanning calorimetry (DSC) is often used to evaluate the API solubility in polymers and their respective physical stability [13]. The physical stability of an ASD is not only promoted by a polymer of high glass transition temperature (T g ), but also by the solubility of the API in the polymer matrix [10,11,13,14].…”

Section: Introductionmentioning

confidence: 99%

Micro-scale prediction method for API-solubility in polymeric matrices and process model for forming amorphous solid dispersion by hot-melt extrusion

Bochmann

Neumann

Gryczke

et al. 2016

European Journal of Pharmaceutics and Biopharmaceutics

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Qualitative and quantitative methods to determine miscibility in amorphous drug–polymer systems

Cited by 94 publications

References 59 publications

Application of miscibility analysis and determination of Soluplus solubility map for development of carvedilol-loaded nanofibers

Application of miscibility analysis and determination of Soluplus solubility map for development of carvedilol-loaded nanofibers

Ternary Amorphous Solid Dispersions

Micro-scale prediction method for API-solubility in polymeric matrices and process model for forming amorphous solid dispersion by hot-melt extrusion

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