Estimation of Drug–Polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters

Marsac, Patrick J.; Li, Tonglei; Taylor, Lynne S.

doi:10.1007/s11095-008-9721-1

Cited by 442 publications

(399 citation statements)

References 60 publications

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“…Close examination of the table underlines the importance of the various factors that have been implicated in determining the phase behavior of ASDs containing a hydrophobic API following exposure to moisture: hygroscopicity of the ASD system (6), hydrophobicity of the API (7), and the strength of API-polymer interactions (7,8,17). Hence, previous studies have shown that ASDs prepared with a less hygroscopic polymers, for example HPMCAS, are in general, less susceptible to moisture induced amorphous-amorphous phase separation (3).…”

Section: Discussionmentioning

confidence: 99%

Understanding the Tendency of Amorphous Solid Dispersions to Undergo Amorphous–Amorphous Phase Separation in the Presence of Absorbed Moisture

et al. 2011

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Abstract. Formulation of an amorphous solid dispersion (ASD) is one of the methods commonly considered to increase the bioavailability of a poorly water-soluble small-molecule active pharmaceutical ingredient (API). However, many factors have to be considered in designing an API-polymer system, including any potential changes to the physical stability of the API. In this study, the tendency of ASD systems containing a poorly water-soluble API and a polymer to undergo amorphous-amorphous phase separation was evaluated following exposure to moisture at increasing relative humidity. Infrared spectroscopy was used as the primary method to investigate the phase behavior of the systems. In general, it was observed that stronger drug-polymer interactions, low-ASD hygroscopicity, and a less hydrophobic API led to the formation of systems resistant to moisture-induced amorphous-amorphous phase separation. Orthogonal partial least squares analysis provided further insight into the systems, confirming the importance of the aforementioned properties. In order to design a more physically stable ASD that is resistant to moisture-induced amorphous-amorphous phase separation, it is important to consider the interplay between these properties.

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Section: Discussionmentioning

confidence: 99%

Understanding the Tendency of Amorphous Solid Dispersions to Undergo Amorphous–Amorphous Phase Separation in the Presence of Absorbed Moisture

et al. 2011

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“…Phase diagrams for CBZ and polymer systems were generated using Flory-Huggins Theory as previously described (20)(21)(22)(23)(24)(25)(26). Briefly speaking, the Gibbs free energy of mixing function that results from application of the FloryHuggins model is dependent on the volume fraction of the drug, ϕ, a constant indicative of the relative size of the polymer in relation to the drug, m, and the interaction parameter, χ:…”

Section: Modeling Based On Flory-huggins Theorymentioning

confidence: 99%

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME

Huang

O’Donnell

Keen³

et al. 2015

AAPS PharmSciTech

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Abstract. Hypromellose is a hydrophilic polymer widely used in immediate-and modified-release oral pharmaceutical dosage forms. However, currently available grades of hypromellose are difficult, if not impossible, to process by hot melt extrusion (HME) because of their high glass transition temperature, high melt viscosity, and low degradation temperature. To overcome these challenges, a modified grade of hypromellose, AFFINISOL™ HPMC HME, was recently introduced. It has a significantly lower glass transition temperature and melt viscosity as compared to other available grades of hypromellose. The objective of this paper is to assess the extrudability and performance of AFFINISOL™ HPMC HME (100LV and 4M) as compared to other widely used polymers in HME, including HPMC 2910 100cP (the currently available hypromellose), Soluplus®, Kollidon® VA 64, and EUDRAGIT® E PO. Formulations containing polymer and carbamazepine (CBZ) were extruded on a co-rotating 16-mm twin-screw extruder, and the effect of temperature, screw speed, and feed rate was investigated. The performance of the solid dispersions was evaluated based on Flory-Huggins modeling and characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), Raman spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and dissolution. All formulations extruded well except for HPMC 2910 100cP, which resulted in over-torqueing the extruder (machine overloading because the motor cannot provide efficient energy to rotate the shaft). Among the HME extrudates, only the EUDRAGIT® E PO formulation was crystalline as confirmed by DSC, XRD, and Raman, which agreed with predictions from Flory-Huggins modeling. Dissolution testing was conducted under both sink and non-sink conditions. Sink dissolution testing in neutral media revealed that amorphous CBZ in the HME extrudates completely dissolved within 15 min, which was much more rapid than the time for complete dissolution of bulk CBZ (60 min) and EUDRAGIT® E PO solid dispersion (more than 6 h). Non-sink dissolution in acidic media testing revealed that only CBZ contained in the AFFINISOL™ HPMC HME, and EUDRAGIT® E PO solid dispersions rapidly supersaturated after 15 min, reaching a twofold drug concentration compared to the CBZ equilibrium solubility. In summary, AFFINISOL™ HPMC HME 100LV and AFFINISOL™ HPMC HME 4M are useful in the pharmaceutical HME process to increase wetting and dissolution properties of poorly water-soluble drugs like CBZ.

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“…Secondly, the molten drug and polymer are uniformly mixed. Thirdly, the molten mixture is cooled down to room temperature to get a solid product (25)(26)(27). In case of eutectic mixtures, the melting point of the mixture is less than the individual components which means less energy is required for the first step and hence higher solubility and miscibility.…”

Section: Introductionmentioning

confidence: 99%

Fusion Method for Solubility and Dissolution Rate Enhancement of Ibuprofen Using Block Copolymer Poloxamer 407

2016

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ABSTRACT. Aim of current research was to prepare ibuprofen-poloxamer 407 binary mixtures using fusion method and characterize them for their physicochemical and performance properties. Binary mixtures of ibuprofen and poloxamer were prepared in three different ratios (1:0.25, 1:0.5, and 1:0.75, respectively) using a water-jacketed high shear mixer. In vitro dissolution and saturation solubility studies were carried out for the drug, physical mixtures, and formulations for all ratios in de-ionized water, 0.1 N HCl (pH = 1.2), and phosphate buffer (pH = 7.2). Thermal and physical characterization of samples was done using modulated differential scanning calorimetry (mDSC), X-ray powder diffraction (XRD), and infrared spectroscopy (FTIR). Flow properties were evaluated using a powder rheometer. Maximum solubility enhancement was seen in acidic media for fused formulations where the ratio 1:0.75 had 18-fold increase. In vitro dissolution studies showed dissolution rate enhancement for physical mixtures and the formulations in all three media. The most pronounced effect was seen for formulation (1:0.75) in acidic media where the cumulative drug release was 58.27% while for drug, it was 3.67%. Model independent statistical methods and ANOVA based methods were used to check the significance of difference in the dissolution profiles. Thermograms from mDSC showed a characteristic peak for all formulations with T peak of around 45°C which suggested formation of a eutectic mixture. XRD data displayed that crystalline nature of ibuprofen was intact in the formulations. This work shows the effect of eutectic formation and micellar solubilization between ibuprofen and poloxamer at the given ratios on its solubility and dissolution rate enhancement.

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Estimation of Drug–Polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters

Abstract: Miscibility of various drugs with polymers can be explored by coupling solution theories with experimental data. These approximations provide insight into the physical stability of drug-polymer mixtures and the thermodynamic driving force for crystallization.

Cited by 442 publications

References 60 publications

Understanding the Tendency of Amorphous Solid Dispersions to Undergo Amorphous–Amorphous Phase Separation in the Presence of Absorbed Moisture

Understanding the Tendency of Amorphous Solid Dispersions to Undergo Amorphous–Amorphous Phase Separation in the Presence of Absorbed Moisture

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME

Fusion Method for Solubility and Dissolution Rate Enhancement of Ibuprofen Using Block Copolymer Poloxamer 407

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