A thermal analysis method to predict the complete phase diagram of drug–polymer solid dispersions

Ding, Lin; Huang, Yanbin

doi:10.1016/j.ijpharm.2010.08.013

Cited by 105 publications

(100 citation statements)

References 25 publications

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“…The limitation of using the solubility parameter method in this model is that it overlooks the interactions between polymer and CBZ (45). These interactions, however, were well represented at elevated temperatures using the experimental methods (23). Therefore, the F-H modeling results of CBZ-VA64 and CBZ-Soluplus might not be accurate at room temperature.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…DSC experiments was used to determine the melting enthalpy of the drug, ΔH, and either the melting temperature (22,23), onset of melting (24), or ending of melting (25) have been applied by various authors to determine χ, which is a function of temperature (27). For CBZ and polymer systems, melting temperature was selected based on the reproducibility of this value in experimental trials.…”

Section: Modeling Based On Flory-huggins Theorymentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Modeling Based On Flory-huggins Theorymentioning

confidence: 99%

Section: Modeling Based On Flory-huggins Theorymentioning

confidence: 99%

See 1 more Smart Citation

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME

Huang

O’Donnell

Keen³

et al. 2015

AAPS PharmSciTech

View full text Add to dashboard Cite

show abstract

“…Subsequently, linear fit of χ d-p vs. 1/T yielded values of constants A and B as per Eq. 3 (27). Approach 2.…”

Section: Construction Of Phase Diagrammentioning

confidence: 99%

“…These results were consistent with the observation that indomethacin forms stronger hydrogen bonds with the polymer than does nifedipine. F-H theory was used to predict the temperature-composition phase diagram of the model system indomethacin-PVP-VA and felodipine-PAA system (27,28). Small-scale thermal methods have been proposed that can be used in combination with F-H interaction theory to predict the physical stability of drug-polymer systems, e.g., HPMCAS-HFfelodipine and Soluplus-felodipine amorphous solid dispersions systems (26).…”

Section: Introductionmentioning

confidence: 99%

Construction and Validation of Binary Phase Diagram for Amorphous Solid Dispersion Using Flory–Huggins Theory

2015

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Abstract. Drug-polymer miscibility is one of the fundamental prerequisite for the successful design and development of amorphous solid dispersion formulation. The purpose of the present work is to provide an example of the theoretical estimation of drug-polymer miscibility and solubility on the basis of FloryHuggins (F-H) theory and experimental validation of the phase diagram. The F-H interaction parameter, χ d-p , of model system, aceclofenac and Soluplus, was estimated by two methods: by melting point depression of drug in presence of different polymer fractions and by Hildebrand and Scott solubility parameter calculations. The simplified relationship between the F-H interaction parameter and temperature was established. This enabled us to generate free energy of mixing (ΔG mix ) curves for varying drugpolymer compositions at different temperatures and finally the spinodal curve. The predicted behavior of the binary system was evaluated through X-ray diffraction, differential scanning calorimetry, and in vitro dissolution studies. The results suggest possibility of employing interaction parameter as preliminary tool for the estimation of drug-polymer miscibility.

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Translational Pharmaceutics and Early Phase Clinical Development

Bhattachar

Tan

Stamatis

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Translational pharmaceutics is a relatively new cross‐disciplinary construct that integrates discovery and development for efficiently enabling discovery activities to deliver commercially viable medicines. This article describes the role and deliverables of its various subfunctions, namely, preclinical formulations, physical chemistry, drug product prototyping and development, and biopharmaceutics. The integrated aspects of these deliverables, that enable drug discovery, while also influencing and enabling the selection of compounds for clinical testing, in a manner that embraces the principles of R&D essentialism and design thinking, are also described. This article also illustrates how cost and time savings can be achieved through the application of robust mathematical modeling where possible, to guide the generation of the most relevant experimental data, followed by risk‐based decision‐making to inform commercial product design. Although the article is mostly focused on traditional small molecules, the principles described here can be adapted to include other types of molecular and biologic entities, including the newer molecular modalities that are rapidly gaining importance in the industry.

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A thermal analysis method to predict the complete phase diagram of drug–polymer solid dispersions

Cited by 105 publications

References 25 publications

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME

Construction and Validation of Binary Phase Diagram for Amorphous Solid Dispersion Using Flory–Huggins Theory

Translational Pharmaceutics and Early Phase Clinical Development

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