Composition Dependent Miscibility Research Articles

Effect of Hypromellose Acetate Succinate Substituents on Miscibility Behavior of Spray-dried Amorphous Solid Dispersions: Flory–Huggins Parameter Prediction and Validation

• Theoretical predictions and validation of miscibility was investigated. • Gibbs-composition phase diagram predicts the composition dependent miscibility. • Substituent ratios have significant effect on miscibility and drug loading. • Higher succinoyl content leads to higher dissolution efficiency. • Non-polar drugs show higher miscibility with HG grade, but low dissolution. This study reports the impact of physicochemical properties of lipophilic drugs such as Fenofibrate (FBT), Itraconazole (ITZ), Efavirenz (EFV) and Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) grades on the miscibility, dissolution, and stability of the spray dried Amorphous Solid Dispersions (ASDs). The miscibility between of the drugs and HPMCAS grades was predicted using solubility parameter-derived Flory-Huggins interaction parameter and later phase diagram was constructed to delineate the composition dependent miscibility. By varying the HPMCAS grade−drug combinations and loadings, the amorphicity of prepared ASDs was analyzed using Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD) and in vitro dissolution experiments were conducted to measure apparent solubility and finally, investigate the interplay between substituent ratio and functionality. Interactions between the drugs and polymeric grades and drug concentration in polymer is crucial in determining the drug precipitation within the ASDs which is further supported by Fourier Transform Infrared Spectroscopy (FTIR). The dissolution efficiency and dissolution rate of the ASDs were dependent on the acetyl-succinoyl ratio in HPMCAS.

Composition dependent miscibility in the crystalline state of polyamide 6 /polyamide 4,10 blends: From single to double crystalline blends

We studied the composition-dependent miscibility of polyamide 6 and biobased polyamide 4,10 (PA6/PA410) blends, as triggered by crystallization driven phase segregation. The blends were prepared by extrusion in a wide composition range and characterized by X-ray diffraction (both in-situ and ex-situ SAXS/WAXS), Differential Scanning Calorimetry (DSC), and Polarized Light Optical Microscopy (PLOM) during non-isothermal crystallization. The blends were miscible in the amorphous state, as demonstrated by a single Tg that follows the Fox equation as a function of composition. The blends were also considered to be miscible in the melt, as no evidence of phase segregation was found by SAXS or phase contrast microscopy in the melt. Remarkably, the blends can also be miscible in the crystalline state in a limited composition range. When only 10 or 20% PA6 was present in the blends, co-crystallization was evidenced by DSC and WAXS and the blends exhibited a single PA410 rich crystalline phase. On the other hand, as 30% or more PA6 was added to PA410, crystallization driven phase segregation occurred and progressively increased with PA6 content in the blends. Hence double crystalline blends are formed with both PA6 rich and PA410 rich crystalline phases. Clear evidence of the presence of either one or two crystalline phases was obtained by temperature-dependent measurements employing DSC, PLOM, WAXS and SAXS. Both the single and double crystalline PA6/PA410 blends exhibited good mechanical properties in view of the excellent compatibility displayed by the blends. The mechanical properties were in line with those exhibited by miscible blends following a simple rule of mixtures.

Theoretical and experimental investigation of drug-polymer interaction and miscibility and its impact on drug supersaturation in aqueous medium

Amorphous solid dispersions (ASDs) have the potential to offer higher apparent solubility and bioavailability of BCS class II drugs. Knowledge of the solid state drug-polymer solubility/miscibility and their mutual interaction are fundamental requirements for the effective design and development of such systems. To this end, we have carried out a comprehensive investigation of various ASD systems of dipyridamole and cinnarizine in polyvinylpyrrolidone (PVP) and polyacrylic acid (PAA) at different drug loadings. Theoretical and experimental examinations (by implementing binary and ternary Flory-Huggins (F-H) theory) related to drug-polymer interaction/miscibility including solubility parameter approach, melting point depression method, phase diagram, drug-polymer interaction in the presence of moisture and the effect of drug loading on interaction parameter were performed. The information obtained from this study was used to predict the stability of ASDs at different drug loadings and under different thermal and moisture conditions. Thermal and moisture sorption analysis not only provided the composition-dependent interaction parameter but also predicted the composition dependent miscibility. DPM-PVP, DPM-PAA and CNZ-PAA systems have shown molecular level mixing over the complete range of drug loading. For CNZ-PVP, the presence of a single Tg at lower drug loadings (10, 20 and 35%w/w) indicates the formation of solid solution. However, drug recrystallization was observed for samples with higher drug weight fractions (50 and 65%w/w). Finally, the role of polymer in maintaining drug supersaturation has also been explored. It has been found that drug-polymer combinations capable of hydrogen-bonding in the solution state (DPM-PVP, DPM-PAA and CNZ-PAA) are more effective in preventing drug crystallization compared to the drug-polymer systems without such interaction (CNZ-PVP). The DPM-PAA system outperformed all other ASDs in various stability conditions (dry-state, in the presence of moisture and in solution state), which was attributed to the drug’s low crystallization tendency, the strong DPM-PAA interaction, the robustness of this interaction against moisture or water and the ability of PAA in maintaining DPM supersaturation.

Hot melt extruded Aprepitant–Soluplus solid dispersion: preformulation considerations, stability and in vitro study

Context: Solubility limitation of BCS class II drugs pose challenges to in vitro release.Objective: To investigate the miscibility of Aprepitant (APR) and Soluplus® (SOL) for hot melt extrusion (HME) viability and improved in vitro release of APR.Methods: Solubility parameters of APR and SOL from group contribution methods were evaluated. Heat–cool–heat differential scanning calorimetry (DSC) scans were assessed for determining the glass forming ability (GFA) and glass stability (GS) of APR. An optimum HME temperature was selected based on melting point depression in physical mixtures. Moisture sorption isotherms were collected using a dynamic vapor sorption (DVS) analyzer at 25 °C. A 1:4 APR:SOL physical mixture was extruded in a co-rotating 12 mm twin screw extruder and in vitro release was assessed in fasted state simulated intestinal fluid (FaSSIF) with 0.25% SLS. Extrudates were analyzed using TGA, DSC, XRD and FTIR.Results: APR was classified as a class II glass former. APR and SOL had composition dependent miscibility based on Gibb’s free energy of mixing. Extrudate prepared using HME had an amorphous as well as a crystalline phase that showed good stability in accelerated stability conditions. Smaller particle size extrudates exhibited a higher % moisture uptake and in vitro release compared to larger particle size extrudates. Enhanced in vitro release of APR from extrudates was attributed to amorphization of APR, solubilization as well as crystal growth inhibition effect of SOL due to H-bond formation with APR.Conclusions: A solid dispersion of APR with improved in vitro release was successfully developed using HME technology.

Characterization of interfaces in Binary and Ternary Polymer Blends by Positron Lifetime Spectroscopy

A miscible blend is a single-phase system with compact packing of the polymeric chains/segments due configuration/conformational changes upon blending. Differential Scanning Calorimetry (DSC) is the most employed method to ascertain whether the blend is miscible or immiscible. Positron Lifetime Spectroscopy (PLS) has been employed in recent times to study miscibility properties of polymer blends by monitoring the ortho-Positronium annihilation lifetimes as function of composition. However, just free volume monitoring and the DSC methods fail to provide the composition dependent miscibility of blends. To overcome this limitation, an alternative approach based on hydrodynamic interactions has been developed to derive this information using the same o-Ps lifetime measurements. This has led to the development of a new method of measuring composition dependent miscibility level in binary and ternary polymer blends. Further, the new method also provides interface characteristics for immiscible blends. The interactions between the blend components has a direct bearing on the strength of adhesion at the interface and hence the hydrodynamic interaction. Understanding the characteristic of interfaces which decides the miscibility level of the blend and their end applications is made easy by the present method. The efficacy of the present method is demonstrated for few binary and ternary blends.

Prediction of Drug–Polymer Miscibility through the use of Solubility Parameter based Flory–Huggins Interaction Parameter and the Experimental Validation: PEG as Model Polymer

Important consideration for developing physically stable solid dispersion is miscibility of drug in carrier matrix. It is possible to predict thermodynamics of binary system through free energy calculations based on Flory-Huggins interaction parameter (χ(dp)). In present study, PEG 6000 as model polymer and dataset comprising commonly used drugs/excipients was selected. The three-dimensional solubility parameter based on group contribution method was utilized for systemic calculation of χ(dp) of the polymer with each compound in data set. On the basis of the values of χ(dp), it was possible to categorize all the compounds into three distinct categories, Types I and II: compounds predicted to be miscible and immiscible respectively with the polymer in all proportions and Type III: compounds expected to exhibit composition dependent miscibility behavior. The Bagley plot showed that majority of points for Type I fall in a region, which can approximately be delimited by a circle. Experimental verification through thermal analysis revealed that though it was possible to predict correctly miscibility behavior of Type II class compounds, distinction between Types I and III was less evident. Hence, solubility parameter based χ(dp) may be used as an initial tool for fast screening of immiscible combination of polymer and drug.

Free volume as an internal material parameter to probe interfaces in ternary polymer blends: A positron lifetime study

ABSTRACTA new method to characterize individual interfaces in ternary polymer blends from experimentally measured fractional free volume from Positron Annihilation Lifetime Spectroscopy (PALS) has been developed. By this, we derive the composition dependent miscibility level in ternary polymer blends. This method has its genesis in KRZ (Kirkwood–Risemann–Zimm) theory which introduces hydrodynamic interaction parameter as a measure of excess friction generated at the interface between dissimilar polymer chains resulting in energy dissipation. The method successfully applied for binary blends has been theoretically modified to suit ternary blends in the present work. The efficacy of this method has been tested for two ternary blends namely polycaprolactone/poly(styrene‐co‐acrylonitrile)/poly(vinyl chloride) (PCL/SAN/PVC) and polycaprolactone/poly(vinyl chloride)/poly(vinyl acetate) (PCL/PVC/PVAc) in different compositions. We obtained a maximum effective hydrodynamic interaction (αeff) of −12.60 at composition 80/10/10 of PCL/PVC/PVAc while PCL/SAN/PVC showed −1.60 at 68/16/16 composition. These results suggest that these compositions produce high miscibility level as compared to other compositions. DSC measurements have also been used to supplement positron results. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 3335–3344, 2013

Positron annihilation lifetime study of interfaces in ternary polymer blends

A new method based on positron lifetime spectroscopy is developed to characterize individual interfaces in ternary polymer blends and hence determine the composition dependent miscibility level. The method owes its origin to the Kirkwood-Risemann-Zimm (KRZ) model for the evaluation of the hydrodynamic interaction parameters (αij) which was used successfully for a binary blend with a single interface. The model was revised for the present work for ternary polymer blends to account for three interfaces. The efficacy of this method is shown for two ternary blends namely poly(styrene-co-acrylonitrile)/poly (ethylene-co-vinylacetate)/poly(vinyl chloride) (SAN/EVA/PVC) and polycaprolactone /poly(styrene-co-acrylonitrile)/poly(vinyl chloride) (PCL/SAN/PVC) at different compositions. An effective hydrodynamic interaction parameter, αeff, was introduced to predict the overall miscibility of ternary blends.

Characterization of interfaces in Poly (styrene-co-acrylonitrile) (SAN) based ternary polymer blends: A new approach from positron lifetime spectroscopy

Positron lifetime spectroscopy is used to develop a new approach to characterize the individual interfaces in ternary polymer blends and hence determine composition dependent miscibility level. This approach has its genesis in KSR and KRZ models for the evaluation of hydrodynamic interaction parameters (αij). The method successfully applied for binary blends (single interface) earlier is theoretically modified for ternary blends and experimentally verified by measuring free volume content in blends and their constituents. We have tested the efficacy of this method in two ternary blends namely SAN/PVC/PMMA and SAN/EVA/PVC at different compositions. The effective hydrodynamic parameter αeff evaluated using individual α values turns out to be handy in predicting the overall miscibility level of a ternary blend. Results show that SAN/PVC/PMMA exhibits maximum αeff of −9.67 at composition 75/5/20 and SAN/EVA/PVC shows −3.18 at 50/35/15 indicating that miscibility level is high at these compositions for these two blends. DSC and SEM studies have also been used to supplement positron results.

Theoretical and Experimental Investigation on the Solid Solubility and Miscibility of Naproxen in Poly(vinylpyrrolidone)

The objective of the present study was to determine the solid state solubility and miscibility of naproxen in poly(vinylpyrrolidone) (PVP) and the mutual interaction using the standard thermodynamic models and thermal analysis. Solid dispersions were prepared by spray drying several compositions of naproxen and PVP with different molecular weights, viz., PVP K 12, PVP K 25 and PVP K 90, and analyzed using modulated differential scanning calorimetry (mDSC). The kinetic miscibility limit in terms of a single mixed phase glass transition temperature was found to be relatively similar for the dispersions containing PVP with different chain lengths (>or=50% w/w drug in PVP). But the systems with different PVP followed diverse patterns of composition dependent mixed phase glass transition temperature as well as the degree of plasticization by water. The crystalline solid solubility values of naproxen in PVP estimated by using its solubility data in n-methylpyrrolidone, a low molecular weight analogue of PVP, were 6.42, 5.85 and 5.81% w/w of drug in PVP K 12, PVP K 25 and PVP K 90 respectively. The values estimated for corresponding amorphous solubility showed no marked difference. The remarkable difference between thermodynamic solubility/miscibility and kinetic miscibility implied that naproxen was highly supersaturated in the PVP solid dispersions and only stabilized kinetically. The negative value of the drug-polymer interaction parameter (-0.36) signified the systems to be favorably mixing. The melting point depression data of naproxen in PVP pointed to the composition dependence and chain length effect on the interaction. The moisture sorption by the physical mixtures not only provided the composition dependent interaction parameter but also conferred an estimate of composition dependent miscibility of naproxen in PVP in the presence of water.