Costas G. Gogos

Effects of extrusion process parameters on the dissolution behavior of indomethacin in Eudragit E PO solid dispersions.

This work studied the dissolution of indomethacin (INM) into polymer excipient Eudragit E PO (E PO) melt at temperatures lower than the melting point of INM using a laboratory-size, twin-screw counter-rotating batch internal mixer. The effects of three process parameters--set mixer temperature, screw rotating speed and residence time--were systematically studied. Scanning electron microscopy (SEM), optical microscopy (OM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) were employed to investigate the evolution of INMs dissolution into the molten excipient. Differential scanning calorimetry (DSC) was used to quantitatively study the melting enthalpy evolution of the drug. The results showed that the dissolution rate increased with increasing the mixer set temperature, or the screw rotating speed. It was concluded that the dissolution of the drug in the polymer melt is a convective diffusion process, and that laminar distributive mixing can significantly enhance the dissolution rate. More importantly, the time needed for the drug to dissolve inside the molten polymer and the typical residence time for an extrusion process fall in the same range.

Solid dispersion of acetaminophen and poly(ethylene oxide) prepared by hot-melt mixing

In this study, a model drug, acetaminophen (APAP), was melt mixed with poly(ethylene oxide) (PEO) using a Brabender mixer. APAP was found to recrystallize upon cooling to room temperature for all the drug loadings investigated. Higher drug loading leads to faster recrystallization rate. However, the morphology of the recrystallized drug crystals is identical in samples with different drug loadings and does not change with the storage time. To adjust the drugs dissolution rate, nanoclay Cloisite 15A and 30B were added into the binary mixture. The presence of either of the nanoclay dramatically accelerates the drugs recrystallization rate and slows down the drugs releasing rate. The drop of the releasing rate is mainly due to the decrease of wettability, as supported by the contact angle data. Data analysis of the dissolution results suggests that the addition of nanoclays changes the drugs release mechanism from erosion dominant to diffusion dominant. This study suggests that nanoclays may be utilized to tailor the drugs releasing rate and to improve the dosage forms stability by dramatically shortening the lengthy recrystallization process.

Miscibility Studies of Indomethacin and Eudragit® E PO by Thermal, Rheological, and Spectroscopic Analysis

The objective of this study is to understand the underlying mechanisms responsible for the superior stability of indomethacin (INM)-Eudragit® E PO (E PO) system by exploring the miscibility and intermolecular interactions through the combination of thermal, rheological, and spectroscopic analysis. The zero shear-rate viscosity drops monotonically with the increase of INM concentration at 145 °C, suggesting that E PO and INM form a solution and the small molecular drug acts as a plasticizer. Flow activation energy was calculated from the viscosity data at different temperature. The glass transition temperature (T(g)) of the mixture at different composition was determined using differential scanning calorimetry. The T(g) and flow activation energy peak at the INM concentration around 60%-70%. Fourier transform infrared analysis provided direct evidence for the intermolecular ionic interactions, which may disrupt the dimer formation of amorphous INM. The study explained the superior stability of INM-E PO mixtures, and demonstrated that a combination of thermal, rheological, and spectroscopic technologies can help us to obtain a full picture of the drug-polymer interactions and to determine the formulation and processing conditions.

Relation between Molecular Structure and Flow Instability for Ethylene/α-Olefin Copolymers

Surface instabilities in a capillary extrusion have been studied for various ethylene/α-olefin copolymers. It is found that the onset stress of shark-skin failure for ethylene/1-hexene copolymer (EHR) decreases rapidly with increasing 1-hexene content, whereas that of ethylene/propylene copolymer (EPR) is independent of propylene content in the experimental region. Consequently, EHR with high 1-hexene content exhibits shark-skin at low stress level compared to EPR. Lower rubbery plateau modulus, leading to higher Deborah number at the same stress level, is attributed to the lower onset stress. Further, the low entanglement density will cause cracks at lower stress level like glassy polymers, which is also responsible for the low onset stress for shark-skin.

Melting behaviour of controlled rheology polypropylene

Abstract The melting behaviour of reactor-made isotactic polypropylene (PP) and various controlled rheology polypropylene (CR-PP) samples crystallized under both isothermal and non-isothermal conditions were studied by differential scanning calorimetry and the crystal structure of isothermally crystallized samples at 120°C was investigated using wide angle X-ray diffraction. Multiple endotherms were observed dependent on the molecular weight of the samples, heating rate and cooling rate, and method of crystallization. Recrystallization or reorganization occurred more easily for low molecular weight samples and also for fast cooled samples during the reheating and the melting process. The isothermally crystallized CR-PPs produced by peroxide controlled degradation showed a small melting endotherm peak at ∼143°C which is probably connected to the β form crystal, while unreacted PP showed the α form crystal only. The small endotherm peak was more prominent in one CR-PP sample of intermediate molecular weight. Attempts were made to explain this behaviour through the observed maximum in the half-time of crystallization versus molecular weight plot.

Fabrication of microporous polymeric membranes by melt processing of immiscible blends

Abstract Microporous flat film membranes from immiscible polypropylene (PP)/polystyrene (PS) blends with and without a compatibilizing copolymer were produced via melt processing and post-extrusion drawing. The blends were first compounded in a corotating twin-screw extruder and subsequently extruded through a sheet die to obtain the precursor films. These were uniaxially drawn (100–500%) with respect to the original dimensions to induce a microporous structure and then post-treated at elevated temperatures to stabilize the porous structure, which consisted of uniform microcracks in the order of a few nanometers in width. The effects of composition and process parameters on porosity and solvent (methanol) permeability of the prepared membranes are presented. Comparison of the data with those of commercial membranes prepared by phase-inversion processes suggests significant differences in pore size distribution as well as overall surface porosity.

Improving the API dissolution rate during pharmaceutical hot-melt extrusion I: Effect of the API particle size, and the co-rotating, twin-screw extruder screw configuration on the API dissolution rate

The dissolution rate of the active pharmaceutical ingredients in pharmaceutical hot-melt extrusion is the most critical elementary step during the extrusion of amorphous solid solutions - total dissolution has to be achieved within the short residence time in the extruder. Dissolution and dissolution rates are affected by process, material and equipment variables. In this work, we examine the effect of one of the material variables and one of the equipment variables, namely, the API particle size and extruder screw configuration on the API dissolution rate, in a co-rotating, twin-screw extruder. By rapidly removing the extruder screws from the barrel after achieving a steady state, we collected samples along the length of the extruder screws that were characterized by polarized optical microscopy (POM) and differential scanning calorimetry (DSC) to determine the amount of undissolved API. Analyses of samples indicate that reduction of particle size of the API and appropriate selection of screw design can markedly improve the dissolution rate of the API during extrusion. In addition, angle of repose measurements and light microscopy images show that the reduction of particle size of the API can improve the flowability of the physical mixture feed and the adhesiveness between its components, respectively, through dry coating of the polymer particles by the API particles.

Prediction of acetaminophen’s solubility in poly(ethylene oxide) at room temperature using the Flory–Huggins theory

Solid dispersion technologies such as hot-melt extrusion and spray drying are often used to enhance the solubility of poorly soluble drugs. The biggest challenge associated with solid dispersion systems is that amorphous drugs may phase-separate from the polymeric matrix and recrystallize during storage. A more fundamental understanding of drug-polymer mixtures is needed for the industry to embrace the solid dispersion technologies. In this study, a theoretical model based on Flory–Huggins lattice theory was utilized to predict the solubility of a model drug acetaminophen (APAP) in a semi-crystalline polymer poly(ethylene oxide) (PEO) at 300 K. The interaction parameter χ was calculated to be −1.65 from the depression of drug’s melting temperature determined from rheological and differential scanning calorimetry analysis. The equilibrium solubility in amorphous PEO was estimated to be 11.7% at 300 K. Assuming no APAP molecules dissolve in the crystalline part of PEO, the adjusted theoretical solubility is around 2.3% considering PEO being 80% crystalline. The solubility of APAP in PEG 400 was calculated to be 14.6% by using the same χ value, close to the experimental measurement 17.1%. The drug’s solubility could be altered noticeably by the change of both χ and polymer molecular weight. The study also suggests that the depression of drug’s melting point is a good indicator for preliminary polymer screening. The polymer that reduces the melting point the most is likely to be most miscible with the drug.

The importance of plastic energy dissipation (PED) to the heating and melting of polymer particulates in intermeshing co-rotating twin-screw extruders

Unlike the melting in single-screw extruders (SSEs), which has been extensively studied and modeled, the so-called “dissipative melting” occurring in intermeshing co-rotating twin-screw extruders (Co-TSEs) is still not well understood and modeled. In this article, the heating/melting phenomena and mechanisms in Co-TSEs are briefly examined from the energy point of view. Experiments are carried out on the heating/melting behavior of a typical semicrystalline polymer (polypropylene) with two different particulate forms (pellets, powder) and an amorphous polymer (polystyrene), both in different screw configurations. The results of this work show clearly the importance of plastic energy dissipation (PED) of individual pellets in the partially filled kneading section and polymer particulate assemblies, when densified, to the heating/melting of polymer particulates in Co-TSEs.

Preparation of Microporous Films from Immiscible Blends via Melt Processing

Microporous films from immiscible blends were produced via melt processing and post-step treatments. Polystyrene (PS)/polypropylene (PP) and poly(ethylene terephthalate) (PET)/polypropylene blend systems with different viscosity ratios were studied. The blends were first compounded in a co-rotating twin-screw extruder and subsequently extruded through a sheet die to obtain the precursor films. These were uniaxially or biaxially drawn (100–400%) with respect to the original dimension to induce microporous structure and post treated at elevated temperature to maintain the porous structure which consisted of uniform microcracks in the order of a few hundred nanometers. The fabrication process here is shown to be a promising technique for producing microporous films that can be used for liquid and gas separations.