Ecevit Bilgili

Preparation and characterization of hydroxypropyl methyl cellulose films containing stable BCS Class II drug nanoparticles for pharmaceutical applications.

The design and feasibility of a simple process of incorporating stable nanoparticles into edible polymer films is demonstrated with the goal of enhancing the dissolution rate of poorly water soluble drugs. Nanosuspensions produced from wet stirred media milling (WSMM) were transformed into polymer films containing drug nanoparticles by mixing with a low molecular weight hydroxylpropyl methyl cellulose (HPMC E15LV) solution containing glycerin followed by film casting and drying. Three different BCS Class II drugs, naproxen (NPX), fenofibrate (FNB) and griseofulvin (GF) were studied. The influence of the drug molecule on the film properties was also investigated. It was shown that film processing methodology employed has no effect on the drug crystallinity according to X-ray diffraction (XRD) and Raman spectroscopy. Differences in aggregation behavior of APIs in films were observed through SEM and NIR chemical imaging analysis. NPX exhibited the strongest aggregation compared to the other drugs. The aggregation had a direct effect on drug content uniformity in the film. Mechanical properties of the film were also affected depending on the drug-polymer interaction. Due to strong hydrogen bonding with the polymer, NPX exhibited an increase in Youngs Modulus (YM) of approximately 200%, among other mechanical properties, compared to GF films. A synergistic effect between surfactant/polymer and drug/polymer interactions in the FNB film resulted in an increase of more than 600% in YM compared to the GF film. The enhancement in drug dissolution rate of films due to the large surface area and smaller drug particle size was also demonstrated.

Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water-soluble drugs

Micronization and nanoparticle production of poorly water-soluble drugs was investigated using single wet milling equipment operating in the attritor and stirred media modes. The drug particles in the median size range of 0.2–2 µm were prepared by changing the milling mode and operating conditions of a Micros mill with a purpose of elucidating the dynamics of the wet milling process. It was determined that particle breakage due to mechanical stresses and aggregation due to insufficient stabilization are two competing mechanisms which together control the wet milling dynamics of the poorly water-soluble drugs. The study in the attritor mode using four different classes of stabilizers with six drugs indicated that steric stabilization worked better than electrostatic stabilization for the drugs studied. In addition, the existence of different minimum polymer concentrations for the stabilization of microsuspensions and nanosuspensions was indicated. The major role of a non-ionic polymer during the production of fine particles is its stabilization action through steric effects, and no experimental evidence was found to support the so-called Rehbinder effect. Periodic addition of the polymer as opposed to the addition of the polymer at the start of milling process was introduced as a novel processing method. This novel method of polymer addition provided effective stabilization and breakage of drug particles leading to a narrower and finer particle size distribution. Alternatively, it may allow shorter processing time and lower overall power consumption of the milling process for a desired particle size.

A combined microhydrodynamics-polymer adsorption analysis for elucidation of the roles of stabilizers in wet stirred media milling.

Although polymers and surfactants are commonly used as stabilizers to impart physical stability to the suspensions produced by wet stirred media milling of poorly water-soluble drugs, scant information is available in pharmaceutical literature regarding their impact on the breakage kinetics. We present a combined microhydrodynamics-polymer adsorption analysis to elucidate the roles of stabilizers with a focus on the kinetics. Griseofulvin (GF), a model poorly water-soluble drug, was milled at various concentrations of hydroxypropyl cellulose (HPC) in the presence-absence of sodium dodecyl sulfate (SDS). Particle sizing, scanning electron microscopy, thermal analysis, and rheometry were used to determine the breakage kinetics, adsorption isotherm, and apparent viscosity, which were then used to analyze the aggregation state of the milled suspensions and the microhydrodynamics. In the absence of SDS, an increase in HPC concentration slowed the particle aggregation leading to faster apparent breakage. On the other hand, due to a synergistic stabilizing action of HPC with SDS, lower HPC concentration was needed to stabilize the suspensions, and an optimum HPC concentration for the fastest apparent breakage was identified. The microhydrodynamic analysis quantified, for the first time, the viscous dampening effect of polymers, while only the combined analysis could explain the observed optimum.

Continuous production of drug nanoparticle suspensions via wet stirred media milling: a fresh look at the Rehbinder effect

Nanoparticles of BCS Class II drugs are produced in wet stirred media mills operating in batch or recirculation mode with the goal of resolving the poor water-solubility issue. Scant information is available regarding the continuous production of drug nanoparticles via wet media milling. Griseofulvin and Naproxen were milled in both recirculation mode and multi-pass continuous mode to study the breakage dynamics and to determine the effects of suspension flow rate. The evolution of the median particle size was measured and described by an empirical breakage model. We found that these two operation modes could produce drug nanosuspensions with similar particle size distributions (PSDs). A reduced suspension flow rate slowed the breakage rate and led to a wider PSD and more differentiation between the two operation modes. The latter part of this study focused on the roles of stabilizers (hydroxypropyl cellulose and sodium lauryl sulfate) and elucidation of the so-called Rehbinder effect (reduction in particle strength due to adsorbed stabilizers such as polymers and surfactants). Milling the drugs in the absence of the stabilizers produced primary nanoparticles and their aggregates, while milling with the stabilizers produced smaller primary nanoparticles with minimal aggregation. Using laser diffraction, BET nitrogen adsorption, scanning electron microscopy imaging, and a microhydrodynamic analysis of milling, this study, for the first time, provides sufficient evidence for the existence of the Rehbinder effect during the milling of drugs. Not only do the polymers and surfactants allow proper stabilization of the nanoparticles in the suspensions, but they also do facilitate drug particle breakage.

Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet stirred media milling: a microhydrodynamic view.

Wet stirred media milling has proven to be a robust process for producing nanoparticle suspensions of poorly water-soluble drugs. As the process is expensive and energy-intensive, it is important to study the breakage kinetics, which determines the cycle time and production rate for a desired fineness. Although the impact of process parameters on the properties of final product suspensions has been investigated, scant information is available regarding their impact on the breakage kinetics. Here, we elucidate the impact of stirrer speed, bead concentration, and drug loading on the breakage kinetics via a microhydrodynamic model for the bead-bead collisions. Suspensions of griseofulvin, a model poorly water-soluble drug, were prepared in the presence of two stabilizers: hydroxypropyl cellulose and sodium dodecyl sulfate. Laser diffraction, scanning electron microscopy, and rheometry were used to characterize them. Various microhydrodynamic parameters including a newly defined milling intensity factor was calculated. An increase in either the stirrer speed or the bead concentration led to an increase in the specific energy and the milling intensity factor, consequently faster breakage. On the other hand, an increase in the drug loading led to a decrease in these parameters and consequently slower breakage. While all microhydrodynamic parameters provided significant physical insight, only the milling intensity factor was capable of explaining the influence of all parameters directly through its strong correlation with the process time constant. Besides guiding process optimization, the analysis rationalizes the preparation of a single high drug-loaded batch (20% or higher) instead of multiple dilute batches.

Pulverization of rubber granulates using the solid state shear extrusion process. Part II. Powder characterization

Abstract Rubber powder obtained from the solid state shear extrusion (SSSE) process and the unprocessed rubber granulates were analyzed using physical, thermal, and chemical characterization methods. A portion of the granulates and two different size fractions of the powder produced by several passes of the rubber through the extruder were sampled by sieves and then characterized. Particle size distribution of the samples was determined using a laser diffraction technique. The shape of the particles was observed with an optical microscope, and the details of the particle surfaces were visualized using a scanning electron microscope. The total surface area was obtained using a BET method. Thermal analysis techniques were used to determine the composition, thermal, and thermo-oxidative degradation characteristics. The cross-link density and gel fraction of the rubber were determined using swelling and Soxhlet extraction methods, respectively. The microscopy study revealed that the particles generally had irregular shapes with rough surfaces, whereas the granulates had angular shapes with smooth surfaces. The larger particles produced by the SSSE process were mainly agglomerates of smaller particles. The total and external surface areas of the particles produced by the SSSE process were significantly greater than those of a cryogenically ground rubber of a similar size range. The extent of thermo-oxidation depended on the external and total surface areas of the samples. However, characteristic temperatures and kinetic parameters of the thermal degradation in the nitrogen environment were not affected by the size or surface area. The composition of the granulates was the same as that of the particles. However, the cross-link density and gel fraction of the rubber particles were smaller than those of the granulates suggesting the cleavage of chemical bonds due to the high mechanical stresses and possible oxidation during the SSSE process. The particle agglomeration during the reprocessing was instrumental in the alteration of the rubber properties.

Production of pigment nanoparticles using a wet stirred mill with polymeric media

Abstract Pigment nanoparticles with a size range of 10∼100 nm were produced from large agglomerates via a stirred media mill operating in the wet-batch mode and using polymeric media. The effects of several operating variables such as the surfactant concentration, polystyrene media loading, and media size on the pigment size distribution of the product were studied. The process dynamics was also investigated. Dynamic light scattering and electron microscopy were used as the characterization techniques. The polymeric grinding media are found to be effective for the production of pigment nanoparticles. The experimental results suggest the existence of an optimum media size and surfactant concentration. A population balance model of the process reveals a transition from first-order breakage kinetics for relatively coarse particles to non-first-order kinetics, with a delay period, for the smaller particles. The model implies that large agglomerates split in a first-order fashion whereas the breakage of individual nanoparticles may depend on induced fatigue of the particles.

Pulverization of rubber granulates using the solid-state shear extrusion (SSSE) process:: Part I. Process concepts and characteristics

A single screw extruder was used to pulverize rubber granulates at high shear and compression without using cryogenic fluid for cooling. This process, solid-state shear extrusion (SSSE), is based on the large compressive shear deformation of rubber granulates, which results in the storage of a large amount of strain energy and the formation of cracks. When the stored energy reaches a critical level, the granulate cannot sustain itself. As a result, the stored elastic energy is converted into surface energy through the formation of new surfaces and, in turn, pulverization occurs. The stored elastic energy is dependent on the viscoelastic response of rubber granulates to the processing condition. The independent variables of the process were identified as the degree of compression of the rubber, number of extruder passes, barrel wall temperatures, rotation rate of the extruder screw, and feed rate of the granulates. The effects of these variables on the dependent variables, such as material and screw temperatures, particle size distribution (PSD), torque, and mechanical power consumption at steady state, were systematically studied. Fine rubber particles were obtained when the granulates were compressed sufficiently, and loss of strain energy due to viscoelastic stress relaxation was minimized by significant cooling in the pulverization zone. Agglomeration of rubber particles was found to be competing with the pulverization process.

Redispersible fast dissolving nanocomposite microparticles of poorly water-soluble drugs.

Enhanced recovery/dissolution of two wet media-milled, poorly water-soluble drugs, Griseofulvin (GF) and Azodicarbonamide (AZD), incorporated into nanocomposite microparticles (NCMPs) via fluidized bed drying (FBD) and spray-drying (SD) was investigated. The effects of drying method, drug loading, drug aqueous solubility/wettability as well as synergistic stabilization of the milled suspensions on nanoparticle recovery/dissolution were examined. Drug nanoparticle recovery from FBD and SD produced NCMPs having high drug loadings was evaluated upon gentle redispersion via optical microscopy and laser diffraction. During wet-milling, hydroxypropyl cellulose (HPC) alone stabilized more wettable drug (AZD) nanoparticles with slight aggregation, but could not prevent aggregation of the GF nanoparticles. In contrast, well-dispersed, stable nanosuspensions of both drugs were produced when sodium dodecyl sulfate (SDS) and HPC were combined. The FBD and SD NCMPs without SDS exhibited incomplete nanoparticle recovery, causing slower dissolution for GF, but not for AZD, likely due to higher aqueous solubility/wettability of AZD. For high active loaded NCMPs (FBD ∼50 wt%, SD ∼80 wt%) of either drug, HPC-SDS together owing to their synergistic stabilization led to fast redispersibility/dissolution, corroborated via optical microscopy and particle sizing. These positive attributes can help development of smaller, high drug-loaded dosage forms having enhanced bioavailability and better patient compliance.

A New Recycling Technology: Compression Molding of Pulverized Rubber Waste in the Absence of Virgin Rubber

Recycling of rubber waste poses a challenging environmental, economical, and social problem. In the present study, we propose a new two-stage recycling process to reuse a rubber waste. First, the granulates of the waste were pulverized into small particles using a single screw extruder in the Solid State Shear Extrusion (SSSE) process. Then, the produced powder was compression molded in the absence of virgin rubber. The slabs prepared at various molding conditions were subjected to mechanical, chemical, and microscopic tests. It is found that the slabs have high extensibility with low-medium tensile strength. Compressive creep of the powder, self-adhesion of rubber molecules, and interchange reactions of polysulfidic crosslinks are proposed as the basis of particle bonding.