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We prepared hybrid nanocrystal–amorphous solid dispersions (HyNASDs) to enhance the dissolution of a poorly soluble drug, griseofulvin (GF), and elucidated the roles of a surfactant, sodium dodecyl sulfate (SDS), and two polymers, HPC and Soluplus. Wet-milled suspensions containing 1:1 to 1:5 GF:polymer mass ratios, with and without SDS, were spray-dried. HyNASD formation was confirmed via DSC, XRPD, and Raman spectroscopy. In dissolution tests, due to its sub-ambient glass transition temperature, poor miscibility with GF, its inability to inhibit GF recrystallization, HPC provided HyNASDs with low supersaturation capability (≤50%) even at the highest loading (1:5) with/without SDS. Contrarily, owing to its stronger intermolecular interactions–miscibility with GF, and its kinetic solubilization–inhibition of GF recrystallization observed in desupersaturation tests, Soluplus, with SDS, in HyNASDs achieved remarkably high supersaturation (>250%). SDS provided enhanced wettability, allowing for fast supersaturation from Soluplus-based HyNASDs (~300% within 20 min), while higher Soluplus loading led to higher supersaturation.

Dissolution of poorly soluble drugs can be improved by wet-milling their suspensions and drying the suspensions to form nanocomposites. Different classes of dispersants and their concentration can affect both nanoparticle aggregation in the suspensions and drug dissolution from the nanocomposites. In this study, we examine the impact of various classes of dispersants on nanoparticle aggregation–dissolution of itraconazole (ITZ) from spray-dried wet-milled ITZ nanosuspensions. 2.5% hydroxypropyl cellulose (HPC), 0.2% sodium dodecyl sulfate (SDS), and their combination were used as baseline dispersant formulations. Mannitol and sucrose, as model water-soluble dispersants, were added to the wet-milled ITZ suspensions with HPC. As swellable dispersants, superdisintegrants such as sodium starch glycolate (SSG), crospovidone (CP), and croscarmellose sodium (CCS) were wet-co-milled with ITZ–HPC. The wet-milled suspensions were spray-dried to prepare nanocomposites. Laser diffraction results show that wet milling with HPC–SDS and HPC with concentration at/above 4.5% led to a median drug size below ~0.20 μm due to electrosteric and steric stabilizing effects, respectively. Their nanocomposites led to immediate, fast ITZ release: >%80 dissolved in 20 min. Unlike these suspensions, other suspensions with mannitol, sucrose, and superdisintegrants along with HPC exhibited more aggregation and pseudoplasticity. Nonetheless, the addition of these dispersants resulted in faster drug release especially at higher concentrations, as quantified by the higher value of the product kn of the Korsmeyer–Peppas model, due to faster erosion/disintegration of the nanocomposite matrix. Wet co-milled superdisintegrants achieved faster drug release than mannitol and sucrose. Their dissolution impact was positively correlated with their swelling capacity (SSG > CCS > CP), which signifies a swelling-induced erosion/disintegration mechanism. Surfactant-free nanocomposites with >60% drug loading that exhibited immediate drug release were prepared with either HPC–co-milled SSG/CCS or HPC with optimal concentration.

A multi-scale modeling approach is formulated which combines the use of the discrete element method (DEM) and population balance model (PBM) to simulate the evolution of particle size distribution (PSD) in dry milling. As a major novelty, a pseudo-coupled DEM–non-linear PBM approach is proposed, in which the parameters of a non-linear PBM were calibrated using the DEM simulations of the microdynamic environment in a mill by using the DEM intermittently. To demonstrate the application of this approach, breakage dynamics of silica particles in a vibrating cylindrical vessel containing an alumina grinding ball was simulated numerically. DEM simulations were performed to obtain the collision frequency and impact energy spectra, calculate the first-order breakage rate parameters from short milling of mono-sized feeds, and calibrate the parameters of the effectiveness factor of the non-linear PBM. As another novelty, the form of the effectiveness factor chosen accounted for both acceleration effects and deceleration effects simultaneously, which have been observed in various experimental milling studies. By incorporating DEM input, the non-linear PBM with the effectiveness factor was used to simulate the evolution of the PSD. This study demonstrates that a non-linear PBM, whose parameters were calibrated using DEM at early milling times, could predict the PSD evolution during prolonged milling and potentially obviate the need for using computationally expensive DEM simulations for the whole milling duration.

The advantages of using superdisintegrants, sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone (CP) over traditional high molecular weight (MW) viscosity enhancing agents, guar gum (GG), xanthan gum (XG), pectin and high MW HPMC are examined for improving drug content uniformity without compromising dissolution of films containing nanoparticles of griseofulvin (GF), used as a model poorly water-soluble drug. Films were fabricated by preparing low MW HPMC solutions to which a fixed amount of viscosity enhancing agents was added and mixed with GF nanosuspensions produced via wet milling, followed by casting and drying. The addition of superdisintegrants and high MW HPMC led to an increase in viscosity of precursor suspensions without GF particle aggregation, and hence excellent drug content uniformity along with retention of the high surface area of the GF nanoparticles in dried films. In contrast, the addition of XG and pectin resulted in aggregation of GF particles in suspensions, leading to poor content uniformity and incomplete recovery of GF nanoparticles upon redispersion of dried films. In spite of their high precursor viscosity, the films containing superdisintegrants did not lead to increased mechanical strength and demonstrated fast drug release, suggesting faster matrix erosion. In contrast, films with high MW polymers (GG, XG, and pectin and high MW HPMC) had increased mechanical strength and their subsequent slow erosion/disintegration along with longer hydration times resulted in significant delay of drug release, which was found to be directly proportional to their MW. These results demonstrate novel use for superdisintegrants as economical and superior alternative to traditional viscosity enhancing agents in forming drug laden biocompatible polymer films.

While population balance models (PBMs) have described the impact of mechanical interparticle interactions on the specific breakage rate in dry milling processes through a phenomenological effectiveness factor, such models lack particle-scale information and thus a mechanistic basis. In this study, a mechanistic effectiveness factor of the non-linear PBM was derived and calculated by coupling a particle-scale breakage model with interparticle interactions obtained from discrete element method (DEM) simulations of a grinding ball impacting an unconfined particle bed. Mono, binary, ternary, and polydispersed particle beds were simulated to determine the effects of granular composition on breakage kinetics. The effectiveness factor obtained from the DEM simulations shows a reduction in the specific breakage rate for coarse particles in binary mixtures. The origin of this phenomenon, commonly known as cushioning or decelerated breakage in dry milling processes, was explained by the DEM simulations: fine particles in a particle bed increase mechanical energy loss, and reduce and distribute interparticle forces thereby inhibiting the breakage of the coarse component. On the other hand, the specific breakage rate of fine particles increased due to contacts associated with coarse particles. Such phenomenon, known as acceleration, was shown to be less significant, but should be considered in future attempts to accurately quantify non-linear breakage kinetics in the modeling of dry milling processes. The phenomenological effectiveness factor was also assessed and found to accurately describe the impact of mechanical interparticle interactions in binary particle beds as well as predict the non-linear breakage behavior in ternary and polydispersed particle beds. Aside from gaining particle-scale insight into non-linear breakage kinetics, the above findings provide the guidelines for the usage of non-linear PBM framework and are expected to improve the design, control, and optimization of dry milling processes that exhibit non-linear breakage kinetics.

This study focuses on the preparation of sub-100 μm freely flowing yet fast dissolving core–shell nanocomposite powders via fluidized bed (FB) coating of poorly water-soluble drug nanosuspensions onto fine carrier particles (sub-50 μm). This is in contrast to conventional FB coating processes that utilize carrier particles as large as 850 μm resulting in much larger final nanocomposites. Fluidization and subsequent FB processing of sub-50 μm, Geldart group C powders, is a major technological barrier, which can be overcome by either increasing the body weight of the powders, or decreasing their cohesion. Here, the latter is considered as a practical way to enhance fluidization, accomplished through applying a discrete, fairly uniform layer of nano-sized silica particles onto the surface of the cohesive host particles dry coating. Fenofibrate was considered as a model poorly water-soluble drug, and was wet-milled in a stirred media mill and stabilized via an optimized polymer and surfactant combination. The nanoparticle suspensions were then coated onto hydrophilic nano-silica (M5P) coated sub-50 micron lactose (Granulac® 200) or potato starch carrier particles in a FB process. Their coating with drug particle nanosuspensions was achieved without appreciable agglomeration, which is a major novelty of this work. In spite of having a median particle size well under 100 μm, the resulting final composite powders were freely flowing, had high bulk density, and allowed for fast dissolution of a poorly water-soluble drug in comparison to either micronized or nano-milled drug along with the same excipients in physical mixtures.

In this work, we provide experimental evidence supporting the dual role of stabilizers on controlling growth and agglomeration of formed particles via liquid antisolvent (LAS) process and use this knowledge to demonstrate the feasibility of integrating these engineered particles into fast dissolving edible pharmaceutical strip films (PSF). A T-mixer was used to produce griseofulvin (GF) particles for incorporation into PSF in continuous mode, while the experiments crucial to elucidate the role of stabilizers were conducted in batch system. Stabilization was examined via addition of the non-ionic surfactant Pluronic F127 (PF 127), the polymer hydroxypropyl methyl cellulose (HPMC LV 15) and their combinations. Centrifugation was evaluated as a means to concentrate suspensions and minimize levels of residual solvent, while keeping the produced particles non-agglomerated. Laser diffraction, SEM imaging, Differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Near-infrared Spectroscopy (NIR) were employed to characterize the particles and strip films. It was observed that the simultaneous evolution of particle growth and agglomeration is controlled if HPMC LV 15 and PF 127 are present before precipitation while only agglomeration is suppressed if added after precipitation. The addition of PF 127 along with HPMC LV 15 to GF suspensions results in controlling initial growth and suppression of agglomeration during downstream processing via synergistic effects. The optimal formulation results in faster and higher extent of dissolution than a poorly stabilized suspension, a film made from the unprocessed drug, a physical mixture or a compact of similar composition. Along with particle size data, cluster size analysis from NIR imaging emphasizes the role of wettability and re-dispersion in the particle dispersion in the film and recoverability of engineered particles to improve bioavailability.

Incorporation of BCS Class II drug nanoparticles into solid dosage forms entails drying of nanosuspensions as an intermediate step, which can unfortunately lead to loss of their large surface area through size growth and/or agglomeration. Ensuing incomplete nanoparticle recovery and redispersion during dissolution of the solid dosage forms may lead to poor bioavailability. In this study, nanoparticle recovery from nanocomposite microparticles redispersed in water or an aqueous surfactant solution was investigated as a function of various excipients. Nanosuspensions of griseofulvin (GF), considered as a model BCS Class II drug, were prepared by wet media milling and subsequently dried through coating on Pharmatose® carrier particles in a fluidized bed processor. A polymer (hydroxypropyl cellulose, HPC), a surfactant (sodium dodecyl sulfate, SDS), and their combinations at various concentrations were used as stabilizers during milling; mannitol was used as dispersant in one formulation. The core–shell type nanocomposite microparticles obtained from the fluidized bed coating were redispersed in water using various methods of agitation to recover the GF nanoparticles. Particle size analysis, SEM imaging, and dissolution testing were used to elucidate the redispersion phenomenon and its relevance to dissolution. It was found that the presence of SDS was critical to the full recovery of nanoparticles and their dissolution, whereas HPC appeared to have positive yet convoluted effects. The redispersion methods studied had a slight impact on the recovery of nanoparticles when SDS was present either in the formulation or in the redispersion medium (water). Incomplete recovery of the nanoparticles caused relatively poor drug dissolution, signifying the importance of complete redispersion. The HPC–SDS combination resulted in a synergistic effect in the formation of finer nanoparticles as well as in fast redispersion of GF nanoparticles from the nanocomposite microparticles. A similar redispersion response was observed with another BCS Class II drug, phenylbutazone (PHB).

Non-linear population balance models (PBMs) have recently been shown to be superior to their linear counterparts for quantifying the breakage kinetics in dense-phase dry milling processes, where mechanical multi-particle interactions are significant. At the particle ensemble scale, particles of different sizes interact causing a population dependence of the specific breakage rate function. Non-linear PBMs explicitly account for these multi-particle interactions through a population-dependent functional called the effectiveness factor. Due to the inherent difficulty and complexity of proposing and selecting an appropriate form of the effectiveness factor, a general and systematic approach is desired to assess breakage kinetics in an unbiased manner. In this study, toward addressing the need for a general form of the effectiveness factor, we propose a rational function approximation. First, computer generated effectiveness factor was approximated by a rational function. Then, evolution of the particle size distribution during batch dry milling of quartz in a tumbling ball mill was fitted with various forms of the effectiveness factor in the context of linear and non-linear PBMs. Goodness-of-fit and statistical significance of the parameters estimated were evaluated to discriminate various forms of the effectiveness factor. The statistical analysis suggests that a rational function may replace specific forms of the effectiveness factor for a less restrictive analysis of the multi-particle interactions. Additionally, fitting a non-linear PBM using the rational function approximation allowed us to describe the dense-phase dry milling data accurately. Accordingly, this study enables experimenters to quantify the impact of the multi-particle interactions in a robust, systematic, and unbiased manner via the rational function approximation to the effectiveness factor within the context of the non-linear PBM.

Discrete linear population balance models have been widely used for comminution processes and particle breakage tests that involve a series of breakage events. The fundamental tenet of these models is the independence of particle breakage from the surrounding particle population. On the other hand, ample experimental data have shown that multi-particle interactions among particles of different sizes at the particle ensemble scale lead to a population-dependent breakage probability. In an attempt to analyze and model the multi-particle interactions, we formulate a time- or space-discrete and particle size-discrete non-linear population balance model using a recently introduced non-linear kinetics framework for rate-based comminution processes. The discrete model is developed as a limiting case and presented in equivalent matrix and index notation. The practical applicability, accuracy, and stability aspects of the model are discussed. With an empirical, flexible, non-linear functional accounting for multi-particle interactions explicitly, the proposed model can serve as a framework for quantitatively analyzing multi-particle interactions. Numerical simulations with a simplified discrete model have provided significant insight into the retardation effect of fines on the breakage probability of the coarser particles experimentally observed in dense-phase particulate systems such as particle bed compression tests.

Non-linear population balance models (PBMs), which have been recently introduced due to the limitations of the classical linear time-invariant (LTINV) model, account for multi-particle interactions and thus are capable of predicting many types of complex non-first order breakage kinetics during size reduction operations. No attempt has been made in the literature to estimate the non-linear model parameters by fitting the model to experimental data and to discriminate various models based on statistical analysis. In this study, a fully numerical back-calculation method was developed in the Matlab environment to determine the model parameters of the non-linear PBM. Not only does the back-calculation method identify the parameters of complicated non-linear PBMs, but also it gives the goodness of fit and certainty of the parameters. The performance of the back-calculation method was first assessed on computer-generated batch milling data with and without random error. The back-calculation method was then applied to experimental batch milling data exhibiting non-first order effects using both the LTINV model and two separate non-linear models. The back-calculation method was able to correctly determine the model parameters of relatively small sets of batch milling data with random errors. Applied to experimental batch milling data, the back-calculation method with a two-parameter non-linear model yielded parameters with reasonable certainty and accurately predicted the slowing-down phenomenon during dry batch milling. This study encourages experimenters to use advanced non-linear population balance models along with the back-calculation method toward estimating the breakage rate and distribution parameters from dense batch milling data sets.

In a porous metal bed, two-dimensional heat and mass transfer are analyzed for hydrogen absorption in the cylindrical coordinates. For high cooling rates an annular geometry is selected for the porous metal bed, and the bed is cooled by a fluid on both the internal and the external surfaces. The absorption process is analyzed numerically for the porous LaNi5 P/M metal bed. Variations of the metal hydride temperature and hydrogen/metal atomic ratio are calculated in the radial and axial directions using a computational fluid dynamics (CFD) program. It is observed that the hydride formation takes places near the cold boundaries. The results are compared with the numerical results given in the literature for different geometries. (c) 2005 Elsevier B.V. All rights reserved.

Specific breakage rate (selection) and breakage distribution functions are used to describe the birth and death terms in population balance models (PBMs) for milling processes. Traditional PBMs for milling processes are inherently linear because the breakage rate is assumed first-order. The specific breakage rate is independent of the population density while it depends on particle size and possibly on time. Even though the linear theory has been applied with some success to the modeling, optimization, and design of various mills in the last 50 years, many researchers have indicated its restrictions and subjected it to serious criticism. In this paper, we first categorize the experimentally observed deviations from the linear theory and suggest the multi-particle interactions as the origin of these deviations. To account for the peculiar non-linear effects, a phenomenological theory has been proposed via multiplicative decomposition of the specific breakage into a size-dependent apparent breakage rate and a population density dependent functional. The proposed theory recovers the first-order breakage kinetics in the limit, yet it is sufficiently general to explain all experimentally observed deviations. Numerical simulations of a batch milling process have demonstrated the potential of the non-linear theory.

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.