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Although heat is generated during the wet stirred media milling of drug suspensions, leading to notable temperature rise, a comprehensive analysis of heat generation does not exist. Hence, we investigated the impact of stirrer speed, bead loading, and bead size at three levels on the evolution of suspension temperature at the mill outlet during the milling of fenofibrate. The particle sizes and viscosities of the milled suspensions and power were measured. Our results suggest that stirrer speed had the most significant impact on the temperature increase, followed by bead loading and bead size. Both the time when the temperature reached 22 °C and the temperature at 5 min of milling were strongly correlated with the power. Assessing the impacts of the process parameters on the temperature rise, cycle time, power, and median particle size holistically, an optimal milling process was identified: 3000 rpm with 50% loading of 200 or 400 µm beads. A power number correlation was established to calculate power at any milling condition which determines the heat generation rate. Overall, this study indicated the importance of developing a good understanding of heat generation during nanomilling for development of a robust milling process especially for thermally labile drugs.

Spray drying is one of the widely used manufacturing processes in pharmaceutical industry. While there are voluminous experimental studies pertaining to the impact of various process-formulation parameters on the quality attributes of spray dried powders such as particle size, morphology, density, and crystallinity, there is scant information available in the literature regarding process scale-up. Here, we first analyze salient features of scale-up attempts in literature. Then, spray drying process is analyzed considering the fundamental physical transformations involved, i.e., atomization, drying, and gas-solid separation. Each transformation is scrutinized from a scale-up perspective with non-dimensional parameters & multi-scale analysis, and comprehensively discussed in engineering context. Successful scale-up entails similar key response variables from each transformation across various scales. These variables are identified as droplet size distribution, outlet temperature, relative humidity, separator pressure loss coefficient, and collection efficiency. Instead of trial-and-error-based approaches, this review paper advocates the use of mechanistic models and scale-up rules for establishing design spaces for the process variables involved in each transformation of spray drying. While presenting a roadmap for process development and scale-up, the paper demonstrates how to bridge the current gap in spray drying scale-up via a rational understanding of the fundamental transformations.

The impact of dry coating with hydrophobic or hydrophilic nano-silica at 25–100% surface area coverage on dissolution of micronized poorly water-soluble drugs was investigated by examining their agglomeration and surface hydrophobicity. Ibuprofen (20 µm and 10 µm) and griseofulvin (10 µm) were selected having differing solubility, hydrophobicity, and surface morphology. Characterization involved particle agglomeration via two dry dispersion methods, drug dissolution using the USP IV method, cohesion reduction through shear testing, and powder wettability via the modified Washburn method. Dry coating dramatically reduced the cohesion hence agglomerate size of both the coated ibuprofen particles, but less for griseofulvin, attributed to its surface morphology. For hydrophobic silica, agglomerate size reduction outweighed the adverse impact of increased surface hydrophobicity for ibuprofen. For griseofulvin, the agglomerate reduction was much lower, not able to overcome the effect of increased drug particle hydrophobicity with hydrophobic silica coating. Hydrophilic silica coating reduced hydrophobicity for all three drug powders, leading to the synergistic improvement in the dissolution along with agglomerate size reduction. Overall, the combined effect of the drug particle surface hydrophobicity and agglomerate size, represented by specific surface area, could explain the dissolution behavior of these poorly water-soluble drugs.

Although wet stirred media milling has proven to be a robust process for producing nanoparticle suspensions of poorly water-soluble drugs and thereby enhancing their bioavailability, selection of bead size has been largely empirical, lacking fundamental rationale. This study aims to establish such rationale by investigating the impact of bead size at various stirrer speeds on the drug breakage kinetics via a microhydrodynamic model. To this end, stable suspensions of griseofulvin, a model BCS Class II drug, were prepared using hydroxypropyl cellulose and sodium dodecyl sulfate. The suspensions were milled at four different stirrer speeds (1000-4000rpm) using various sizes (50-1500μm) of zirconia beads. Laser diffraction, SEM, and XRPD were used for characterization. Our results suggest that there is an optimal bead size that achieves fastest breakage at each stirrer speed and that it shifts to a smaller size at higher speed. Calculated microhydrodynamic parameters reveal two counteracting effects of bead size: more bead-bead collisions with less energy/force upon a decrease in bead size. The optimal bead size exhibits a negative power-law correlation with either specific energy consumption or the microhydrodynamic parameters. Overall, this study rationalizes the use of smaller beads for more energetic wet media milling.

Polymer strip films have emerged as a robust platform for poorly water-soluble drug delivery. However, the common conception is that films cannot exceed low drug loadings, mainly due to poor drug stability, slow release, and film brittleness. This study explores the ability to achieve high loadings of poorly water-soluble drug nanoparticles in strip films while retaining good mechanical properties and enhanced dissolution rate. Aqueous suspensions containing up to 30wt% griseofulvin nanoparticles were prepared via wet stirred media milling and incorporated into hydroxypropyl methylcellulose (HPMC) films. Griseofulvin loading in films was adjusted to be between 9 and 49wt% in HPMC-E15 films and 30 and 73wt% in HPMC-E4M films by varying the mixing ratio of HPMC solution-to-griseofulvin suspension. All films exhibited good content uniformity and nanoparticle redispersibility up to 50wt% griseofulvin, while E4M films above 50wt% griseofulvin had slightly worse content uniformity and poor nanoparticle redispersibility. Increasing drug loading in films generally required more time to achieve 100% release during dissolution, although polymer-drug clusters dispersed from E4M films above 50wt% griseofulvin, resulting in similar dissolution profiles. While all films exhibited good tensile strength, a significant decrease in percent elongation was observed above 40-50wt% GF, resulting in brittle films.

Formation of core-shell nanocomposites of Fenofibrate and Itraconazole, model poorly water soluble drugs, via fluidized bed (FB) coating of their well-stabilized high drug loaded nanosuspensions is investigated. Specifically, the extent of dissolution enhancement, when fine carrier particles (sub–50 μm) as opposed to the traditional large carrier particles (>300 μm) are used, is examined. This allows testing the hypothesis that greatly increased carrier surface area and more importantly, thinner shell for finer carriers at the same drug loading can significantly increase the dissolution rate when spray-coated nanosuspensions are well-stabilized. Fine sub–50 μm lactose (GranuLac® 200) carrier particles were made fluidizable via dry coating with nano-silica, enabling decreased cohesion, fluidization and subsequent nanosuspension coating. For both drugs, 30% drug loaded suspensions were prepared via wet-stirred media milling using hydroxypropyl methyl cellulose and sodium dodecyl sulfate as stabilizers. The stabilizer concentrations were varied to affect the milled particle size and prepare a stable nanosuspension. The suspensions were FB coated onto hydrophilic nano-silica (M-5P) dry coated sub-50 μm lactose (GranuLac® 200) carrier particles or larger carrier particles of median size >300 μm (PrismaLac®40). The resulting finer composite powders (sub-100 μm) based on GranuLac® 200 were freely flowing, had high bulk density, and had much faster, immediate dissolution of the poorly water-soluble drugs, in particular for Itraconazole. This is attributed to a much higher specific surface area of the carrier and corresponding thinner coating layer for fine carriers as opposed to those for large carrier particles.

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 Young's 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.

This paper describes a novel approach for designing drug delivery systems for intra-articular (i.a.) treatment of rheumatoid arthritis. Retention of these systems was evaluated by radiolabeling with Tc-99m and gamma scintigraphy in arthritic rabbits. Liposome, niosome, lipogelosome and niogelosome formulations of Diclofenac Sodium (DFNa) have been prepared and drug release properties and in vitro characterisation studies have been carried out. According to characterisation results L1 (DMPC: CHOL: DCP (7:1:2)), L1J1 (DMPC: CHOL: DCP (7:1:2) in C-940 1:1 (w/w)), N (SUR I: CHOL: DCP (7:1:2)) and NJ1 (SUR I: CHOL: DCP (7:1:2) in C-940 1:1 (w/w)) formulations were chosen for the further studies. Retention time of these formulations was evaluated by gamma scintigraphic imaging studies. Rabbits with antigen-induced arthritis were injected intra-articularly with Tc-99m labelled drug delivery systems. Serial scintigraphic images were obtained to investigate the retentions of labelled drug delivery systems in the arthritic joints and choose a suitable formulation for the treatment protocol of arthritis. At the end of the scintigraphic imaging studies it was observed that radiolabelled lipogelosome formulation containing DFNa (L1J1) retained much longer in the experimentally arthritic knee joints of the rabbits. This formulation was used for the treatment protocol of arthritis. Mono articular arthritis was induced in the knee joints of rabbits and it was monitored at regular time intervals by measuring changes in knee joint diameter. Also macroscopic and histopathologic evaluations were performed for further evaluation of arthritis. Great retention of DFNa in the arthritic joint might reduce potential adverse systemic effects of the drug because of local administration into the diseased area. It appeared to be a promising drug delivery system for intra-articular drug delivery.

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.

Fast drying of nano-drug particle laden strip-films formed using water-soluble biocompatible polymers via forced convection is investigated in order to form films having uniform drug distribution and fast dissolution. Films were produced by casting and drying a mixture of poorly water soluble griseofulvin (GF) nanosuspensions produced via media milling with aqueous hydroxypropyl methylcellulose (HPMC E15LV) solutions containing glycerin as a plasticizer. The effects of convective drying parameters, temperature and air velocity, and film-precursor viscosity on film properties were investigated. Two major drying regimes, a constant rate period as a function of the drying conditions, followed by a single slower falling rate period, were observed. Films dried in an hour or less without any irreversible aggregation of GF nanoparticles with low residual water content. Near-infrared chemical imaging (NIR-CI) and the content uniformity analysis indicated a better drug particle distribution when higher viscosity film-precursors were used. Powder X-ray diffraction showed that the GF in the films retained crystallinity and the polymorphic form. USP IV dissolution tests showed immediate release (~20 min) of GF. Overall, the films fabricated from polymer-based suspensions at higher viscosity dried at different conditions exhibited similar mechanical properties, improved drug content uniformity, and achieved fast drug dissolution.

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.

Thromboembolic diseases including deep vein thrombus (DVT) are major causes of morbidity and mortality. Detection of DVT in low extremities is difficult. There are some accepted imaging techniques in clinic but most of them have several disadvantages limiting their effective use. Because of this, researchers are still performed to develop a rapid, specific means of detecting and/or imaging venous thrombi-based on the changing composition of the thrombus. Urokinase, fibrinolytic enzyme isolated form human urine, is a direct activator of plasminogen. In thrombus formation, plasminogen seems to be trapped in or absorbed onto fibrin matrix thus leading to a localised concentration of plasminogen. This suggests that radiolabelled urokinase would be a suitable compound for the detection of thrombi. The most important disadvantage of this enzyme is short plasma half life. To overcome this problem, it was decided to encapsulate the enzyme in drug delivery systems such as liposomes, niosomes or sphingosomes. In this study, we prepared, characterized and monitored the biodistribution of three types of vesicular systems containing urokinase. All types of prepared vesicles show in vitro an acceptable encapsulation, stability and release profile. Thrombus uptake was increased by encapsulation of urokinase into vesicles.