Michael R. Thompson

Biocomposites reinforced with cellulose nanocrystals derived from potato peel waste

This study investigated the effectiveness of cellulose nanocrystals derived from potato peel waste as a reinforcement and vapor barrier additive. The nanocrystals were derived from cellulosic material in the potato peel by alkali treatment and subsequently acid hydrolysis. TEM images revealed the average fiber length of the nanocrystals was 410 nm with an aspect ratio of 41; its aspect ratio being considerably larger than cotton-derived nanocrystals prepared using similar reaction conditions. Cellulose nanocrystals (CNC)-filled polyvinyl alcohol (PVA) and thermoplastic starch (TPS) films were prepared by solution casting method to maintain uniform dispersion of the 1-2% (w/w) filler content. An increase of 19% and 33% (starch composite) and 38% and 49% (PVA composite) in tensile modulus was observed for the 1% and 2% CNC-reinforced composites, respectively. Water vapor transmission measurements showed a marginal reduction of water permeability for the PVA composite, whereas no effect was observed for the thermoplastic starch composite.

Wet granulation in a twin-screw extruder: implications of screw design.

Wet granulation in twin-screw extrusion machinery is an attractive technology for the continuous processing of pharmaceuticals. The performance of this machinery is integrally tied to its screw design yet little fundamental knowledge exists in this emerging field for granulation to intelligently create, troubleshoot, and scale-up such processes. This study endeavored to systematically examine the influence of different commercially available screw elements on the flow behavior and granulation mechanics of lactose monohydrate saturated at low concentration (5-12%, w/w) with an aqueous polyvinyl-pyrrolidone binder. The results of the work showed that current screw elements could be successfully incorporated into designs for wet granulation, to tailor the particle size as well as particle shape of an agglomerate product. Conveying elements for cohesive granular flows were shown to perform similar to their use in polymer processing, as effective transport units with low specific mechanical energy input. The conveying zones provided little significant change to the particle size or shape, though the degree of channel fill in these sections had a significant influence on the more energy-intensive mixing elements studied. The standard mixing elements for this machine, kneading blocks and comb mixers, were found to be effective for generating coarser particles, though their mechanisms of granulation differed significantly.

Foam granulation: new developments in pharmaceutical solid oral dosage forms using twin screw extrusion machinery

This paper investigates foam granulation in a twin screw extruder as a new continuous wet granulation technique for pharmaceutical powder drug formulations. Foamed aqueous binder has a reportedly lower soak-to-spread ratio than drop or spray liquid addition in batch granulation. This work demonstrates a twin screw extruder configuration for foam granulation and subsequently compares the new approach against liquid injection in the granulation of α-lactose monohydrate with a methylcellulose binder. Trials were conducted at high powder output rates (20–40u2009kg/h) and high screw speeds (220–320 RPM) with two screw configurations. Process stability improved with the new technique allowing granulation with less binder. The extruded mass maintained a low exit temperature, being insensitive to operating conditions unlike the liquid injection approach, where temperatures rose significantly as flow rate increased. The particle size distribution by foam granulation reflected a more uniformly wetted mass with larger granule growth noted even for conditions where dry powder exited by liquid injection. Other factors were found similar between the two binder delivery methods such as consumed mechanical energy, as well as fracture strength and compressibility of produced granules.

Twin screw granulation – review of current progress

Abstract Twin screw granulation (TSG) is a new process of interest to the pharmaceutical community that can continuously wet granulate powders, doing so at lower liquid concentrations and with better product consistency than found by a high shear batch mixer. A considerable body of research has evolved over the short time since this process was introduced but generally with little comparison of results. A certain degree of confidence has been developed through these studies related to how process variables and many attributes of machinery configuration will affect granulation but some major challenges still lay ahead related to scalability, variations in the processing regimes related to degree of channel fill and the impact of wetting and granulation of complex powder formulations. This review examines the current literature for wet granulation processes studied in twin screw extrusion machinery, summarizing the influences of operational and system parameters affecting granule properties as well as strives to provide some practical observations to newly interested users of the technique.

Hot-Melt Granulation in a Twin Screw Extruder: Effects of Processing on Formulations with Caffeine and Ibuprofen

Hot-melt granulation (HMG) by twin screw extrusion is a novel technology for the continuous processing of pharmaceuticals but confidence must still be gained regarding whether the environment affects drug properties. In this preliminary study, granulation was studied for a model product containing lactose monohydrate and active ingredients of differing water solubility, namely ibuprofen versus caffeine. The formulations were granulated at 220 rpm and 100°C with polyethylene glycol binders of differing molecular weights and at concentrations between 6.5% and 20%. In terms of granule properties, the low melting point of ibuprofen had a dominant influence by producing larger, stronger granules, whereas the caffeine products were more comparable to a blank containing no active ingredient. Drug degradation was study by differential scanning calorimetry, X-ray diffraction, and high-pressure liquid chromatography. The only detected change was the dehydration of lactose monohydrate for the caffeine and blank products, whereas the lubricating influence of the ibuprofen protected its granules. The short residence time (∼60 s) was consider to be influential in minimizing damage of the drug despite the high temperature and shear attributed to HMG inside a twin screw extruder.

Examining drug hydrophobicity in continuous wet granulation within a twin screw extruder

The influence of active pharmaceutical ingredient (API) hydrophobicity on continuous wet granulation was studied in twin screw granulation utilizing foamed binder delivery. The APIs examined were caffeine, acetaminophen, ibuprofen and griseofulvin and the drug load was maintained constant at 15 wt%. In order to understand the impact of these APIs on the granulation process, API and binder distribution, particle size, porosity, and fracture strength were analyzed on samples collected along the screw length. It was found that the API and binder distributions were uniform along the screws regardless of the hydrophobicity of the formulation, in contrast to literature results with liquid injection. The absence of de-mixing of the hydrophobic ingredient was hypothesized to be a result of the high spread-to-soak ratio of a foamed binder that cages those particles within the mass of local hydrophilic solids.

Rolling phenomenon in twin screw granulation with controlled-release excipients.

Abstract The developed knowledge regarding use of twin screw granulators for continuous wet granulation has been primarily limited to immediate release formulations in the literature. The present study highlights an issue previously unreported for wet granulation with twin screw extruders when using formulations containing controlled-release (CR) excipients. Long (3–10u2009mm), twisted noodle-like granules can be produced in the presence of these excipients that are difficult to control and are anticipated to create complications in downstream unit operations to the granulator. Working with two different CR excipients, METHOCEL™ K4M and Kollidon® SR, each blended at different ratios with a mixture of 80% α-lactose monohydrate/20% microcrystalline cellulose, these unique particles were found to be produced in the conveying elements of the extruder, arising from a rolling action at the top of the screw flights. The CR excipients adhesively strengthen the wetted mass, forming this undesired granule shape such that they persisted to the exit of the machine; the shape appeared most strongly affected by screw speed, producing particles of higher aspect ratio as speed was increased. Adjusting the concentration of these CR excipients in the formulation, the flow rate or the type of compression element used in the screws proved ineffective in controlling the problem. Rather, a re-design of the extruder screws was required to prevent generation of these extended-form granules.

Optimization of Spray Drying Conditions for Yield, Particle Size and Biological Activity of Thermally Stable Viral Vectors

PurposeThis work examines the relevance of viral activity in the optimization of spray drying process parameters for the development of thermally stable vaccine powders. In some instances, the actual active pharmaceutical ingredient (API) is not included in the process optimization as it is deemed too costly to use until the final selection of operating conditions, however, that approach is inappropriate for highly labile biopharmaceutics. We investigate the effects of spray drying parameters on i) yield, ii) particle size and iii) viral vector activity of a mannitol/dextran encapsulated recombinant human type 5 adenoviral vector vaccine, to demonstrate the effects and magnitude of each effect on the three responses, and further show that the API must be included earlier in the optimization.MethodsA design of experiments approach was used with response surface methodology (RSM) to optimize parameters including inlet temperature, spray gas flow rate, liquid feed rate and solute concentration in the feed.ResultsIn general, good conditions for maintaining viral activity led to reduced yield and fewer particles of the desired size. Within the range of parameters tested, the yield varied from 50 to 90%, the percentage of ideally size particles was 10–50%, and the viral vector titre loss was 0.25–4.0 log loss.ConclusionsRSM indicates that the most significant spray drying parameters are the inlet temperature and spray gas flow rate. It was not possible to optimize all three output variables with one set of parameters, indicating that there will only be one dominant criteria for processing which in the case of viral vaccines will likely be viral vector activity.

Evaluation of excipients for enhanced thermal stabilization of a human type 5 adenoviral vector through spray drying.

We have produced a thermally stable recombinant human type 5 adenoviral vector (AdHu5) through spray drying with three excipient formulations (l-leucine, lactose/trehalose and mannitol/dextran). Spray drying leads to immobilization of the viral vector which is believed to prevent viral protein unfolding, aggregation and inactivation. The spray dried powders were characterized by scanning electron microscopy, differential scanning calorimetry, Karl Fischer titrations, and X-ray diffraction to identify the effects of temperature and atmospheric moisture on the immobilizing matrix. Thermal stability of the viral vector was confirmed in vitro by infection of A549 lung epithelial cells. Mannitol/dextran powders showed the greatest improvement in thermal stability with almost no viral activity loss after storage at 20°C for 90days (0.7±0.3 log TCID50) which is a significant improvement over the current -80°C storage protocol. Furthermore, viral activity was retained over short term exposure (72h) to temperatures as high as 55°C. Conversely, all powders exhibited activity loss when subjected to moisture due to amplified molecular motion of the matrix. Overall, a straightforward method ideal for the production of thermally stable vaccines has been demonstrated through spray drying AdHu5 with a blend of mannitol and dextran and storing the powder under low humidity conditions.

Influence of filler selection on twin screw foam granulation.

Abstract The influence of filler selection in wet granulation was studied for the novel case where the binder is delivered as an unstable, semi-rigid aqueous foam to an extrusion process. The work primarily examined the impact of differing concentrations of microcrystalline cellulose (Avicel PH® 101) in a formulation with spray-dried α-lactose monohydrate (Flowlac® 100) in regards to wetting and granule nucleation for this relatively new technique known as continuous foam granulation. Foam stability was varied within the work to change its drainage and coarsening behavior atop these powder excipients, by use of different foamable binding agents (METHOCEL™ F4 PLV and METHOCEL™ Premium VLV) as well as by adjusting the foam quality. A static bed penetration test was first used to study the foam behavior in wetting these powders without the processing constraints of an extruder which limit possible liquid-to-solids ratios as well as introduce shear which may complicate interpretation of the mechanism. The test found that the penetration time to saturate these powders decreased as their water absorption capacity increased which in turn decreased the size of the formed nuclei. Differences in the stability of the foamed binder had minimal influence on these attributes of wetting despite its high spread-to-soak behavior. The size of granules produced by extrusion similarly demonstrated sensitivity to the increasing water absorption capacity of the filler and little dependency on foam properties. The different liquid-to-solids ratios required to granulate these different formulations inside the extruder highlighted an evolving concept of powder lubricity for continuous foam granulation.