Primary Newcastle disease vaccination of broilers: comparison of the antibody seroresponse and adverse vaccinal reaction after eye-nose drop or coarse spray application, and implication of the results for a previously developed coarse dry powder vaccine.

To compare antibody seroresponse and adverse vaccinal reaction induced by Newcastle disease (ND) vaccination after eye-nose drop or coarse spray, groups of SPF broiler hens were vaccinated at day 4 (day of hatch is day 0) and intratracheally inoculated with Escherichia coli at day 11. Body weight gain (BWG) was assessed between day 4 and day 18; colibacillosis lesions and serum antibodies were determined at day 18. Meaningful comparison requires similar vaccine uptake. Vaccine virus loss during spray relative to eye-nose drop, which was assessed by comparing the results of endpoint titrations, was 3 log10. Colibacillosis lesions in birds spray vaccinated with 106.4 EID50/chicken were significantly more severe (P < 0.05), compared to those in birds eye-nose drop vaccinated with 103.4 EID50/chicken, while the seroresponse was slightly but significantly (P < 0.05) stronger. Colibacillosis lesion scores inversely paralleled BWG. It is concluded that: (1) There is room to improve the coarse ND vaccine spray used regarding adverse vaccinal reaction, while maintaining a sufficient immune response. This is also applicable to the coarse ND powder vaccine studied in previous research, which induced similar antibody response and adverse vaccinal reaction as the spray vaccine used here. (2) The vaccine virus dose influences the colibacillosis susceptibility at seven days post vaccination, as the dynamics of the vaccine virus infection is likely dose-dependent. (3) Low vaccine virus doses likely result in heterogeneous vaccine-take followed by vaccine virus spread from vaccine shedding birds to their non-vaccine virus infected flock mates ("rolling vaccinal reaction").

Comparison of Newcastle disease vaccine administered as powder or liquid in relation to the serum antibody response and adverse vaccinal reactions in broilers.

Liquid spray and aerosol mass vaccination of poultry have several drawbacks, such as uncontrolled deposition of vaccine particles in the respiratory tract and vaccine virus inactivation by formation and evaporation of droplets. These may be addressed by using dry powder vaccines with defined particle size distribution targeting the upper (primary vaccination) or the entire respiratory tract (booster vaccination). Therefore, a coarse Newcastle disease (LZ58 strain) powder vaccine was administered to specified pathogen free (SPF) broiler hens to compare the antibody response and adverse vaccinal reactions with those induced by a coarse liquid spray and a fine liquid aerosol. Groups of 40 broilers each housed in isolators were vaccinated at 4 days of age and intratracheally inoculated with Escherichia coli (strain 506) at 11 days of age. Adverse vaccinal reactions were evaluated by measuring body weight gain and mortality between 4 and 11 days of age and between 11 and 18 days of age, and by recording colibacillosis lesions at 18 days of age. The antibody serum response was measured at 18 days of age by the haemagglutination inhibition test. Despite the relative low initial vaccine virus loss and narrow particle size distribution of the powder vaccines in comparison with their liquid counter parts, no significant differences (P > 0.05) regarding adverse vaccinal reactions and antibody response were observed between broilers vaccinated with the powder vaccines or with their liquid counterparts.

Semi-crystalline materials for pharmaceutical fused filament fabrication: Dissolution and porosity.

A better understanding of crystallization kinetics and the effect on drug product quality characteristics is needed to exploit the use of semi-crystalline polymers in pharmaceutical fused filament fabrication. Filaments were prepared from polycaprolactone or polyethylene oxide loaded with a crystallization inhibitor or inducer, which was either 10% (w/w) ibuprofen or theophylline. A design-of-experiments approach was conducted to investigate the effect of nozzle temperature, bed temperature and print speed on the printed tablets' microstructure and dissolution kinetics. Helium pycnometry derived porosity proved an ideal technique to capture significant distortions in the tablets' microstructure. On the other hand, terahertz time domain spectroscopy (THz-TDS) analysis proved valuable to investigate additional enclosed pores of the tablets' microstructure. The surface roughness was analyzed using optical coherence tomography, showing the importance of extensional viscosity for printed drug products. Drug release occurred via erosion for tablets consisting of polyethylene oxide, which partly reduced the effect of the inner microstructure on the drug release kinetics. An initial burst release effect was noted for polycaprolactone tablets, after which drug release continued via diffusion. Both the pore and crystalline microstructure were deemed essential to steer drug release. In conclusion, this research provided guidelines for material and process choice when a specific microstructure has to be constructed from semi-crystalline materials. In addition, non-destructive tests for the characterization of printed products were evaluated.

Batch vs. continuous direct compression - a comparison of material processability and final tablet quality.

In this study, an in-depth comparison was made between batch and continuous direct compression using similar compression set-ups. The overall material processability and final tablet quality were compared and evaluated. Correlations between material properties, process parameters and final tablet properties were made via multivariate data analyses. In total, 10 low-dosed (1% w/w) and 10 high-dosed (40% w/w) formulations were processed, using a total of 10 different fillers/filler combinations. The trials indicated that the impact of filler type, drug load or process settings was similar for batch and continuous direct compression. The main differentiator between batch and continuous was the flow dynamics in the operating system, where properties related to flow, compressibility and permeability played a crucial role. The less consistent flow throughout a batch process resulted in a significantly higher variability within the tablet press (σCF) and for the tablet quality responses (σMass, σTS). However, the better controlled blending procedure prior to batch processing was reflected in a more consistent API concentration variability. Overall, the comparison showed the benefits of selecting appropriate excipients and process settings to achieve a specific outcome, keeping in mind some key differentiators between both processes.

Optimization of drug delivery systems for intraperitoneal therapy to extend the residence time of the chemotherapeutic agent.

Intraperitoneal (IP) chemotherapy is an effective way of treating peritoneal carcinomatosis of colorectal origin after complete cytoreduction. Although IP therapy has been already performed for many years, no standardized treatment design has been developed in terms of schedule, residence time, drug, or carrier solution. Because of the fast clearance of the conventional intravenous (IV) drug delivery systems used for IP therapy, a lot of research is performed to optimize IP drug delivery and extend the residence time of the cytotoxic agent in the peritoneal cavity. This paper reviews the recent advances made in drug delivery systems for IP chemotherapy, discussing the use of microparticles, nanoparticles, liposomes, micelles, implants, and injectable depots for IP delivery.

Exploiting common ion addition to accelerate zolpidem hemitartrate release from Eudragit EPO extrudates.

The current study aimed at optimizing a previously developed non-clinical formulation for use in zolpidem deprescribing. The formulation under investigation consists of extruded zolpidem hemitartrate (30% w/w) and Eudragit EPO (70% w/w) mixtures which display unsatisfactory dissolution behavior. Both milled extrudates and physical mixtures were compressed to produce tablets with identical target weight and solid fraction. First, the susceptibility of zolpidem hemitartrate towards heat and shear degradation was identified utilizing thermal and HPLC-DAD analysis. The drug salt proved prone to thermally induced disproportionation. Moreover, the impurity content increased after applying hot melt extrusion although ICH guidelines were still attained. Secondly, extrudates and physical mixtures were subjected to FTIR analysis. As a result, interaction and protonation of the dimethyl aminoethyl group from Eudragit EPO resulting from zolpidem disproportionation was elucidated. As such, the formulations' slow dissolution kinetics in comparison to formulations containing non-ionizable polymers (e.g. Kollidon 12PF and Kollidon VA64) is explained. Finally, addition of tartaric acid, a microenvironmental pH modulator and common ion, proved a successful method to increase dissolution kinetics. The amount of drug released after 15 min increased drastically from 10 to 40% upon the addition of 5% tartaric acid. Immediate release behavior (80% within 15 min) was however not yet attained.

Identification of continuous twin-screw melt granulation mechanisms for different screw configurations, process settings and formulation.

Twin-screw melt granulation (TSMG) is a promising continuous manufacturing technology for the processing of high drug load formulations and to formulate heat- and moisture-sensitive active pharmaceutical ingredients (APIs). This study evaluates the influence of process parameters for TSMG, mainly focusing on the effect of the screw configuration combined with screw speed, throughput and barrel temperature, to elucidate the melt granulation mechanisms. For the kneading zone, the stagger angle was varied between 30°, 60° and 90°, and investigated for both the forward and the reversed direction. In addition to the process parameters, the influence of the formulation differing in their API-binder miscibility was evaluated. As responses, the granule (size, friability and porosity) and process properties such as torque were evaluated, indicating that the screw configuration is the most influential factor. Nucleation, consolidation and breakage are the granulation mechanisms for the forward and the neutral configuration, while consolidation and densification with shear elongation are identified for the reversed configuration. The formulations differ mainly in the forward and neutral configuration since the immiscible formulation shows a bimodal granule size distribution with a larger fraction of fines and weaker granules is obtained. For the reversed configuration, similar granulation mechanisms are seen for both formulations.

Visualization of the granule temperature using thermal imaging to improve understanding of the granulation mechanism in continuous twin-screw melt granulation.

The aim of this study is to increase process understanding of the granulation mechanism in twin-screw melt granulation by evaluating the influence of different screw configurations on granule formation and granule temperature via thermal imaging. The study used a Design of Experiments (DoE) to process a miscible and immiscible formulation (85% API/binder w/w) using a twin-screw extruder with varying screw configurations. The barrel temperature (°C), screw speed (rpm), throughput (kg/h), and kneading zone (direction and stagger angle) were varied. Granule and process properties were evaluated for samples collected at four different locations along the length of the granulation barrel to visualize the granule formation, and granule temperature was monitored by an infrared camera to measure heat transfer on the granules. The resulting temperature was linked to the granule properties and the granule formation along the length of the barrel. The most influencing factors on the granule temperature are the direction of the kneading zone and the set barrel temperature. It was observed that granule formation mainly occurred in the zones that apply more kneading on the granules. The highest temperature increase was observed when the smallest stagger angle in reverse configuration was used, and could be linked to better granule quality attributes.

Elucidation of granulation mechanisms along the length of the barrel in continuous twin-screw melt granulation.

In the pharmaceutical industry, innovative continuous manufacturing technologies such as twin-screw melt granulation (TSMG) are gaining more and more interest to process challenging formulations. To enable the implementation of TSMG, more elucidation of the process is required and this study provides a better understanding of the granule formation along the length of the barrel. By sampling at four different zones, the influence of screw configuration, process parameters and formulation is investigated for the granule properties next to the residence time distribution. It showed that conveying elements initiate the granulation by providing a limited heat transfer into the powder bed. In the kneading zones, the consolidation stage takes place, shear elongation combined with breakage and layering is occurring for the reversed configurations and densification with breakage and layering for the forward and neutral configurations. Due to the material build-up in the reversed configurations, these granules are larger, stronger, more elongated and less porous due to the higher degree of shear and densification. This configuration also shows a significantly longer residence time compared to the forward configuration. Hence, the higher level of shear and the longer period of time enables more melting of the binder resulting in successful granulation.

Drying behaviour and visualization of surfactants after co-spray drying of surfactant-stabilized aqueous suspensions.

Surfactants are widely used in many industries as dispersants or flocculants for suspensions. As the addition of low concentrations of surfactant is sufficient to execute their effect, they barely alter the formulation composition. In this research it was examined whether surfactants, in particular polysorbate 80 (PS80), were suitable as suspension stabilizers for co-spray drying of drug-filler combinations. Therefore, their drying behaviour at different process and formulation settings was studied and mapped by means of fluorescently labelled PS80. Co-spray drying of 10% w/w aqueous suspensions stabilized with 0.1% w/w PS80 resulted in excessive loss of sticky powder in the conical lower part of the drying chamber and the powder conveyor ducts. Up to 16% of powder was lost in the first transporter (i.e. the first part of the conveyor ducts). The amount of powder deposited in the first transporter, and by extension the stickiness of the recovered powder, was correlated with the presence of PS80 on the surface of the spray dried particles. Redistribution of free surfactant molecules during droplet drying depended on the process and formulation parameters. Enrichment of PS80 at the particle surface was most pronounced after co-spray drying of liquid feedstocks with low suspended fraction at process conditions favouring rapid droplet drying.

Preparation and evaluation of sustained-release matrix tablets based on metoprolol and an acrylic carrier using injection moulding.

Sustained-release matrix tablets based on Eudragit RL and RS were manufactured by injection moulding. The influence of process temperature; matrix composition; drug load, plasticizer level; and salt form of metoprolol: tartrate (MPT), fumarate (MPF) and succinate (MPS) on ease of processing and drug release were evaluated. Formulations composed of 70/30% Eudragit RL/MPT showed the fastest drug release, substituting part of Eudragit RL by RS resulted in slower drug release, all following first-order release kinetics. Drug load only affected drug release of matrices composed of Eudragit RS: a higher MPT concentration yielded faster release rates. Adding triethyl citrate enhanced the processability, but was detrimental to long-term stability. The process temperature and plasticizer level had no effect on drug release, whereas metoprolol salt form significantly influenced release properties. The moulded tablets had a low porosity and a smooth surface morphology. A plasticizing effect of MPT, MPS and MPF on Eudragit RS and Eudragit RL was observed via DSC and DMA. Solubility parameter assessment, thermal analysis and X-ray diffraction demonstrated the formation of a solid solution immediately after production, in which H-bonds were formed between metoprolol and Eudragit as evidenced by near-infrared spectroscopy. However, high drug loadings of MPS and MPF showed a tendency to recrystallise during storage. The in vivo performance of injection-moulded tablets was strongly dependent upon drug loading.

Impact of blend properties and process variables on the blending performance.

In this study, quantitative relationships were established between blend properties, process settings and blending responses via multivariate data-analysis. Four divergent binary blends were composed in three different ratios and processed at various throughputs and impeller speeds. Additionally, different impeller configurations were tested to see their impact on the overall blending performance. During each run, feeder mass flows were compared with the API concentration (BU) in order to investigate the dampening potential of the blender. The blender hold-up mass (HM), mean residence time (MRT), strain on the powder (#BP) and BU variability (RSDBU) were determined as blending descriptors and analyzed via PLS-regression. This elucidated the correlation between process settings (i.e. throughput and impeller speed) and blending responses, as well as the impact of blend properties on MRT and RSDBU. Furthermore, the study revealed that HM does not need to be in steady state conditions to assure a stable BU, while it became clear that long/large feeder deviations can only be dampened by the blender when using dedicated impeller configurations. Overall, this study demonstrated the generic application of the blender, while the developed PLS models could be used to predict the blender performance based on the blend properties.

The effect of binder types on the breakage and drying behavior of granules in a semi-continuous fluid bed dryer after twin screw wet granulation.

Current study investigated the effect of different binder types on the granule drying process and the granule breakage behavior in a semi-continuous fluid bed dryer integrated in the C25 ConsiGma-system. The studied binders (i.e. hydroxypropyl pea starch, hydroxypropyl methylcellulose E15, polyvinylpyrrolidone K12, and starch octenyl succinate CO 01) required different liquid amounts to produce similar granule quality. These different liquid requirements were translated into different drying conditions for each binder to result in sufficiently dry granules at the end of a drying cycle. By comparing the size distribution of the granules before entering and after exiting the fluid bed dryer, granule breakage could be evaluated. No effect of the binder type on the granule breakage during drying was observed. However, differences in granule breakage were observed for the binders when processed with the horizontal set-up of the C25 system, as granule breakage during pneumatic transport depended on the binder type. Only one binder (hydroxypropyl pea starch) allowed to avoid granule breakage during the entire process. Furthermore, this research showed that the drying process was mainly steered by the liquid requirements for granulation, and that these liquid requirements depended on the binder used.

Continuous direct compression: Development of an empirical predictive model and challenges regarding PAT implementation.

In this study, an empirical predictive model was developed based on the quantitative relationships between blend properties, critical quality attributes (CQA) and critical process parameters (CPP) related to blending and tableting. The blend uniformity and API concentration in the tablets were used to elucidate challenges related to the processability as well as the implementation of PAT tools. Thirty divergent ternary blends were evaluated on a continuous direct compression line (ConsiGma™ CDC-50). The trials showed a significant impact of the impeller configuration and impeller speed on the blending performance, whereas a limited impact of blend properties was observed. In contrast, blend properties played a significant role during compression, where changes in blend composition significantly altered the tablet quality. The observed correlations allowed to develop an empirical predictive model for the selection of process configurations based on the blend properties, reducing the number of trial runs needed to optimize a process and thus reducing development time and costs of new drug products. Furthermore, the trials elucidated several challenges related to blend properties that had a significant impact on PAT implementation and performance of the CDC-platform, highlighting the importance of further process development and optimization in order to solve the remaining challenges.

In-depth analysis of the long-term processability of materials during continuous feeding.

This study determined the feasibility of long-term continuous powder feeding and its effect on the overall process performance. Additionally, quantitative relationships were established between material properties, process settings and screw feeding responses during gravimetric feeding. Twelve divergent raw materials were processed over longer periods using a GEA Compact Feeder integrated in a continuous direct compression line (ConsiGma™ CDC-50). The resulting gravimetric feeding responses were combined with the material properties and process settings into an overall PLS model. The model elucidated the impact of the material descriptors for density; powder flow; particle size; compressibility; permeability and wall friction angle on the feeding process. Furthermore, long-term processing of the materials exhibited challenges related to the processability and refill consistency where a significant impact of the compressibility and cohesive/adhesive properties of the materials was observed. Overall, this approach provided insights into the feasibility of long-term continuous feeding which is not possible through 'short-term' feeding trials. Additionally, throughout this study, the need for material-specific adjustments of the feeding and refill equipment was highlighted.

Development and evaluation of injection-molded sustained-release tablets containing ethylcellulose and polyethylene oxide.

PURPOSE: It was the aim of the present study to develop sustained-release matrix tablets by means of injection molding of ethylcellulose (EC) and polyethylene oxide (PEO) mixtures and to evaluate the influence of process temperature, matrix composition, and viscosity grade of EC and PEO on processability and drug release. METHODS: Formulations consisting of metoprolol tartrate (MPT, concentration: 30%), EC plasticized by dibutyl sebacate, and PEO were extruded and consequently injection molded into tablets. The influence of process temperature (120°C and 140°C), matrix composition, viscosity grade of EC (4, 10, 20, 45, and 100 mPa·s) and PEO (7 × 10(6), 1 × 10(6), and 1 × 10(5) Mw) on processability and drug release was determined. RESULTS: Formulations consisting of 70% EC and 30% MPT showed incomplete drug release, whereas drug release was too fast for formulations without EC. Higher PEO concentrations increased drug release. Formulations containing 30% metoprolol, EC, and different concentrations of PEO showed first-order release rates with limited burst release. Drug release from direct compressed tablets showed faster drug release rates compared to injection-molded formulations. There was no clear relationship between the molecular weight of EC and drug release. The melting endotherm (113.9°C) of MPT observed in the differential scanning calorimeter thermogram of the tablets indicated that a solid dispersion was formed which was confirmed by X-ray diffractogram. X-ray tomography demonstrated a difference in pore structure between tablets processed at 120°C and 140°C. CONCLUSION: It was concluded that injection molding can be applied successfully to develop sustained-release PEO/EC matrix tablets.

Feasibility of the Ussing chamber technique for the determination of in vitro jejunal permeability of passively absorbed compounds in different animal species.

The aim of this study was to assess the feasibility of the Ussing chamber technique for the determination of the jejunal permeability of passively absorbed, high permeability model compounds (acetaminophen and ketoprofen) in different animal species. Additionally, electrophysiological measurements and histological examination of pre- and post-incubation tissue specimens were performed. Apparent permeability coefficients of turkey and dog jejunum were low and highly variable due to tissue fragility caused by differences in thickness of the remaining intestinal layers after stripping and resulting in severe damage. Pig and horse jejunum were markedly more suitable for permeability determinations and mild signs of deterioration were noticed after 120 min of incubation. Transepithelial electrical resistance and potential difference did not correlate well with the observed tissue damage. From these data, the Ussing chamber technique appears to allow for permeability measurements within a species, but seems unsuitable for interspecies permeability comparison. However, further validation of the method with low permeability compounds and actively transported compounds is needed.

Evaluation of torque as an in-process control for granule size during twin-screw wet granulation.

The potential of torque as in-process control (IPC) to monitor granule size in twin-screw wet granulation (TSG) was investigated. An experimental set-up allowing the collection of granules at four different locations (i.e., in the wetting zone, after the first and second kneading zone and at the end of the granulator) of the granulator screws was used to determine the change in granule size, granule temperature and the contribution of each compartment to the overall torque for varying screw speed, mass feed rate and liquid-to-solid ratio. The only observed correlation was between the granule size and torque increase after the first kneading zone because the torque increase was an indication of the degree in granule growth which was consistently observed with all applied granulation process parameters. No correlation was observed in the other locations as changes of torque were accompanied to either granule breakage and/or growth. Moreover, torque increase was correlated to higher granule temperature, suggesting that energy put into the granulator was partly used to heat up the material being processed and explains additionally the lack of correlation between granule size and torque. Therefore, this study showed that torque could not be used as IPC to monitor granule size during TSG.

Extrusion-based 3D printing of oral solid dosage forms: Material requirements and equipment dependencies.

Extrusion-based 3D printing is steadily gaining importance as a manufacturing technique due to its flexibility and wide range of possible end-products. In the medical field, the technique is being exploited for a variety of applications and one of these is the production of personalised medicines. However, despite many proof-of-concept studies, more thorough insights in the production technique itself and the required material properties are needed before 3D printing can be fully exploited in a hospital or pharmacy setting. This research aims at clarifying the complex interplay between material properties, process parameters and printer-dependent variables. A variety of different polymers and polymer-drug blends were extruded (diameter 1.75±0.05 mm) and characterised in terms of mechanical, thermal and rheological properties. These properties, together with the processing temperature, printing speeds and different nozzle diameters of the 3D printer were linked to the quality of the end-product. Different failure mechanisms (mechanical, thermal) were assessed. Decisive material parameters (e.g. cross-over point) for optimal printing behaviour and the importance of printer construction (nozzle diameter) were clarified. In general, this study offers insight into the 3D printing process and will help to speed up future pharmaceutical formulation development for printlets.

TPLS as predictive platform for twin-screw wet granulation process and formulation development.

In recent years, the interest in continuous manufacturing techniques, such as twin-screw wet granulation, has increased. However, the understanding of the influence of the combination of raw material properties and process settings upon the granule quality attributes is still limited. In this study, a T-shaped partial least squares (TPLS) model was developed to link raw material properties, the ratios in which these raw materials were combined and the applied process parameters for the twin-screw wet granulation process with the granule quality attributes. In addition, the predictive ability of the TPLS model was used to find a suitable combination of formulation composition and twin-screw granulation process settings for a new API leading to desired granule quality attributes. Overall, this study helped to better understand the link between raw material properties, formulation composition and process settings on granule quality attributes. Moreover, as TPLS can provide a reasonable starting point for formulation and process development for new APIs, it can reduce the experimental development efforts and consequently the consumption of expensive (and often limited available) new API.