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Comprehensive comparisons of similar lipid based drug delivery systems produced by different technologies are scarce. Spray drying and fluid bed layering technologies were compared with respect to the process and product characteristics of otherwise similar simvastatin loaded dry emulsion systems. Fluid bed layering provided higher process yield (83.3 % vs 71.5 %), encapsulation efficiency (80.0 % vs 68.4 %), relative one month product stability (93.8 % vs 85.5 %), larger and more circular particles (336 µm vs 56 µm) and lower median oil droplet size after product reconstitution in water (2.85 µm vs 4.27 µm), compared to spray drying. However, spray dried products exhibited higher drug content (22.2 mg/g vs 9.34 mg/g). An in-vivo pharmacokinetic study in rats was performed and a pharmacokinetic model was developed in order to compare the optimised simvastatin loaded dry emulsion systems, a simvastatin glyceride mimetic loaded in the dry emulsion and a simvastatin loaded SMEDDS with a reference physical mixture. Of the formulation tested, fluid bed layered pellets excelled and provided a 115 % relative increase in bioavailability. Among the two technologies, fluid bed layering provided dry emulsion products with higher relative bioavailability and better product characteristics for further processing into final dosage forms. Abstract. Bibliografija: str. 238-239. ARRS

Background: A spray pattern (SP) test is one of the most challenging in vitro tests for nasal spray products (NSPs) associated with a high degree of variation. The total results variation observed in such studies should be in major part representative of product performance to assure high confidence when making conclusions based on obtained results. Analytical methods should be developed in a way to minimize variation contribution of random factors. A systematic statistical assessment of sources of variation is encouraged to be performed during any method development. Methods: This study includes the development of a product-shaking procedure, definition of in vivo relevant actuation parameters, and the development of a robust SP method considering NSP behavior. The final SP method is tested on different days and in different laboratories to evaluate the contribution of individual factors and interactions to the observed variance in SP using a gauge repeatability and reproducibility (GRR) model. Results: It was found that the time lag between consecutive actuations significantly influences the variability of the SP area, suggesting the importance of determining a recovery period. Factor analyst was not found to be important. Factor day was found to have the potential to impact results, mostly through interactions with other factors, suggesting that one should pay attention when performing any comparative studies within the same laboratory on different days. Significant differences were observed when the same product was tested in different laboratories. Conclusion: Key random factors, which significantly contribute to total variation, were identified using a GRR approach. By applying an appropriate control strategy over these factors, one can assure that assessed total variation can be representative of product performance. The same general approach is not only applicable to development of SP method for NSP but to all types of analytical testing as well.

In the presented study, insight into the development and optimisation of the dry emulsion formulation and spray drying process is provided. The aim was to facilitate the dissolution of the poorly soluble, highly lipophilic drug, simvastatin, by forming spray-dried dry emulsion particles having adequate powder flow properties, while assuring sufficient drug content. Simvastatin and a mixture of caprylic, capric triglyceride and 1-oleoyl-rac-glycerolwere employed as a model drug and solubilising oils, respectively. A matrix of the dry emulsions was composed at a fixed ratio mixture of mannitol and HPMC. Tween 20 was used in low amounts as the primary emulsion stabiliser. To facilitate process optimisation, a DoE surface response design was used to study the influence of formulation and process parameters on the particle size distribution, powder bulk properties, emulsion reconstitution ability, drug stability and process yield of spray-dried products. Two-fluid nozzle geometry was identified, studied and confirmed to be important for most product critical quality attributes. Models obtained after the study showed acceptable coefficients of determination and provided good insight in the relationship governing the process and product characteristics. Five model optimised products showed adequate process yield, suitable particle size distribution, good reconstitution ability and improved dissolution profile, when compared to a non-lipid-based tablet and the pure drug. However, the obtained dry emulsion powders exhibited poor flow character according to the Carr index. The optimised product was further analysed with NMR during lipolysis to gain insight into the species formed during digestion and the kinetics of their formation. Refereed/Peer-reviewed

Mini-tablets with diameters of 2.0, 2.5, and 3.0 mm are coated in two different lab-scale fluidized bed coaters equipped with a Wurster draft tube. The main focus of the research is to evaluate the inter-particle coating variability, and to assess the contribution of cycle time variation. Cycle times are measured using a photoluminescent tracer with a detector mounted on the top of the draft tube. The number of passes variability is represented from 5 to 28% of the total coating variability. Additionally, transmittance measurements at the top of the Wurster draft tube are performed in order to assess the inter-particle sheltering effects. Transmittance results are correlated to the amount of coating deposited per single pass of the spray zone and are converted to solids volume fractions. The dynamics of the transmittance signal further reveal the persistence of a particle arrangement within the draft tube of the two different coaters. The gathered results give insight into the different performance of two fluidized bed coaters in terms of inter-particle coating variability.

Objective The main objective of the study was to evaluate the influence of a novel modification of the Wurster draft tube on the particle coating performance. Modification embodies enabling of the additional radial flow of pressurized air through the perforations in the draft tube inner wall. Materials and methods After coating the neutral pellets with polymeric solution, comprising colouring agent, pellet batches were characterized for coating variation, yield and degree of agglomeration. By employing the piezoelectric probe flow regime zones and particle number density profiles inside the draft tube were evaluated, utilizing the power spectral density and particle impact frequency analysis of captured signals, respectively. Results The results clearly indicate that the additional radial airflow improves the coating uniformity, expressed by the relative standard deviation (RSD) value of the dye amount dispersed in the coating layer of each set of pellets. Lower RSD values were noticed in the case of pellets coated using a classic Wurster (CW) chamber equipped with a perforated draft tube (CW-P) compared to the reference experiments conducted with a conventional draft tube; regardless of the air flow rate (105, 130 or 156 m3/h) and the gap size (10 or 20 mm). As demonstrated in our previous studies, swirling inlet airflow (SW) contribute to much more uniform per particle deposition of the coating material when compared to CW process. By utilizing the SW chamber equipped with a modified draft tube (SW-P), the significant improvement in the coating uniformity was achieved at the gap size of 20 mm, regardless of the air flow rate. In the case of additional air flow through the draft tube perforations, additional number of inner tube zones, possessing predominant particle fluctuation frequencies in the range from 1 to 5 Hz, were noted. By utilizing the modified draft tube the lower number of the particle impacts in comparison to coater equipped with the conventional Wurster draft tube were recorded, regardless the coater type.

Particle cycle time variation in a fluid bed coater is an important parameter that affects inter-particle coating uniformity. For the purpose of analyzing the pellet circulation process, a tracer particle photoluminescence detection system was developed and used in a laboratory scale fluid bed Wurster chamber. In order to tackle the problem of optically dense flow within the Wurster tube, transitions of a photoluminescent pellet were recorded in the down-flow region. Tracer pellets were representative for evaluated populations of pellets in terms of size and density. Pellet cycle time distributions were assessed for processes with varying particle size, gap, fluidizing air flow rate and loading mass. A higher air flow rate and gap decreased the distribution mode whereas a decrease in gap and an increase in the air flow rate and loading mass decreased the magnitude of pellet cycle time variation. Additionally, the variation in the position of tracer pellet successive passes was assessed and the change in transition azimuth was connected to stability of gas–solids flow. We also estimated that for the homogeneous spray case the average circulation process variability contribution to the total coating mass variability is relatively small.

To ensure robust manufacturing of unit-based oral solid dosage forms with minimal structural imperfections and high mechanical reliability across subsequent processing unit operations (e.g., withstanding mechanical stresses during coating, optional axial compression, handling, packaging, storage, and transport conditions), process design should include consideration of precise limits of accurate micro, macro, and bulk properties of the constituent pellets. This communication presents a comprehensive intricate database of micromechanical properties' and breakage probability distribution functions of pellets, illustrating the stiffening and strengthening effects of coatings and the softening and weakening effects of structural moisture. Further insights such as the (contact) history-dependent softening during decompression, strain hardening on repeated stressing, strength recovery by drying, and the fragmentation pattern by cracking are also presented. The contents herein are based on conveniently performable lab-scale diametrical compression measurements on model microcrystalline cellulose pellets—demonstrating feasibility of the approach and validity of the contribution.

A fast method for pellet coating uniformity analysis, using a commercial computer scanner was developed. The analysis of the individual particle coating thicknesses was based on using a transparent orange colored coating layer deposited on white pellet cores. Besides the analysis of the coating thickness the information of pellet size and shape was obtained as well. Particle size dependent coating thickness and particle size independent coating variability was calculated by combining the information of coating thickness and pellet size. Decoupling coating thickness variation sources is unique to presented method. For each coating experiment around 10000 pellets were analyzed, giving results with a high statistical confidence. Proposed method was employed for the performance evaluation of classical Wurster and swirl enhanced Wurster coater operated at different gap settings and air flow rates.

The objective of this work was to assess the effect of process parameters of a dosator nozzle machine on the powder bed uniformity of inhalation powders with various characteristics during a low-dose dosator capsule filling process. Three grades of lactose excipients were extensively characterized and filled into size 3 capsules using different dosing chamber lengths (2.5, 5mm), nozzle diameters (1.9, 3.4mm), powder bed heights (5, 10mm) and filling speeds (500, 3000capsules/h). The fill weight and the weight variability of Lactohale 100 (large particles, good flowability, low cohesion) remained almost the same, regardless of the process parameters throughout the capsule filling run time. Moreover, for this powder an increase in the fill weight at a higher filling speed was observed in all cases. Fill weight variability was significantly higher for lower dosing chamber volumes at a filling speed of 3000 capsules per hour. Lactohale 220 (small particles, poor flowability, high cohesion) delivered entirely different results. After a certain run time, depending on instrumental settings, a 'steady-state' with constant fill weights and low weight variability was achieved. For this highly cohesive powder, a high dosing chamber volume requires a low filling speed in order for the powder to completely fill the dosator nozzle. Moreover, it was established that a dosing chamber length of 2.5mm and a powder bed height of 10mm were required due to the powder's high fill weight variability over time, while the dosator size had no effect on it. In summary, the layer uniformity, the fill weight and the weight variability strongly depend on the powder characteristics and the instrumental settings. The results indicate that Lactohale 220 requires special attention during low-dose capsule filling. The study presents excellent insights into the effect of material attributes and process parameters on the layer uniformity and the quality of end product.

The tablet pan coating process involves various types of transverse tablet bed motions, ranging from rolling to cascading. To preserve satisfactory results in terms of coating quality after scale-up, understanding the dynamics of pan coating process should be achieved. The aim of this study was to establish a methodology of estimating translational surface velocities of the tablets in a pan coater and to assess their dependence on the drum’s filling degree, the pan speed, the presence of baffles and the selected tablet properties in a dry bed system and during coating while varying the drum’s filling degree and the pan speed. Experiments were conducted on the laboratory scale and on the pilot scale in side-vented pan coaters. Surface movement of biconvex two-layer tablets was assessed before, during and after the process of active coating. In order to determine the tablets’ surface flow velocities, a high-speed video of the tablet surface flow was recorded via a borescope inserted into the coating drum and analysed via a cross-correlation algorithm. The obtained tablet velocity data were arranged in a linear fashion as a function of the coating drum’s radius and frequency. Velocity data obtained during coating were close to those of dry tablets after coating. The filling degree had little influence on the tablet velocity profile in a coating drum with baffles but clearly affected it in a coating drum without baffles. In most but not all cases, tablets with a lower static angle of repose had tablet velocity profiles with lower slopes than tablets with higher inter-tablet friction. This particular tablet velocity response can be explained by case specific values of tablet bed’s dynamic angle of repose.

Particle concentration in a coating zone of fluid bed coater is important to ensure appropriate coating uniformity and process yield. A transmissive optical setup at the top of the Wurster draft tube was used in a lab scale coater. Measured transmittances were converted to particle chord average volume fraction distributions using results of Monte Carlo calculations. The ranges of measured transmittances were from 0.002 to 0.285 and the range of particle chord average volume fraction was from 1.36% to 5.44%. The effect of gap between the draft tube and distribution plate, fluidizing air flow rate, particle size and load was studied. Comparisons of particle chord average volume fraction results with results of global particle volumetric fraction in the draft tube and particle cordal fraction obtained from CFD simulations are shown. In order to study the dynamics of the system as a function of different process parameters frequency analysis of transmittance signals was performed. Four distinct frequency responses were identified. Findings indicate presented local light attenuation method as suitable for assessing particle chord average volume fraction at the top of Wurster draft tube and with a potential for in-line method development.

In this work the preparation of drug loaded polymeric nanoparticles using electrospraying method and their subsequent characterization is presented. Our purpose was to incorporate the drug with extremely low solubility and low oxidative stability into polyvinylpyrolidone nanoparticles in order to improve its solubility and preserve its chemical stability and hence evaluate the ability of the technology to stabilize such systems in nanoparticulate form. Through the initial screening and optimization of process parameters and polymer solution properties, we detected different morphologies of electrosprayed product particles, where the use of lower molecular weight polymer resulted in a higher process instability as well as in a broader particle size distribution. On the other hand, the solution containing polyvinylpyrolidone with higher molecular weight showed sensitivity to different flow rates and electric field changes, which again resulted in differing the particle size and morphology. The electrosprayed products, prepared by sufficient process stability and having adequately narrow size distribution span, showed lower initial simvastatin contents than theoretically expected, which indicated an oxidative drug degradation already during the electrospraying process. The addition of antioxidants improved simvastatin chemical stability in the particles, during the process itself as well as after accelerated stability study. With an addition of butylated hydroxyanisole antioxidant mixture into initial polymer solution more than 95% of the drug content was preserved after one month at accelerated conditions, whereas in formulations without antioxidants simvastatin content was less than 6%. Antioxidants addition however did not influence only simvastatin stability but also simvastatin solubility. Surprisingly, antioxidants addition did decrease drug solubility in buffers (pH=4 and pH=6.8) for more than a half without any solid state changes of simvastatin. Potential hydrophobic interaction between simvastatin and antioxidants are hindering the drug solubility in the respective buffer, despite drug being in amorphous state.

The aim of this work is to evaluate average bioequivalence (ABE) and population bioequivalence (PBE) statistical approaches so as to identify which approach is most suitable for in vitro bioequivalence (IVBE) testing of nasal spray products. For droplet size distribution (DSD) and spray pattern (SP), in vitro data were collected using a well-established nasal spray on the market (Nasonex®, manufactured by Merck Sharp & Dohme Limited). Simulations were performed using in vitro data to comparatively investigate ABE and PBE tests. For highly variable parameters such as SP area, this study clearly demonstrates that the level of agreement between ABE and PBE test conclusions is much smaller as compared with that of DSD Dv(50), which was found to have moderate variability. PBE approach dictates equivalence for both means and variances, and was found to handle both SP and DSD parameters with similar passing rates compared to the passing rates from the ABE approach. However, pronounced asymmetric behavior of PBE empirical power curves for highly variable SP area was observed. A modified PBE statistical approach is proposed for DSD span and Dv(50) in vitro parameters, where acceptance criteria would be based on comparison of reference/branded product to itself as part of "pre-IVBE study" via innovative statistical bootstrap simulations. Due to inherent high variability of the SP area parameter driving pronounced asymmetric behavior of PBE power curves, and due to unclear in vivo relevance for SP area and ovality, authors propose that SP parameters be used as development and quality control tools rather than for demonstration of IVBE.

Film coating thickness of minitablets was estimated in-line during coating in a fluid-bed equipment by means of visual imaging. An existing, commercially available image acquisition system was used for image acquisition, while dedicated image analysis and data analysis methods were developed for this purpose. The methods were first tested against simulated minitablet’s images and after that examined on a laboratory-scale fluid-bed Wurster coating process. An observation window cleaning mechanism was developed for this purpose. Six batches of minitablets were coated in total, using two different dispersions, where for the second dispersion coating endpoint was determined based on the in-line measurement. Coating thickness estimates were calculated from the increasing size distributions of the minitablet’s major and minor lengths, assessed from the acquired images. Information on both the minitablet’s average band and average cap coating thicknesses was obtained. The in-line coating thickness estimates were compared to the coating thickness weight gain calculations and the optical microscope measurements as a reference method. Average band coating thickness estimate was found the most accurate in comparison to microscope measurements, with root mean square error of 1.30 μm. The window cleaning mechanism was crucial for the accuracy of the in-line measurements as was evident from the corresponding decrease of the root mean square error (9.52 μm, band coating thickness). The presented visual imaging approach exhibits accuracy of at least 2 μm and is not susceptible to coating formulation or color variations. It presents a promising alternative to other existing techniques for the in-line coating thickness estimation.

The purpose of the study was to develop a redispersible dry emulsion, containing a lipophilic, poorly water soluble model drug simvastatin, by employing fluid bed coating technology. The presented dry emulsion manufacturing approach produces pellets in a way, where a layer of the dry emulsion is applied to a neutral core. In the preliminary formulation development phase 1-oleoyl-rac-glycerol was chosen as the oily lipid phase, based on the high drug solubility and potential bioavailability enhancement capability. Mannitol, HPMC and Tween 20 were selected as the solid carriers and surfactant, respectively. The design of experiments, specifically the mixture design approach, was used to obtain the optimal formulation composition. The emulsion reconstitution ability and stability were the main responses, used as the decisive parameters for formulation optimisation. Optimised formulations showed narrow droplet size distribution upon reconstitution, high stability, suitable drug loading and enhanced dissolution profile, compared to a non-lipid based tablet and the pure drug. The scanning electron microscopy, Raman spectroscopy and image analysis disclosed a uniform morphology of the applied layer with separated droplets with simvastatin and uniform size distribution and a circular shape of coated pellets. The study represents the proof of concept of designing redispersible dry emulsions using a fluid bed layering approach.

Hot melt extrusion and prilling are gaining importance as solvent free and continuous techniques in the production of solid oral dosage forms with added value, by incorporating active compound in a molten carrier which is further solidified to form solid dispersion. This article reviews these two techniques in terms of understanding process basics, equipment characteristics, required properties of processed materials and application of the processes for development of solid oral dosage forms. Studies revealed that both hot-melt extrusion and prilling are regarded as simple, robust and continuous methods for processing different types of materials and production of solid dosage forms based on solid matrices. However, understanding of their concepts and requirements together with careful material selection is crucial for stable material processing and obtaining stable products of high-quality. Hot-melt extrusion proved to be a suitable method for production of modified release dosage forms, taste masked dosage forms and dosage forms offering improved drug dissolution rate and solubility. Prilling till now has been successfully applied just in the production of multiple unit drug delivery systems for immediate and sustained drug delivery. Further studies on product development and process understanding are required for full implementation of prilling in the pharmaceutical field.

During the past few years, the studies of bi- and multi-layered tablets increased due to the consumption of several different drugs per day by a patient and requests for appropriate patient compliance. The demographic shift toward older population increases the use of combination therapy as polypharmacy. Hydrochlorothiazide (HCTZ), as a model drug, is most commonly used in the treatment of hypertension, congestive heart failure and as a diuretic. The aim of the present study is to investigate the effect of the local environment on dissolution and stability behaviour of HCTZ in fixed multilayered tablet combinations, which are commonly used in polypharmacy. For this purposes, three different systems were introduced: (i) two conventional tablets (HCTZ and pH modifying placebo), (ii) 2-layer tablets (HCTZ, pH modifying placebo) and (iii) 3-layer tablets (HCTZ, barrier and pH modifying placebo). Disintegration of tablets, dissolution of HCTZ from tablets and HCTZ related substances were monitored for all systems. Results showed that there was a significant difference between dissolution profiles of the conventional two-tablet system (HCTZ tablet and pH modifying tablet) and the 2-layer and 3-layer tablets, which include the pH modifying layer. In the case of the conventional two-tablets system, 85 % of HCTZ was dissolved in less than 15 minutes. The dissolution profiles of HCTZ from 2-layered and 3-layered tablets showed a decrease in the dissolution rate. In addition, during the stability studies, it has been confirmed that the typical degradation product of HCTZ is formed, impurity B (4-amino-6-chloro-1,3-benzenedisulfonamide), which implies formation of formaldehyde as hydrolytic impurity not reported in the Ph. Eur. (16). Both impurities are particularly raised in 2-layered tablets with alkaline and neutral placebo layers. Stability of HCTZ was improved in the case of the 3-layer tablet, where the intermediate separation layer of glycerol monostearate was present. It is presumed that the HCTZ dissolution rate was decreased due to formation of non-soluble substances as a result of HCTZ degradation in the presence of alkaline layer.

Mini-tablets are gaining great attention as systems capable of being formulated into multiple unit systems providing a specific drug release pattern. Within the presented research a combined, multiple-unit system, based on different coated matrix mini-tablets, has been developed in order to achieve 24-h specific sigmoid extended release of the model drug paliperidone. The mini-tablets were based on different amounts of polyvinyl acetate/polyvinyl pyrolidone mixture as the matrix former, providing extended release, and two different types of pH-dependent, acrylic polymer coatings, providing delay in release onset, and thus achieving the required specific sigmoid release pattern imposed by the original drug on the market. The selected formulation proved to be consistent with pharmacopoeial requirements. It was also in vitro similar (f2) to the original drug and the theoretical linear release profile, as well as robust and reproducible regarding in vitro release in different fasted gastro-intestinal conditions. This is proof of concept that 24-h, specific, and almost linear release profile of drugs with high solubility can be achieved by employing technology of coated matrix mini-tablets.

Vertical chute transport is a common and widespread means of transporting powders and powder blends in the pharmaceutical industry; conversely, it is also a ready source of segregation. All components of powder mixtures (i.e., active pharmaceutical ingredients, as well as excipients) are subjected to particle size-based segregation, and therefore all properties of the final product, which depend on the particle size of its constituents, may be affected (e.g., compressibility, dissolution rate, API content, and content uniformity). Segregation of single-component pharmaceutical powders with continuous size distributions (excipients or model API) based on particle size was experimentally investigated. Single-component pharmaceutical powders were subjected to fall in a laboratory-scale vertical chute with a closed bottom, and powder samples from various powder bed heights were collected and analysed for particle-size distributions. The results show particle size-based segregation in all materials tested, and the segregation extent and pattern are material-specific. Certain segregation effects were explained with the flow patterns of falling powder and powder bulk properties. An interesting finding is that less cohesive materials with better flowability exhibit increased segregation of smaller sized-D(0.1) particles, which has been attributed to the vertical chute system with a closed, airtight bottom. The size limit, below which particles concentrate at the top of the sediment, and above which particles concentrate at the bottom of the sediment, seems to be universal at 0.46 of D(0.9) value for tested materials.

Coating thickness is the most important attribute of coated pharmaceutical pellets as it directly affects release profiles and stability of the drug. Quality control of the coating process of pharmaceutical pellets is thus of utmost importance for assuring the desired end product characteristics. A visual imaging technique is presented and examined as a process analytic technology (PAT) tool for noninvasive continuous in-line and real time monitoring of coating thickness of pharmaceutical pellets during the coating process. Images of pellets were acquired during the coating process through an observation window of a Wurster coating apparatus. Image analysis methods were developed for fast and accurate determination of pellets' coating thickness during a coating process. The accuracy of the results for pellet coating thickness growth obtained in real time was evaluated through comparison with an off-line reference method and a good agreement was found. Information about the inter-pellet coating uniformity was gained from further statistical analysis of the measured pellet size distributions. Accuracy and performance analysis of the proposed method showed that visual imaging is feasible as a PAT tool for in-line and real time monitoring of the coating process of pharmaceutical pellets.

Pellet coating is commonly performed in a fluid bed coater such as a Wurster coater. Computational fluid dynamics (CFD) simulations and experimental measurements of laboratory-scale Wurster coating were performed. CFD simulations were performed in a 2D axisymmetric space using the two-fluid model. The effect of the Wurster gap and fluidizing airflow rate on gas–solid flow was analyzed in both simulations and experiments. Experimentally, the draft tube two-phase flow was evaluated by measuring the volume fraction of pellets within the draft tube and local particle velocities at the tube exit and by monitoring the local pressure drop fluctuations. A rather good agreement between the simulated and experimental results was observed and thus it can be assumed that this particular simulation setup represents a computationally reasonable tool that provides a valuable insight into the Wurster coating process due to the impact of two-phase flow properties on the process.

The aim of this work was to study the granule growth kinetics during in situ fluid bed melt granulation process using real-time particle size measurement techniques. In addition, the usefulness of these techniques during scale-up of melt granulation was evaluated.Focused beam reflectance measurement (FBRM) and spatial filtering technique (SFT) probes were used within the process chamber of fluid bed granulator for real-time in-line granule size analysis.The results demonstrated that the use of in-line particle size probes in fluid bed granulator during the process offers an insightful view of granule growth and allows in-process monitoring of granule chord length changes. The effect of selected critical parameters (binder content, inlet air temperature and product endpoint temperature) on the granule growth was clearly presented by in-line measurements in a laboratory scale. A comparison of granule size measurements from both FBRM and SFT probes showed similar particle growth trends, which were in close correlation to the product temperature. Comparable trends in end granule particle size were observed when comparing different in-line, at-line and off-line particle size measurements.The in-line FBRM and SFT probes were successfully employed in in situ fluid bed melt granulation process to study the influence of critical formulation/process parameters on the granule growth kinetics. The scale-up experiment confirmed the potential of these in-line granule size measurement techniques as a viable tool for process monitoring during the transfer of granulation to the larger scale or another manufacturing site/equipment.

The aim of this work is to use an experimental design approach to identify and study influential formulation and delivery device properties, which can be controlled by final product manufacturer, to establish design space, within which desired in vitro performance can be reached.Combining three factors, viscosity of suspension, nozzle orifice diameter (OD), and shot weight (SW), at three levels resulted in D-optimal experimental design with 20 runs. Responses within this study were droplet size distribution (DSD) and spray pattern (SP) in vitro tests. In addition, the amount of mechanical work needed for actuation was integrated from force profiles and used as a response. Results were fit to quadratic model by regression, which allowed also for determination of second-order and interaction effects between factors. Models were further optimized by keeping significant terms only. Optimized models were used to create response surfaces and design space with confidence levels.Viscosity has a dominant effect on DSD and modest effect on SP, with lower viscosities related to generation of smaller DSD and larger SP. Orifice diameter was found to have the highest impact on SP, with larger diameter resulting in larger SP. This effect was additionally confirmed by results of Plume Geometry in vitro test. Shot weight factor exerts significant influence on all tested metrics. Work, however, did not vary greatly with suspension viscosity or orifice diameter. Shot weight is the most dominant factor for work and important for DSD having a positive effect on both responses. In the case of SP, its relationship with shot weight is described by second-order polynomial fit. Inspection of raw data revealed that density of droplets within SP area is different for different shot weights.Presented study elucidated an inherent relationship between factors and responses and established mathematical models (response surfaces) for predictive purposes to target specific in vitro performance of nasal sprays by appropriate specification of factors, taking into account control space with included risk and uncertainty analysis.

A series of various methods were applied to characterize samples of pharmaceutical pellets. Fourteen pellet types were tested to obtain the coefficient of restitution, coefficient of friction, stiffness, flowability, and distribution of size, shape, and density. An atomic force microscope was used to determine the pellet surface properties. The values obtained for the coefficient of restitution ranged from 0.568 to 0.843, and a sample-specific dependence of impact velocity was demonstrated. Mean pellet size was between 807.2 and 1271 μm, granular density ranged between 1.086 and 1.483 g/ml, and the coefficient of friction was around 0.21 for pellet–steel contact and around 0.16 for pellet–glass contact. AFM provided information about surface stiffness and roughness; furthermore, the values obtained correlated well with the results of other methods. The values of Young’s modulus of the pellets using the plate compression method or AFM surface testing were close to 1 GPa. The database of properties of commercially available sample pellets presented here represents a solid foundation for sound CFD and DEM simulations of pharmaceutical processes connected with the production of dosage forms comprising pellets.

The main objective of this study was to develop a piezoelectric probe for measuring the impact rate of particles to enable characterization of the shape of particle number density profiles and characteristic particle impact frequencies inside the draft tube of a Wurster coating chamber. Pellets from 800 μm to 900 μm were subjected to fluidization in a conventional and swirl Wurster coating chambers. Fast Fourier Transform (FFT) analysis of the raw signal obtained at four heights and three different radial distances from the draft tube centerline was performed for experiments in a conventional and a swirl Wurster coating chamber at different process parameters. Power spectra revealed three characteristic frequency bands for both chambers: 1–5 Hz, 5–7 Hz, and 12–14 Hz. Particle number density profiles demonstrated an evident difference between both chambers. In the conventional Wurster coater, the location of the maximum number of particle impacts was close to the tube center, whereas in the swirl Wurster coater the particle impacts were distributed rather uniformly. The difference in particle number density profiles for both process chambers can help to understand the difference in performance of both Wurster coater designs.

The objective of this work was to investigate the influence of selected individual variables (binder content, inlet air temperature, and product endpoint temperature) of in situ fluid bed melt granulation on the granule particle size distribution and percentage of dissolved carvedilol using a three-factor, five-level circumscribed central composite design. Increased binder content had the effect of increasing the granule particle size and drug dissolution rate. The effect of inlet air temperature and product endpoint temperature was found to be more pronounced in case of granule particle size parameters. Within the studied intervals, the optimal quantity of binder as well as optimal process parameters were identified and validated using response surface methodology. Utilizing these optimal process and formulation parameters, successful scaling up of the fluid bed melt granulation process was carried out. Granule characteristics obtained at pilot scale are comparable to those obtained at laboratory scale.

The study's primary goal was to examine the possible use of single particle mechanical properties to estimate the compressibility behaviour of a tablet's excipients during compaction. Nanoindentation was utilised to measure individual mechanical properties ( Young's modulus, nanoindentation hardness, energy of elastic and plastic deformation). On the bulk scale, studied excipients' compressibility was determined by Heckel and Walker models. Single particle hardness was found to provide direct information regarding an excipient's plasticity since an excellent correlation was established with the Walker model on the bulk level. A moderate correlation was obtained with the Heckel model due to its lack of fit for brittle materials. The indentation energy on a single level effectively differentiates materials in which plastic deformation dominates from those materials in which brittle fractures prevail. Elastic properties of materials can be successfully predicted by measuring the energy of elastic deformation on a single scale since an excellent correlation was observed with the bulk parameters such as energy of elastic deformation and the tablets' elastic relaxation index. We found that individual mechanical properties of a tablet's excipients greatly control the materials' deformation behaviour during tablet production despite of numerous other processes occurring during compression in the tablet die such as friction, bonding and local mechanical stress.

The aim of this study was to investigate the influence of binder content, binder particle size, granulation time and inlet air flow rate on granule size and size distribution, granule shape and flowability, as well as on drug release rate. Hydrophilic (polyethyleneglycol 2000) and hydrophobic meltable binder (glyceryl palmitostearate) were used for in situ fluidized hot melt granulation. Granule size was mainly influenced by binder particle size. Binder content was shown to be important for narrow size distribution and good flow properties. The results obtained indicate that conventional fluid bed granulator may be suitable for production of highly spherical agglomerates, particularly when immersion and layering is dominant agglomeration mechanism. Granule shape was affected by interplay of binder content, binder particle size and granulation time. Solid state analysis confirmed unaltered physical state of the granulate components and the absence of interactions between the active and excipients. Besides the nature and amount of binder, the mechanism of agglomerate formation seems to have an impact on drug dissolution rate. The results of the present study indicate that fluidized hot melt granulation is a promising powder agglomeration technique for spherical granules production.

Various types of lactose were used to study compactibility using Pr [11] . The dependence of Pr on the compression pressure, used to produce tablets, makes its comparison very difficult and so this phenomenon was studied in detail. It was demonstrated that Pr in its original form is the quotient of two linear functions and has a mathematical dependence on compression force. Therefore, a modification of this equation is proposed (termed Pr′) that increases its practical usefulness. The equation for pressure-independent Pr′ allows for comparison of various materials and/or studies in which different compression pressure values are used, even at low pressures where comparison of Pr itself is not feasible.

Drug-free microparticles were prepared using a spray congealing process with the intention of studying the influence of processing parameters. By varying the atomizing pressure and liquid feed rate, microparticles with median sizes ( d (0.5) ) from 58 to 278 μm were produced, with total process yields ranging from 81% to 96%. An increased liquid feed rate was found to increase microparticle size, and higher atomizing pressures were found to decrease microparticle size. Greater change in microparticle size was achieved by varying atomizing pressure, which can be considered a dominant process parameter regarding microparticle size. In addition, microparticles with glimepiride, a model poorly water-soluble drug, were prepared by spray congealing using three different hydrophilic meltable carriers: Gelucire ® 50/13, poloxamer 188, and PEG 6000. Spherical microparticles with relatively smooth surfaces were obtained, with no drug crystals evident on the surfaces of drug-loaded microparticles. XRPD showed no change in crystallinity of the drug due to the technological process of microparticle production. All glimepiride-loaded microparticles showed enhanced solubility compared to pure drug; however, Gelucire ® 50/13 as a carrier represents the most promising approach to the dissolution rate enhancement of glimepiride. The influence of storage (30 °C/65% RH for 30 days) on the morphology of glimepiride/Gelucire ® 50/13 microparticles was studied, and the formation of leaf-like structures was observed (a “blooming” effect).

The purpose of this study was to prepare alginate microcapsules with a self-microemulsifying system (SMES) containing celecoxib in the core. An Inotech IE-50 R encapsulator equipped with a concentric nozzle was used to prepare the microcapsules. The encapsulated SMES was shown to increase celecoxib solubility over that of the pure drug more than 400-fold. Microcapsules prepared with a high SMES:celecoxib ratio exhibited distinct core vesicles containing liquid SMES. By modifying the SMES and including an additional chitosan coating, drug loading in the range from 12-40% could be achieved with the degree of encapsulation ranging from 60-82%. Alginate microcapsules loaded with SMES and celecoxib showed increased dissolution rate of celecoxib over that of alginate microcapsules loaded with celecoxib or of the celecoxib alone. Compared to the previous report, drug loading capacity was significantly improved, enabling the formulation of dosage forms which are of suitable size for peroral application.

Paracetamol (PAR) crystals exhibit poor compressibility, poor flowability and its tablets show a tendency to cap. To improve the mechanical strength of tablets several kinds of “Paracetamol for direct compression” are present on the market. Current research demonstrated the best tablet properties with coated paracetamol (mass of tablets, diameter, height and mechanical strength, friability RSD

The effect of dry granulation (roller compaction and slugging) on compactibility and tablet capping tendency in a formulation with macrolide antibiotic and microcrystalline cellulose (MCC) was investigated. Direct tableting of this formulation revealed a pronounced capping tendency. Both dry granulated systems exhibit better compactibility and significant reductions in capping tendency compared to direct tableting. The capping tendency was also reduced through the use of precompression during direct tableting. The main volume reduction mechanism for macrolide antibiotic is fragmentation; this was confirmed by Heckel analysis, the lubricant sensitivity test, and SEM images. The yield pressure (Py) of the direct tableting system is lower than the Py of dry granulated systems, which indicates the lower plasticity of dry granulated systems. These findings do not explain the lower capping tendency of dry granulated systems compared to direct tableting. The main differentiating bonding mechanism is attributed to long distance intermolecular bonds due to the intense amorphization of macrolide antibiotic that occurs during dry granulation. Amorphization leads to a significant increase in surface free energy and consequently stronger long distance bonding between particles, which can withstand elastic relaxation and therefore reduce the capping problem. Solid bridges probably do not make a notable contribution to the mechanical strength of tablets, due to the brittle nature of the particles and the complex molecular structure of macrolide antibiotic.

Gravity transport of granular materials in vertical pipes is one of the most fundamental steps in bulk powder handling and processing. Presented study investigates powder flow characteristics in vertical pipes with open and closed outlets and condition of free powder fall. Powder flow of pharmaceutical grade powders was observed in transparent, vertical pipe model. Description of flow structures was performed. Powder volume flow rate, acceleration, and dilatation were quantified and correlated with powder properties. The results show that in pipes with a closed outlet the escaping air slows down the powder flow, resulting in a much slower flow than in pipes with an open outlet. A dense granular flow was detected in an open outlet condition, whereas in a closed outlet condition two concurrent flow regimes were observed: a slow moving, dense powder bed, and a fast dilute powder flow. Differences in flow regimes may promote segregation, with important implications to industrial processes. Gravitacijski transport granularnih snovi po vertikalnih cevnih povezavah je osnoven in hkrati ključen proces, ki se odvija pri procesiranju granularnih snovi. Proučevali smo tokovne strukture farmacevtskih praškov pri različnih pogojih izpusta vertikalne cevne povezave: zaprta cev, odprta cev in izpust brez cevi. Granularni tok smo opazovali na steklenem, prosojnem, laboratorijskem modelu vertikalne cevne povezave. Opisali smo tokovne strukture padajočih praškov, s slikovno analizo pa smo kvantificirali tokovne parametre (volumski pretok, pospeški, dilatacija) in jih korelirali z izmerjenimi lastnostmi praškov. Volumski pretok praškov v cevi z zaprtim dnom je za red velikosti manjši v primerjavi s pretokom v cevi z odprtim dnom. V cevi z zaprtim dnom se granularni tok pod vplivom izhajajočega zraka organizira v dva tokovna režima: počasen tok gostega nasutja praškov in hiter, redek tok praškov, dispergiranih v izhajajočem zraku. V cevi z odprtim dnom smo opazili hiter, gosti tok granularne snovi. Razlike med opisanimi tokovnimi režimi dveh pogojev izpusta so lahko osnova za segregacijo granularne snovi, kar lahko kritično vpliva na industrijske tehnološke procese.

The aim of this study was to develop, evaluate and compare extended release mini-matrices based on metoprolol tartrate (MPT) and either glyceryl behenate (GB) or glyceryl palmitostearate (GPS). Mini-matrices were produced by three different techniques: hot melt extrusion, compression of melt granulates and prilling. Hot-melt extrusion and compression of granules obtained from melted material proved to be reliable, robust and reproducible techniques with aim of obtaining extended release matrices. Prilling tended to be susceptible to increased melt viscosity. Direct compression was not applicable for mini-matrix production due to poor powder flow. In general MPT release from all matrices was affected by its loading and the size of the units/particles. Processing of GB-MPT mixtures by different techniques did not lead to different drug release rates and patterns, while in case of GPS differently obtained matrices provided diverse MPT release outcomes. Matrices based on GB tended to have higher porosity compared to ones composed of GPS and thus most of the GB-based formulations showed faster drug delivery. FT-IR analysis revealed no interactions between primary components used for matrix production and Raman mapping outlined uniform MPT distribution throughout the units. DSC and X-ray studies revealed significant changes in the crystallinity of glycerides after storage under room conditions (GPS samples) and at increased temperature (GB and GPS samples), which was correlated to the changes seen in drug release rate and pattern after storage. Media composition in general tended to insignificantly affect GB matrices, while in case of GPS matrices increasing the pH and presence of biorelevant compounds induced faster drug release.

Mini-tablets represent a new trend in solid dosage form design, with the main goal of overcoming some therapeutic obstacles such as impaired swallowing and polypharmacy therapy, and also offering some therapeutic benefits such as dose flexibility and combined release patterns. Mini-tablets are a promising patient-friendly drug delivery system.Mini-tablets are tablets with a diameter ≤ 3 mm produced on conventional tablet presses equipped with multiple tooling. Mini-tablet production is similar to the production of standard tablets but requires excellent powder flow due to the small dies, exact control of process parameters and special caution during tablet press assembly in order to avoid tool damage. Mini-tablets (coated or uncoated and single- or multiple-unit systems) are mainly developed as patient-friendly systems for pediatric and geriatric patients and also for personalized medicine because they offer improved swallowing and flexible dosing, combining various release kinetics, doses and active compounds in only one system. Mini-tablets may also be successfully used as multiple-unit modified release systems (extended release, delayed-colon release, pulsatile and bi-modal release and gastroretentive systems) providing improved drug bioavailability compared with single-unit systems.Mini-tablets used as single- or multiple-unit oral dosage forms have enormous potential as a patient-friendly drug delivery system for targeted populations, providing improved swallowing, flexible dosing and a combination of different release patterns and/or different active compounds (decreasing dosing frequency and/or polypharmacy therapy problems). In terms of complete expression of the benefits of mini-tablets over other oral dosage forms on the market, further investigation in formulation possibilities and development of suitable dosing devices is of essential importance.

The aim of the study was to evaluate a hot-melt technique for preparation of immediate release spherical microparticles containing clarithromycin with acceptable characteristics and process yield. A modified fluid bed apparatus with rotor insert was used to prepare spherical microparticles in the size range of 125-355 µm. Poloxamer 188, PEG-32 glyceryl laurate (Gelucire 44/14) and a mixture of polyethylene glycol (PEG) 4000 with PEG 400 were used as meltable binders. Key process parameters were identified and optimized and their influence on process yield and microparticles characteristics was determined. Microparticles with poloxamer 188 and PEG exhibited relatively good mechanical properties. Process yield was around 70% and 60% in the case of PEG and poloxamer 188 respectively. Microparticles prepared with PEG-32 glyceryl laurate exhibited poor mechanical properties and process yield compared to other microparticles. The process was shown to be limited by the bed temperature, exhibiting the best process stability with poloxamer 188 followed by PEG and PEG-32 glyceryl laurate. Dissolution rate and equilibrium concentration of clarithromycin released from prepared microparticles was improved compared to similar particles prepared by wet granulation.

The objective of this work was to investigate the influence of selected individual variables (binder content, inlet air temperature, and product endpoint temperature) of in situ fluid bed melt granulation on the granule particle size distribution and percentage of dissolved carvedilol using a three-factor, five-level circumscribed central composite design. Increased binder content had the effect of increasing the granule particle size and drug dissolution rate. The effect of inlet air temperature and product endpoint temperature was found to be more pronounced in case of granule particle size parameters. Within the studied intervals, the optimal quantity of binder as well as optimal process parameters were identified and validated using response surface methodology. Utilizing these optimal process and formulation parameters, successful scaling up of the fluid bed melt granulation process was carried out. Granule characteristics obtained at pilot scale are comparable to those obtained at laboratory scale.

Objective: The aim of this study was to investigate the influence of process parameters, binder content and binder addition method on characteristics of the granules obtained by melt granulation (MG) in fluidized bed. Methods: Spray-on experiments were performed according to 2 3 full factorial design. The effect of binder content, molten binder feed rate, and spray air pressure on granule size and size distribution, granule shape, Flowability and drug release rate was investigated. In the in situ experiments, the influence of binder particle size and binder content was evaluated. Solid-state characterization was performed by means of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. Results: Size of the granules obtained by spray-on procedure was significantly influenced by binder content and spray air pressure, while the width of particle size distribution was mainly affected by binder feed rate. Spray air pressure showed the most significant influence on granule shape. It was shown that smooth and spherical particles with good flow properties may be obtained by both procedures, spray-on and in situ MG. The results obtained indicated the influence of agglomeration mechanism on granule sphericity, with higher degree of granule sphericity observed when immersion and layering was the dominant mechanism. Paracetamol release from granulates was very rapid, but after compression of the granules into tablets, drug release was considerably slower. Solid-state analysis confirmed that the physical form of the granulate components remained unaffected after the MG process. Conclusion: The results presented indicate that MG in fluidized bed could be a good alternative to conventional granulation techniques.