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Manufacturing poorly water-soluble active pharmaceutical ingredients (API) with sufficient bioavailability is a significant challenge in pharmaceutical research. A higher bioavailability can reduce both the applied dosage and the side effects for the patient. One method of increasing the bioavailability is to reduce the particle size of the drug down to the nanoscale. An innovative procedure for the preparation of particles in the submicron size range is spray drying with aerosol conditioning, followed by subsequent separation of the particles in an electrostatic precipitator (ESP). This process has been tested before in an earlier work with aqueous model substances at high production rates (1 g/h) and narrow particle-size distributions (mannitol: d 50,0  = 455 nm, span = 0,8) in the submicron range. Spray drying from an aqueous solution with low drug concentrations (<1 wt-%) leads to particles in the lower nanosize range, but the low concentrations make this process inefficient. A custom-made plant was modified in order to handle the organic spray-drying process. In addition, explosion protection had to be considered. This work focuses on the spray drying of submicron particles from organic solvents for the purpose of increasing the dissolution rate of the API griseofulvin. API particles were successfully produced in the submicron size-range, characterized and the dissolution behavior was investigated. The dissolution time to dissolve 80% of the drug, t 80 , was reduced from 21.5 min for the micronized grade API to 8.5 min for the submicron product., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The low bioavailability of poorly water-soluble drugs is currently one of the major focuses of pharmaceutical research. One strategy currently being investigated to overcome this limitation is to decrease the particle size of the active pharmaceutical ingredients (API). An innovative process for this is spray drying with spray conditioning, which can produce submicron particles. One challenge resulting from this process is the recovery of these dispersed particles from a gas flow. Electrostatic precipitation is a common technique for air purification purposes, but an adapted electrostatic precipitator (ESP) design is necessary to achieve high collection efficiencies. The ESP design in this work uses the precipitation method of Penney filters which separates charging and collection into two stages. The ESP dimensions depend on various assumptions and simplifications. Several experiments were conducted to assess the performance of the ESP and characterize its behaviour in long-term tests. The crucial parameters in the charging process are the residence time as well as the operating voltage. These constraints were examined to enhance the collection efficiency. Based on these tests it was possible to determine a suitable charging length as well as the dimensions of the collection stage. In conclusion, an ESP customized for collecting particles in the range of 0.1-1 µm was designed, built and tested, and collection efficiencies higher than 99% were achieved for submicron particle size distributions. For a robust process continuous cleaning of the charging stage is necessary., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The preparation of submicron-sized particles is relevant in chemical, food and pharmaceutical applications. In pharmaceutics, spray dried submicron-sized particles (0.1-1 µm) can increase the dissolution rate as well as the solubility of poorly water-soluble drugs. Since the particle size during spray drying is mainly influenced by the droplet size, the preparation of uniform droplets smaller than 3 µm is of particular interest. In this work, a two-fluid nozzle was combined with a cyclone droplet separator. Droplets larger than the cut-off size were separated with a cyclone droplet separator and returned to the liquid feed. The aerosol at the outlet of the droplet separator was subsequently dried. The drop size of the conditioned aerosol was small, d 50,3 =2 µm, and independent of the liquid-to-gas mass flow ratio and the viscosity of the liquid feed. Thus it only depended on the characteristics of the separator. Finally, the dried particles were spherical in shape and in the submicron-sized range., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Individual dosing of medicines is relevant for paediatrics, geriatrics and personalised medicine. The Solid Dosage Pen (SDP) allows for individual dosing by cutting monolithic, tablet-like drug carriers of pre-defined heights. The aim of the present study was to develop micropellet-loaded rods (MPLRs) with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen. Therefore, micropellets were successfully layered with carbamazepine and coated with polyvinyl acetate (PVAc) and PVAc/polyvinyl alcohol-polyethylene glycol (PVA-PEG). The tensile strength of the sustained release micropellets (300-450 μm) was more than two times higher (12.6-17.1 MPa) than pressures occurring during ram-extrusion of the MPLRs (below 5.8 MPa). Due to relative crystallinities above 93% for PVAc and PVA-PEG a low solubility of the coating films within the PEG-matrix was observed. The sustained release micropellets were successfully incorporated into MPLRs. Drug release properties of the pellets maintained after embedding into the matrix. Hence, the MPLRs provided dose-independent prolonged drug liberation which was not achieved for drug-loaded rods before. The MPLRs permitted the application of the SDP with a precise drug delivery from individually cut single doses. Storage stability was proven for MPLRs containing PVAc/PVA-PEG coated pellets. In conclusion, the MPLRs combined the advantages of multiparticulate dosage forms with the SDP as a device for individual dosing., (Copyright © 2016 Elsevier B.V. All rights reserved.)

As different batches of the same excipients will be intermixed during continuous processes, the traceability of batches is complicated. Simplified formulations may help to reduce problems related to batch intermixing and traceability. Twin-screw granulation with subsequent tableting was used to produce granules and tablets, containing drug, disintegrant and binder (binary and ternary mixtures), only. Drug loads up to 90% were achieved and five different disintegrants were screened for keeping their disintegration suitability after wetting. Granule size distributions were consistently mono-modal and narrow. Granule strength reached higher values, using ternary mixtures. Tablets containing croscarmellose-Na as disintegrant displayed tensile strengths up to 3.1MPa and disintegration times from 400 to 466s, resulting in the most robust disintegrant. Dissolution was overall complete and above 96% within 30 min. Na-starch glycolate offers tensile strengths up to 2.8MPa at disintegration times from 25s to 1031s, providing the broadest application window, as it corresponds in some parts to different definitions of orodispersible tablets. Tablets containing micronized crospovidone are not suitable for immediate release, but showed possibilities to produce highly drug loaded, prolonged release tablets. Tablets and granules from simplified formulations offer great opportunities to improve continuous processes, present performances comparable to more complicated formulations and are able to correspond to requirements of the authorities., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Essential oils and other liquid active pharmaceutical ingredients (APIs) are frequently microencapsulated to improve shelf life, handling, and for tailoring release. A glassy solid solution (GSS), a single-phase system, where the excipient is plasticized by the API, could be an alternative formulation system. Thus this study focuses on the investigation of two formulation strategies using carvacrol as a model compound, namely a microcapsule (MC) and a glassy solid solution (GSS). Applying the solubility parameter approach, polyvinylpyrrolidone (PVP) was chosen as a suitable matrix material for a GSS system, whereas maltodextrin and sucrose served as excipients for a microcapsule (MC) system. Differential scanning calorimetry (DSC) measurements of the excipients' glass transition temperatures and the melting point of carvacrol verified plasticizing properties of carvacrol on PVP. Batch mixing processes, as preliminary experiments for future extrusion processes, were performed to prepare GSSs and MCs with various amounts of carvacrol, followed by crushing and sieving. Maximally 4.5% carvacrol was encapsulated in the carbohydrate material, whereas up to 16.3% were stabilized as GSS, which is an outstanding amount. However, grinding of the samples led to a loss of up to 30% of carvacrol., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Unlabelled: Spheronization is an important pharmaceutical manufacturing technique to produce spherical agglomerates of 0.5-2mm diameter. These pellets have a narrow size distribution and a spherical shape. During the spheronization process, the extruded cylindrical strands break in short cylinders and evolve from a cylindrical to a spherical state by deformation and attrition/agglomeration mechanisms. Using the discrete element method, an integrated modeling-experimental framework is presented, that captures the particle motion during the spheronization process. Simulations were directly compared and validated against particle image velocimetry (PIV) experiments with monodisperse spherical and dry γ-Al2O3 particles., Result: demonstrate a characteristic torus like flow pattern, with particle velocities about three times slower than the rotation speed of the friction plate. Five characteristic zones controlling the spheronization process are identified: Zone I, where particles undergo shear forces that favors attrition and contributes material to the agglomeration process; Zone II, where the static wall contributes to the mass exchange between particles; Zone III, where gravitational forces combined with particle motion induce particles to collide with the moving plate and re-enter Zone I; Zone IV, where a subpopulation of particles are ejected into the air when in contact with the friction plate structure; and Zone V where the low poloidal velocity favors a stagnant particle population and is entirely controlled by the batch size. These new insights in to the particle motion are leading to deeper process understanding, e.g., the effect of load and rotation speed to the pellet formation kinetics. This could be beneficial for the optimization of a manufacturing process as well as for the development of new formulations., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Individual dosing of peroral medicines is important for personalised medicine and patient-centred treatment, e.g., of children and the elderly. The Solid Dosage Pen (SDP) offers the opportunity to dose individually by cutting drug-loaded rods into tablet-like slices. The aim of the present study is the systematic evaluation of the mechanical properties of these drug-loaded rods prepared via hot-melt extrusion. The drug-loaded rods contain carbamazepine as a model drug, and polyethylene glycols and poloxamers as excipients. For the evaluation of the mechanical properties of the extrudates, three parameters were considered: tensile strength, E-modulus, and maximum cutting force. To examine the practicability of the device and the formulations for patient-centred treatment, the needed cutting forces were compared to literature data of the manual forces of different age groups. The maximum cutting force and the tensile strength were marginally changed over a storage period of six months (21±0.2 °C, 45% r.H). A tensile strength below 9.1±0.3 MPa and an E-modulus below 135.9±7.2 MPa were found to be valuable thresholds for the applicability by the Solid Dosage Pen. Formulations containing PEG 1500 as additive fulfilled the pharmacopeial requirements containing the content uniformity even for the smallest dose., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Pellets are frequently used in pharmaceutical applications. The extrusion-spheronization process is a well-established technique used to produce pellets of a spherical shape and narrow size distribution. In this process, cylindrical extrudates are transformed into spherical pellets by spheronization. Most established mechanisms consider only breakage and deformation to explain pellet formation. An interaction between the rounding extrudates via adhesion of fine particles was not considered for many years. This study deals with the evolution of pellet properties over time during the spheronization process in order to quantify the influence of pellet interactions on their properties. Therefore the most important pelletization aids (MCCI, MCCII and κ-carrageenan) were investigated using acetaminophen as a model drug and lactose as a filler. In the first seconds of the spheronization process, a high fine fraction was seen which decreased during the process. Simultaneously, the material transferred between the pellets increased. However the fine fraction is not high enough to explain the mass transfer; therefore a direct transfer between the pellets was assumed. The pelletization aid has a huge influence on the amount of mass transferred. Whereas κ-carrageenan leads to a quite low mass transfer of 15%, MCCI and MCCII show higher values up to 25%., (Copyright © 2012 Elsevier B.V. All rights reserved.)