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Continuous manufacturing provides advantages compared to batch manufacturing and is increasingly gaining importance in the pharmaceutical industry. In particular, the implementation of tablet processes in continuous plants is an important part of current research. For this, in-line real-time monitoring of product quality through process analytical technology (PAT) tools is crucial. This study focuses on an in-line UV/Vis spectroscopy method for monitoring the active pharmaceutical ingredient (API) content in tablets. UV/Vis spectroscopy is particularly advantageous here, because it allows univariate data analysis without complex data processing. Experiments were conducted on a rotary tablet press. The tablets consisted of 7- 13 wt% theophylline monohydrate as API, lactose monohydrate and magnesium stearate. Two tablet production rates were investigated, 7200 and 20000 tablets per hour. The UV/Vis probe was mounted at the ejection position and measurements were taken on the tablet sidewall. Validation was according to ICH Q2 with respect to specificity, linearity, precision, accuracy and range. The specificity for this formulation was proven and linearity was sufficient with coefficients of determination of 0.9891 for the low throughput and 0.9936 for the high throughput. Repeatability and intermediate precision were investigated. Both were sufficient, indicated by coefficients of variations with a maximum of 6.46% and 6.34%, respectively. The accuracy was evaluated by mean percent recovery. This showed a higher accuracy at 20000 tablets per hour than 7200 tablets per hour. However, both throughputs demonstrate sufficient accuracy. Finally, UV/Vis spectroscopy is a promising alternative to the common NIR and Raman Spectroscopy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rene Brands reports financial support was provided by German Research Foundation., (Copyright © 2023. Published by Elsevier B.V.)

The self-diffusion coefficient of active ingredients (AI) in polymeric solid dispersions is one of the essential parameters for the rational formulation design in life sciences. Measuring this parameter for products in their application temperature range can, however, be difficult to realise and time-consuming (due to the slow kinetics of diffusion). The aim of this study is to present a simple and time-saving platform for predicting the AI self-diffusivity in amorphous and semi-crystalline polymers on the basis of a modified version of Vrentas' and Duda's free volume theory (FVT) [A. Mansuri, M. Völkel, T. Feuerbach, J. Winck, A.W.P. Vermeer, W. Hoheisel, M. Thommes, Modified free volume theory for self-diffusion of small molecules in amorphous polymers, Macromolecules. (2023)]. The predictive model discussed in this work requires pure-component properties as its input and covers the approximate temperature range of T < 1.2 T g , the whole compositional range of the binary mixtures (as long as a molecular mixture is present), and the whole crystallinity range of the polymer. In this context, the self-diffusion coefficients of the AIs imidacloprid, indomethacin, and deltamethrin were predicted in polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate, polystyrene, polyethylene, and polypropylene. The results highlight the profound importance of the kinetic fragility of the solid dispersion on the molecular migration; a property which in some cases might entail higher self-diffusion coefficients despite an increase in the molecular weight of the polymer. We interpret this observation within the context of the theory of heterogeneous dynamics in glass-formers [M.D. Ediger, Spatially heterogeneous dynamics in supercooled liquids, Annu. Rev. Phys. Chem. 51 (2000) 99-128] by attributing it to the stronger presence of "fluid-like" mobile regions in fragile polymers offering facilitated routes for the AI diffusion within the dispersion. The modified FVT further allows for identifying the influence of some structural and thermophysical material properties on the translational mobility of AIs in binary dispersions with polymers. In addition, estimates of self-diffusivity in semi-crystalline polymers are provided by further accounting for the tortuosity of the diffusion paths and the chain immobilisation at the interface of the amorphous and crystalline phases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Previously published mechanisms of pellet formation during extrusion-spheronization include a transfer of material between different granules. This research aimed to specify the origin of this transfered mass, enabling further insight into the extrusion-spheronization process. Granules of various diameters were rounded simultaniously in a spheronizer to ascertain if mass transfer between smaller and larger granules is truly in balance, or if mass transfer from smaller to larger granules is preferred. Granules were also marked with a fluorescent tracer to enable quantification of mass transfer. By using differently sized and shaped granules as starting material, different modes of mass transfer were investigated. Samples were taken after various process durations to investigate the kinetics of the tranfer mechanism. It was found that both small and large granules dispense and receive mass during spheronization. In general, small granules increase their size, while large granules maintain their size or show a slight size decrease, resulting in the particularly narrow monomodal size distribution., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Formulation development of amorphous solid dispersions (ASD) still is challenging although several poorly water-soluble drugs have been marketed using this technique. During development of novel drugs, the selection of the preparation technique and polymer matrix is commonly performed for the certain drug via screening tools. However, if general trends regarding material properties are to be investigated, this approach is not beneficial, although often utilized in literature. The main component of the ASD usually is the polymer and thus it predominantly determines the material properties of the system. Therefore, to study the impact of different drugs and their drug loads on mechanical properties and wettability, three poorly soluble model drugs with drug loads ranging from 10% to 40% were incorporated into copovidone via hot-melt extrusion. The obtained extrudates were subsequently characterized regarding mechanical properties by applying diametral compression test and nanoindentation and the results were compared to the performance during tablet compression. Incorporation of all tested drugs resulted in a similar increase in brittleness of the ASDs, whereas the Young's modulus and hardness changed differently in dependence of the incorporated drug. These observations correlated well with the performance during tablet compression and it was concluded, that the brittleness seemed to be the predominant factor influencing the compression behavior of copovidone-based ASDs. Furthermore, the degree of water absorption and wettability was assessed by applying dynamic vapor sorption experiments and contact angle measurements. Here, the incorporated drugs impacted the contact angle to different degrees and a strong correlation between the contact angle and disintegration time was observable. These results highlight the importance of thorough characterization of the ASDs as it helps to predict their performance during tablet compression and thus facilitates the optimal selection of excipients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Production of submicron particles (0.1-1 μm) has been identified by the pharmaceutical industry as a key technology to enhance the bioavailability of poorly water-soluble drugs. However, nanosuspensions derived from commonly applied wet milling suffer from long-term stability issues, making further downstream processing necessary. In previous works, the formulation as a long-term stable solid crystalline suspension (SCS) was introduced, for which the crystalline drug is ground in a (molten) hydrophilic carrier matrix. The model formulation of the antimycotic Griseofulvin and the sugar alcohol Xylitol was reused for comparative purposes. Due to process limitations regarding the degree of comminution, the present work demonstrates the application of fine grinding in the framework of SCS manufacturing. A custom-built mill with annular gap geometry successfully yielded particles in the targeted submicron range. A process optimization study lead to improved energy utilization during grinding, which reduced the necessary grinding time and, thereby, the thermal exposition of the drug. Investigation of solid-state properties of the SCS, via differential scanning calorimetry and x-ray powder diffraction, showed no alteration even for extended grinding times. In dissolution experiments, the melt-milled SCS outperformed its predecessors, although mostly agglomerates were found by SEM imaging in the solidified product. In conclusion, melt milling is a valuable tool to overcome low aqueous solubility., (Copyright © 2020. Published by Elsevier B.V.)

Fusion based methods, such as hot-melt extrusion, are a common way of preparing amorphous solid dispersions. Since the amorphous glass, however, is not in a configurational equilibrium, the molecular arrangement of the obtained material can differ in dependence of the preparation conditions. Although the changes in the configuration of an amorphous material, which are commonly referred to as structural relaxation or physical aging, are well investigated, the impact on mechanical properties of amorphous solid dispersions have widely been neglected so far. The presented study investigated copovidone as a model polymer commonly used in amorphous solid dispersions and revealed that structural relaxation was already introduced into the polymer during hot-melt extrusion while its degree was cooling rate dependent. The degree of structural relaxation significantly affected the mechanical properties of copovidone as assessed by diametral compression tests, macroindentation and nanoindentation. An increase in Young's modulus and indentation hardness was observable with a higher degree of structural relaxation, which, during tablet compression, translated into tablets with significantly lower tensile strength. Furthermore, evaluation of the force-displacement curves during tablet compression revealed a decreased proportion of irreversible deformation with higher degree of structural relaxation correlating well with the increased indentation hardness during macroindentation. Thus, understanding structural relaxation and its impact on material properties is of utmost importance to assess the processability and compaction performance of amorphous solid dispersions in dependence of their preparation conditions and thermal history., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hot-Melt-Extrusion on Twin-Screw-Extruders has been established as a standard processing technique for pharmaceutical products. A major challenge is the transfer from a lab to a production level, since the combination of several unit operations within one apparatus leads to complex conditions for such a continuous manufacturing process. Here the residence time distribution is a crucial measure, which reflects the different mechanisms, e.g. dissolution, mixing or degradation, during processing. In the first part of a Scale-Up study, a methodology for the optimization of an extrusion process with respect to the load and throughput is presented. The developed concept was applied for different extruder scales in order to compare the identified processing windows. A deviation of the dominant material heating mechanisms was observed for the different scales, while the constraints for the transfer of a process to a different scale by the developed optimization concept is demonstrated. Finally, a sufficient operating point on a reference extruder is identified and in the second part of this study, different concepts from literature are applied for the transfer of this Hot-Melt-Extrusion process to two larger scales. The focus of the investigations was on the impact of the different approaches on the residence time distribution and the comparison. The determined results revealed a change of the most sufficient approach for the two different extruder sizes. The impact on the location in the time domain and form of the distribution are discussed and additionally evaluated by the fit to a RTD-model. In conclusion, the ratio of the applied energy for transport to mixing is identified as valuable addition in this context., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of this study was to investigate the influence of qualitatively different powder feeder performances on resulting granule size distributions after twin-screw granulation of a highly drug loaded, hydrophobic mixture and a mannitol powder. It was shown that powder feeder related problems usually cannot be identified by trusting in the values given by the feeder. Therefore, a newly developed model for the evaluation of the performance of powder feeders was introduced and it was tried to connect this model to residence time distributions in twin-screw granulation processes. The influence of feeder performances on resulting granule size distributions varied, depending on the applied screw configuration and the used powder. Regarding the hydrophobic and highly drug loaded formulation, which was granulated at an L/S-ratio of 0.5, a pure conveying screw and a medium kneading configuration, consisting of 60° kneading blocks were negatively influenced by poor feeder settings. For optimal settings more narrow distributions could be obtained. For an extensive kneading configuration good and poor settings resulted in mono-modal granule size distributions but were differing in the overall size. Mannitol, a model substance for a liquid sensitive formulation was granulated at an L/S-ratio of 0.075. It was even more important to maintain optimal feeding as mannitol was highly affected by poor feeder performances. Even an extensive kneading configuration could not level the errors in powder feeder performance, resulting in qualitatively different granule size distributions. The results of this study demonstrate the importance of detailed knowledge about applied feeding systems to gain optimal performance in twin-screw granulation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Pharmaceutical excipients containing volatile odor-active molecules can be used in pharmaceutical development to increase patients' compliance. However, capturing the molecular composition of these odor-active substances is challenging. Therefore, guidance for the analytical investigation of these excipients should be developed. Using a model flavor, lead molecules were chosen and a gas chromatographic method was validated according to pharmaceutical guidelines. Changes during storage as well as batch homogeneity and conformity were investigated. The knowledge gained could be used to understand molecular differences between batches caused by aging. A suitable attempt to capture the volatile molecular composition of flavoring substance was presented and the found results could be used for the determination and interpretation of quality attributes., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Solid lipids are non-toxic excipients, which are known to potentially enhance delivery and bioavailability of poorly water-soluble drugs and moreover to mask unpleasant tasting drugs. Multiple unit matrix dosage forms based on solid lipids, such as lipid pellets, can be obtained by solvent-free cold extrusion and spheronization. This method presents advantages in the processing of sensitive substances, such as low process temperatures, the absence of solvents and a drying step. However, the material temperature during the spheronization showed to be critical so far. The process leads to increased material temperatures, causing particle agglomeration and discontinuity of the spheronization. In the present study, extrudates of 0.5mm in diameter containing metformin hydrochloride, and either semisynthetic hard fat (Witocan® 42/44) or different ternary mixtures based on hard fat, glyceryl trimyristate, and glyceryl distearate, were spheronized. By applying common process parameters, particle agglomeration or material stickiness on equipment walls was observed in preliminary experiments after 2-6min, depending on the lipid composition. Therefore, an innovative instrumental setup to control the spheronization process was developed utilizing an infrared light source, which was positioned over the particle bed. The new approach enabled a spheronization process that reached the desired spheronization temperature after 2-3min and neither particle agglomeration nor material adherence occurred even after longer process times. The different formulations, even those based on high amount of solid lipids, were successfully spheronized over 15min, resulting in small diameter lipid pellets with smooth surface and aspect ratios below 1.3., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Until now extrusion is not applied for pharmaceutical encapsulation processes, whereas extrusion is widely used for encapsulation of flavours within food applications. Based on previous mixing studies, a hot melt counter-rotating extrusion process for encapsulation of liquid active pharmaceutical ingredients (APIs) was investigated. The mixing ratio of maltodextrin to sucrose as matrix material was adapted in first extrusion trials. Then the number of die holes was investigated to decrease expansion and agglutination of extrudates to a minimum. At a screw speed of 180 min(-1) the product temperature was decreased below 142 °C, resulting in extrudates of cylindrical shape with a crystalline content of 9-16%. Volatile orange terpenes and the nonvolatile α-tocopherol were chosen as model APIs. Design of experiments were performed to investigate the influences of barrel temperature, powder feed rate, and API content on the API retentions. A maximum of 9.2% α-tocopherol was encapsulated, while the orange terpene encapsulation rate decreased to 6.0% due to evaporation after leaving the die. During 12 weeks of storage re-crystallization of sucrose occurred; however, the encapsulated orange terpene amount remained unchanged., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In personalized medicine and patient-centered medical treatment individual dosing of medicines is crucial. The Solid Dosage Pen (SDP) allows for an individual dosing of solid drug carriers by cutting them into tablet-like slices. The aim of the present study was the development of sustained release and dual release formulations with carbamazepine (CBZ) via hot-melt co-extrusion for the use in the SDP. The selection of appropriate coat- and core-formulations was performed by adapting the mechanical properties (like tensile strength and E-modulus) for example. By using different excipients (polyethyleneglycols, poloxamers, white wax, stearic acid, and carnauba wax) and drug loadings (30-50%) tailored dissolution kinetics was achieved showing cube root or zero order release mechanisms. Besides a biphasic drug release, the dose-dependent dissolution characteristics of sustained release formulations were minimized by a co-extruded wax-coated formulation. The dissolution profiles of the co-extrudates were confirmed during short term stability study (six months at 21.0 ± 0.2 °C, 45%r.h.). Due to a good layer adhesion of core and coat and adequate mechanical properties (maximum cutting force of 35.8 ± 2.0 N and 26.4 ± 2.8 N and E-modulus of 118.1 ± 8.4 and 33.9 ± 4.5 MPa for the dual drug release and the wax-coated co-extrudates, respectively) cutting off doses via the SDP was precise. While differences of the process parameters (like the barrel temperature) between the core- and the coat-layer resulted in unsatisfying content uniformities for the wax-coated co-extrudates, the content uniformity of the dual drug release co-extrudates was found to be in compliance with pharmacopoeial specification., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Microcrystalline cellulose II (MCC II(1)) is a polymorph of commonly used MCC I; in 2010 it was introduced as new pelletization aid in wet-extrusion/spheronization leading to fast disintegrating pellets. Previous investigations suggested that the storage of the resulting pellets affect the disintegration behavior, the non-hygroscopic substance chloramphenicol that showed no polymorphism or hydrate formation due to relative humidity was used for the investigations. Therefore, theophylline-monohydrate that can dehydrate during storage, but also during manufacturing and drying was used for this study to confirm the results of the previous study and give a more detailed overview of the influence of recrystallization of theophylline monohydrate on disintegration. Storage recommendations should be derived. MCC II-based pellets were prepared of binary mixtures containing 10%, 20% or 50% MCCII as pelletization aid and theophylline-monohydrate as API. These pellets were stored at different relative humidity (0-97%rH; 20°C); the influence on their disintegration and drug release was investigated. The storage conditions had an impact on pellet disintegration. Low relative humidities (⩽ 40%rH) led to a conversion of the monohydrate to the anhydrous form. Newly grown crystals formed a kind of network around the pellet and inhibited the disintegration. High relative humidity (>80%rh) affected the disintegration caused by changes in the MCCII as already seen in the previous study. Due to the changed disintegration behavior also the drug release and release kinetic changed. Therefore, for theophylline containing pellets a storage humidity of 55%rH to 80%rH (20°C) is recommended. All in all, these investigations substantiate the knowledge of MCCII-based pellets providing a better basis for adequate storage conditions of MCCII based pellets., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Hot-melt extrusion is gaining importance for the production of amorphous solid solutions; in parallel, predictive tools for estimating drug solubility in polymers are increasingly demanded. The Hansen solubility parameter (SP) approach is well acknowledged for its predictive power of the miscibility of liquids as well as the solubility of some amorphous solids in liquid solvents. By solely using the molecular structure, group contribution (GC) methods allow the calculation of Hansen SPs. The GC parameter sets available were derived from liquids and polymers which conflicts with the object of prediction, the solubility of solid drugs. The present study takes a step from the liquid based SPs toward their application to solid solutes. On the basis of published experimental Hansen SPs of solid drugs and excipients only, a new GC parameter set was developed. In comparison with established parameter sets by van Krevelen/Hoftyzer, Beerbower/Hansen, Breitkreutz and Stefanis/Panayiotou, the new GC parameter set provides the highest overall predictive power for solubility experiments (correlation coefficient r = -0.87 to -0.91) as well as for literature data on melt extrudates and casted films (r = -0.78 to -0.96)., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Microcrystalline cellulose II (MCC II)--a polymorph of commonly used MCC I--was introduced as new pelletization aid in wet-extrusion/spheronization leading to fast disintegrating pellets. Previous investigations suggested that pellet properties were influenced by the fraction of MCC II. Furthermore, it is unknown whether the storage conditions can affect the disintegration behavior. Therefore, the effects of MCC II fraction and the storage conditions on several pellet properties were investigated. MCC II-based pellets were prepared of pure MCC II or binary mixtures containing 10-50% (steps of 10%) MCC II as pelletization aid and theophylline, chloramphenicol or lactose. The pellets were characterized by their aspect ratio, equivalent diameter, water content, tensile strength, porosity as well as shrinking, and disintegration behavior and drug release according to their MCC II fraction. Furthermore, the pellets were stored at different relative humidities (0-97%rh), and the influence on their disintegration and drug release was investigated. With increasing MCC II fraction, the pellets became lager in size, decreased their porosity, and required higher water contents for spheronization. Moreover, the disintegration time increased and the disintegration itself was incomplete. Furthermore, the storage conditions had an impact on the disintegration properties of MCC II-based pellets. The disintegrating was affected irreversibly after storage at high humidity (80-97%rh) resulting in a slow drug release. Therefore, MCC II-based pellets need to be stored below 80%rh to secure a fast disintegration. A better knowledge of the properties of MCC II-based pellets was obtained providing a basis for a successful manufacturing and adequate storage of MCC II-based pellets prepared by extrusion/spheronization., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The hot melt extrusion process is a widespread technique to mix viscous melts. The residence time of material in the process frequently determines the product properties. An experimental setup and a corresponding mathematical model were developed to evaluate residence time and residence time distribution in twin screw extrusion processes. The extrusion process was modeled as the convolution of a mass transport process described by a Gaussian probability function, and a mixing process represented by an exponential function. The residence time of the extrusion process was determined by introducing a tracer at the extruder inlet and measuring the tracer concentration at the die. These concentrations were fitted to the residence time model, and an adequate correlation was found. Different parameters were derived to characterize the extrusion process including the dead time, the apparent mixing volume, and a transport related axial mixing. A 2(3) design of experiments was performed to evaluate the effect of powder feed rate, screw speed, and melt viscosity of the material on the residence time. All three parameters affect the residence time of material in the extruder. In conclusion, a residence time model was developed to interpret experimental data and to get insights into the hot melt extrusion process., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The improvement of the bioavailability of poorly soluble drugs has been an important issue in pharmaceutical research for many years. Despite the suggestion of several other technologies in the past, drug particle size reduction is still an appropriate strategy to guarantee high bioavailability of various drugs. A few years ago, the Solid Crystal Suspension (SCS) technology was suggested, in which crystalline drug particles are ground and dispersed in a highly soluble crystalline carrier by a hot melt extrusion process. The current study demonstrates the scale-up of the SCS technology to standard, lab-scale extrusion equipment--a change from previous investigations, which used small batch sizes. A twin-screw extruder was modified to account for the rapid crystallization of the carrier. The screw speed and the barrel temperature were identified as critical process parameters and were varied systematically in several experimental designs. Finally, parameters were identified that produced extrudates with rapid dissolution rates. After extrusion, the extrudates were milled to granules and then tableted. These tablets were investigated with respect to their bioavailability in beagle dogs. It was found that drug particle size reduction in the hot melt extrusion led to 3.5-fold higher bioavailability in these dogs than occurred with the physical mixture of the used substances. The solid crystal suspension formulation had a slightly higher bioavailability than the marked product. In conclusion, the SCS technology was successfully scaled up to lab-scale equipment, and the concept was confirmed by a bioavailability study., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Spheronization is a wide spread technique in pellet production for many pharmaceutical applications. Pellets produced by spheronization are characterized by a particularly spherical shape and narrow size distribution. The particle kinematic during spheronization is currently not well-understood. Therefore, particle image velocimetry (PIV) was implemented in the spheronization process to visualize the particle movement and to identify flow patterns, in order to explain the influence of various process parameters. The spheronization process of a common formulation was recorded with a high-speed camera, and the images were processed using particle image velocimetry software. A crosscorrelation approach was chosen to determine the particle velocity at the surface of the pellet bulk. Formulation and process parameters were varied systematically, and their influence on the particle velocity was investigated. The particle stream shows a torus-like shape with a twisted rope-like motion. It is remarkable that the overall particle velocity is approximately 10-fold lower than the tip speed of the friction plate. The velocity of the particle stream can be correlated to the water content of the pellets and the load of the spheronizer, while the rotation speed was not relevant. In conclusion, PIV was successfully applied to the spheronization process, and new insights into the particle velocity were obtained., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The aim of this study was to produce pellet formulations containing a high drug load (80%) of the poorly soluble HIV-protease inhibitor darunavir, using wet extrusion/spheronization with kappa-carrageenan or microcrystalline cellulose (MCC) as pelletization aid. Drug release was assessed in vitro by a standardized paddle-dissolution test and in vivo by a single-dose pharmacokinetic study in dogs. Mean dissolution time (MDT) was 78.2+/-3.5 h from MCC pellets (1301+/-301 microm) and 6.1+/-0.7 min from kappa-carrageenan pellets (966+/-136 microm). In contrast to kappa-carrageenan pellets, MCC pellets did not disintegrate and showed a diffusion-controlled drug release. In line with the in vitro findings, the darunavir peak plasma levels and exposure after the administration of a 300 mg dose were more than 60-fold higher when formulated with kappa-carrageenan pellets when compared with MCC pellets, and 10-fold higher after co-administration with 10mg/kg of ritonavir. The relative bioavailability of darunavir versus the reference tablet (F(rel)) was 155% with kappa-carrageenan pellets and 2% with MCC pellets without ritonavir, while 78% and 9%, respectively, in presence of ritonavir. In conclusion, when compared with MCC pellets, the bioavailability of darunavir was substantially improved in kappa-carrageenan pellets, likely due to their better disintegration behavior.

Lipid-based drug delivery systems have spread in their use in pharmaceutical drug development. This work focuses on the use of lipid binders as alternative non-toxic extrusion aid for pellet formulations. The preparation of immediate release pellets with solid lipid binders through a solvent-free cold extrusion/spheronisation process was investigated in this study. Various binary, ternary and quaternary mixtures of powdered lipids and the model drug sodium benzoate were investigated and compared to well-known wet extrusion binders like microcrystalline cellulose and kappa-carrageenan. The cold lipid extrusion process offers multiple advantages as it is suitable for thermal sensitive as well as for hygroscopic drugs, furthermore no drying process to evaporate the solvent is needed and the process is feasible for different extruder types. Some of the developed pellets showed favourable properties like spherical shape, narrow size distribution, a high drug load of 80% sodium benzoate and a drug release of more than 90% within 40 min. The stability of drug release, which can be problematic when using lipid excipients, was sufficient for some mixtures, as storage under elevated temperatures changed the release profiles only slightly and no formulation released less than 80% within the first 60 min. A formulation with a mixture of hard fat, glycerol distearate and glycerol trimyristate showed the best results, as pellets with a low aspect ratio, narrow size distribution and complete drug release were obtained. Using appropriate mixtures of acylglycerides it becomes possible to produce pharmaceutical pellets with immediate release characteristics by cold extrusion and subsequent spheronisation. Thus, lipids are very promising alternatives to commonly used extrusion/spheronisation binders.

Microcrystalline cellulose (MCC) is the golden standard to manufacture spherical particles (pellets) via extrusion-spheronisation since wetted microcrystalline cellulose has the proper rheological properties, cohesiveness and plasticity to yield strong and spherical particles. However, microcrystalline cellulose is not universally applicable due to a number of limitations: prolonged drug release of poorly soluble drugs, chemical incompatibility with specific drugs, drug adsorption onto MCC fibers. Hence, several products have been evaluated to explore their application as extrusion-spheronisation aid, aiming to avoid the disadvantages of MCC and to provide a broad application platform for extrusion-spheronisation: powdered cellulose, starch, chitosan, kappa-carrageenan, pectinic acid, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyethylene oxide, cross-linked polyvinylpyrrolidone, glycerol monostearate. To determine the true potential of the proposed alternatives for MCC this review critically discusses the properties of the different materials and the quality of the resulting pellets in relation to the properties required for an ideal extrusion-spheronisation aid.

Microcrystalline cellulose (MCC) is commonly used as an excipient in extrusion/spheronisation process. However, MCC has several disadvantages as lack of disintegration and drug adsorption. Therefore, kappa-carrageenan was investigated to substitute MCC in pelletising processes. Formulations with 20% of pelletisation aid (kappa-carrageenan or MCC) and acetaminophen as a model drug have been produced. Different fillers (lactose, mannitol, maize starch and dicalciumphosphate dihydrate) at fractions of 0, 20, 40 and 80% were evaluated and the properties of the resulted pellets were determined (e.g. yield, aspect ratio, mean Feret diameter, 10% interval fraction, tensile strength and release profile). kappa-Carrageenan has proven to be a suitable substitute as pellets with sufficient quality were produced. The pellet batches of different formulations were characterised by high yield, spherical pellet shape and narrow pellet size distribution. The distinguished behaviour between kappa-carrageenan and MCC pellets was the lower tensile strength and the faster release of kappa-carrageenan pellets. For the various types and fractions of fillers only minor effects to the pelletisation process and pellet properties were noticed. From the practical view these effects are neglectable indicating a robust formulation and process.

The extrusion/spheronisation process is an established technique to produce pellets for pharmaceutical applications. Microcrystalline cellulose (MCC) is being usually used as a pelletisation excipient in the extrusion process. However, MCC has some disadvantages, e.g. lack of disintegration and prolonged drug dissolution. Therefore, kappa-carrageenan was investigated as a substitute for MCC to overcome such disadvantages. A fixed ratio of kappa-carrageenan (20%) was combined with different fillers (lactose, mannitol, maize starch and dicalciumphosphate dihydrate) and different drugs (acetaminophen, theophylline, mesalamine and hydrochlorothiazide) in several formulations. Some pellet properties (yield, aspect ratio, mean Feret diameter, 10% interval fraction, tensile strength and dissolution profile) were determined. Most formulations resulted in pellets of a sufficient quality with respect to size, size distribution and shape independent of the incorporated fillers and drugs. In contrast to MCC pellets, the release profile of kappa-carrageenan pellets was much less affected by the solubility of the drug. Generally, kappa-carrageenan pellets owned fast disintegration and fast drug release in contrast to MCC pellets.

The current study pursues the suitability of different types of carrageenan as a novel extrusion aid. The aim was to find out a suitable substitution to the commonly used microcrystalline cellulose (MCC). The types of kappa-carrageenan were found to be the most appropriate material and the required fraction to produce acceptable pellets in the formulation was determined. The investigation showed that 5% of kappa-carageenan was necessary to produce pellets without MCC. Similar formulations produced with MCC or kappa-carrageenan were compared with respect to size and shape of the pellets. kappa-Carrageenan required higher water content for the formation of pellets, but the formulation was more robust as the optimal range of water content was much broader. Hence, kappa-Carrageenan seems to be a suitable and promising extrusion aid. The study showed that the substitution of MCC by kappa-carrageenan in formulations is possible and the produced pellets were of high quality.