Article

An Alternative Technology to Form Tablets

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

The idea of a freeze casting process is introduced in order to convert heat and/or pressure sensitive pharmaceutical ingredients into a tablet form. The process line involves the freezing of a water-based suspension including a pharmaceutically active ingredient and a drying step (sublimation). The results of these procedures are highly porous solid tablet bodies. The tensile strength and dissolution behavior of the bodies are examined. It is shown that the hardness of the tablets depends on the composition of the suspension, which is not quite satisfactorily reached. The porosity, and therefore, the dissolution behavior depend on the process parameters and correlate with the tensile strength. Much better dissolution rates can be obtained with the new tablets than with commercial products. The proof of concept for tablet manufacturing by the route of freeze casting is successfully demonstrated.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Followed by a solvent removal step (an evaporation or sublimation), a porous solid body in the desired mold form is obtained without using any external pressure (Nguyen and Ulrich, 2014). Non external pressure and low processing temperature are advantages which make freeze casting a promising technique for compacting of heat and pressure sensitive materials, especial in pharmaceuticals (Pachuski and Ulrich, 2007a,b;Szepes et al., 2007a,b;Witte and Ulrich, 2010). In addition, a high porosity leads to a high contact surface area and enhance a dissolution/dispersal rate of a solid dosage form. ...
... A tablet owning a higher porosity may have a better dissolution rate, however, a high porous structure also induces a lower mechanical stability and vice versa. In order to get the balance of both the tensile strength and the porosity (or the dissolution/dispersal rate), a binder which is highly soluble in the dispersal medium is strongly recommended (Szepes et al., 2007a,b;Pachuski and Ulrich, 2007a,b;Witte and Ulrich, 2010). ...
... For the fast dissolving tablets, in order to get an improvement in both the tensile strength and dispersal behavior, binders which are highly and fast soluble in the dispersal medium are strongly recommend (Szepes et al., 2007a,b;Pachuski and Ulrich, 2007a,b;Witte and Ulrich, 2010;Nguyen and Ulrich, 2014). In addition, the binders also need to interact well with the main active ingredients in both solid and liquid state to get a stable suspension during the sample preparation step as well as to form a binding to reinforce the tablet body during the freeze casting process. ...
... For instance, the deactivation of proteins or transformations of polymorphic materials are envisaged. Freeze casting is a promising alternative technology in order to convert heat and/or pressure sensitive API's into a tablet form [37][38][39][40][41][42]. A further negative feature of the standard tabletting technique compared to the freeze casting is the high amounts of excipients, for instance, binders and lubricants, which are necessary to make the most of the API's compressible. ...
... The porosity affects, aside the mechanical stability of the tablet bodies (seen in Fig. 13 and explained by Eq. (1)) also the dissolution behaviour of the tablets. By varying the composition (Bindzil Ò 1430) the amount of water is automatically changed and hence the amount of pores as well as size and pore size distribution, which influences the dissolution behaviour of the solid bodies (see Fig. 15) [42]. ...
... In Fig. 15 it can be seen, that by changing the composition of the tablet bodies the dissolution behaviour is influenced, too [42]. Fur-thermore, it is shown in this diagram the dissolution behaviour of a commercial available ibuprofen tablets (Rathiopharm). ...
Article
Product design is a cutting-edge area of research. Over the last few years, many papers have been presented dealing with product design. The review focuses on processing of crystalline solids with a particular filed of application in mind and shows how crystallization can be used as tool to generate materials with particular properties and how to tailor these properties by crystallization. The fact that crystallization is a tool for product design will be highlighted by 4 selected examples, dealing with roughness and shelf life of fertilizer granules (case 1 and 2), with micro container as carrier system and, finally, with an alternative tablet forming technique for heat sensitive materials.
... It is clear that freeze-casting is a potential cold compression technique to produce the porous solid body in the development of solid drug delivery systems [3][4][5][6][7]. Studies on the applications of the processing technique, especially in producing fast dissolving products in pharmaceuticals and food, however, have not quite yet reached its full extent for a complete understanding. ...
... The vertical tube channels which are the negative images of the grown ice crystals in vertical direction can clearly be seen in Fig. 5 c. Previous studies [4][5][6][7] demonstrated that the water-soluble additives recrystallize during solidification and modify the structure of the solid body by building a connection between solid particles [5]. However, as compared with the morphologies of the material substances (see Fig. 6), it is clear that there is no round-shaped particle of the modified starch (Fig. 6 b) or any new particles which can be found in the SEM images of the freeze-casted solid bodies; see Fig. 5 d. ...
Article
A fast-dissolving solid dosage form (tablet), containing in this case paracetamol as an active pharmaceutical ingredient and modified starch as an additive, was successfully produced by means of the freeze-casting process. The structure and two key properties, namely, disintegration time and tensile strength, of freeze-casted tablets were investigated. The produced tablets exhibit a threefold faster disintegration time with equal tensile strength in comparison to the commercial compressed tablets. Sugar as a binder, however, can just improve the disintegration rate but not enhance the tensile strength due to different mechanisms working.
... Estudos demonstram que tamanhos de poros entre 100 μm e 400 μm são ideais para aplicação em biocerâmicos, pois facilitam o crescimento do tecido ósseo, similar ao encontrado nos ossos humanos [8,9]. Outras aplicações para essa técnica são amplamente utilizadas nas indústrias farmacêutica e alimentícia, incluindo a produção de filtros magnéticos e eletrodos [10,11,12]. Destaca-se também o uso de cerâmicas para a filtragem, onde os poros têm uma média de tamanho de 0,1 a 0,7 µm no processo de microfiltração [13]. ...
... [2]) were among the first ice-templated materials, all types of materials have now been ice-templated, from ceramics to polymers, metals [3], gels, carbon-based materials such as graphene or carbon nanotubes, and even food (cocoa! [4]) and drugs such as ibuprofen [5]. Such broad applicability has accelerated progress and understanding in the field. ...
Article
Full-text available
Ice-templating, also known as freeze-casting, has become over the past 15 years a wellestablished materials processing route [...]
... Concurrent investigations of freeze-cast materials for other ceramic-based applications, including filtration membranes [6][7][8] and fuel cell electrodes [9][10][11][12][13][14][15][16], began to reveal the true versatility of the technique. Freeze-casting of metals [17], pharmaceuticals [18][19][20][21][22][23][24], and foodstuffs [25] was demonstrated within the same decade. From the early 2000's to 2017, the number and diversity of potential applications for these materials grew considerably; applications investigated include substrates for supercapacitors [26][27][28][29][30][31][32], photocatalysis [33][34][35][36][37][38][39][40][41][42][43], liquid chromatography [44], sensors (e.g. ...
Article
Full-text available
Freeze-casting produces materials with complex, three-dimensional pore structures which may be tuned during the solidification process. The range of potential applications of freeze-cast materials is vast, and includes: structural materials, biomaterials, filtration membranes, pharmaceuticals, and foodstuffs. Fabrication of materials with application-specific microstructures is possible via freeze casting, however, the templating process is highly complex and the underlying principles are only partially understood. Here, we report the creation of a freeze-casting experimental data repository, which contains data extracted from ~800 different freeze-casting papers (as of August 2017). These data pertain to variables that link processing conditions to microstructural characteristics, and finally, mechanical properties. The aim of this work is to facilitate broad dissemination of relevant data to freeze-casting researchers, promote better informed experimental design, and encourage modeling efforts that relate processing conditions to microstructure formation and material properties. An initial, systematic analysis of these data is provided and key processing-structure-property relationships posited in the freeze-casting literature are discussed and tested against the database. Tools for data visualization and exploration available through the web interface are also provided.
... Also a work done by Witte et al. showed that the freeze-casting of aqueous solution of Ibuprofen produced immediate release tablets. The fast release was a result of the high porosity of the tablet body because of the unoccupied space left after the sublimation of the frozen water molecules [5]. Despite of the high quality of the dried product, freeze-drying is energy intensive and consequently an expensive technique [6]. ...
Chapter
The freezing of colloids occurs in many natural and synthetic processes, from geophysics to food engineering and biology. In the last 15 years, a particular attention has been paid to materials processing and shaping routes based on the freezing of colloids, called ice-templating or freeze-casting. The versatility of these routes, in terms of materials, as well as the variety of structure that could be achieved, makes freezing an appealing route to investigate. This chapter aims to be a simple, practical guide to getting started with ice-templating. After considerations about the budget needed, practical guidelines are given regarding the development of your own freezing set-ups, freeze-drying, and the best procedures to prepare and characterise your samples, in particular regarding the description of the porosity. The last section, troubleshooting, describes the most common difficulties you may encounter, in terms of process control, but also of defects formed in the materials, and briefly discuss their origin, along with possible solutions to overcome them. This chapter will hopefully help you getting started in the fun world of ice-templating while avoiding the most common pitfalls and time-consuming mistakes, and thus concentrating on new science.
Chapter
This chapter is focused on materials science studies and applications of the freezing of colloids. Both porous and dense materials can be obtained by freezing colloids, a process known as ice-templating or freeze-casting in materials science. This chapter describes properties and applications of ice-templated materials, which includes ceramics, polymers, metals, and composites. The first two sections report and discuss the mechanical and functional properties. Because of the material-agnostic nature of the freezing route, a variety of materials and functional properties have been reported, including electrical, dielectric, piezoelectric, catalytic, acoustic, and thermal properties. The following section covers the applications that have been targeted by these materials, which, again, are diverse. For each application, the specificities of the freezing route and the resulting materials are described. The last section summarizes the current motivations for freezing, the physical limits currently encountered, and discusses the barriers (scale-up, cost, processes) for transferring these studies into industrial products and applications.
Article
Porous materials exhibiting aligned, elongated pore structures can be created by directional solidification of aqueous suspensions—where particles are rejected from a propagating ice front and form interdendritic, particle-packed walls—followed by sublimation of the ice, and sintering of the particle walls. Theoretical models that predict dendritic lamellae spacing—and thus wall and pore width in the final materials—are currently limited due to an inability to account for gravity-driven convective effects during solidification. Here, aqueous suspensions of 10–30 nm TiO2 nanoparticles are solidified on parabolic flights under micro-, lunar (∼0.17 g; gl = 1.62 m/s²), and Martian (∼0.38 g; gm = 3.71 m/s²) gravity and compared to terrestrially-solidified samples. After ice sublimation and sintering, all resulting TiO2 materials exhibit elongated lamellar pores replicating the ice dendrites. Increasing the TiO2 fraction in the suspensions leads to decreased lamellar spacing in all samples, regardless of gravitational acceleration. Consistent with previous studies of microgravity solidification of binary metallic alloys, lamellar spacing decreases with increasing gravitational acceleration. Mean lamellar spacing for 20 wt% TiO2 nanoparticles suspensions under micro-, lunar, Martian, and terrestrial gravity are, respectively: 50 ± 8, 34 ± 11, 30 ± 6, and 23 ± 9 μm, indicating that gravity-driven convection strongly affects lamellae spacing under terrestrial gravity conditions. Gravitational effects on lamellar spacing are highest at low TiO2 fractions in the suspension; for 5 wt% TiO2 suspensions, the microgravity lamellar spacing is more than twice that under terrestrial gravity (182 ± 21 vs. 81 ± 23 μm). Results of this study are in good agreement with previous studies of binary metallic alloy solidification where primary dendrite spacing increases under microgravity. Literature data from ice-templating systems are used to discuss a dependence on lamellae spacing of the density ratio of particles and fluid.
Article
A fast and easily dissolving/dispersible tablet is introduced as a new convenient dosage form to substitute fine powders. Cocoa was taken as a first potential food candidate to produce a fast dispersible tablet. The experimental setup of a successfully applied freeze-casting process is presented. By controlling the temperature gradient and the freezing mode, two pore morphologies including needle-columnar and planar-lamellar structures were found. Sugar used as a binder dramatically improved the properties of the produced tablets. A fast-dispersal cocoa tablet of 16 mm in diameter and 10 mm in height was obtained, with a dispersal time of less than 1 min and a crushing force higher than 34.5 N, i.e., a diametral tensile strength σt of 0.14 N mm−2. In other words, a tablet meeting the dissolution time and mechanical strength requirements for fast-dispersal tablets was generated.
Article
Formation of a low-fat oil-in-water (O/W) nanoemulsion enriched with vitamin E using the nonionic surfactant Tween 40 is studied by means of a high-pressure homogenizer. The effect of different process variables of the emulsification process, including pressure, temperature, and concentration of the emulsifying agent, is evaluated. The relation between pressure and the obtained mean droplet diameter is derived and described by an equation which can be taken as a basis of any process design. The droplet size can be decreased by increasing the vitamin E concentration. A higher fat content slightly affects the droplet size distribution and the mean droplet diameter of the nanoemulsion, so it is recommended to use preparations of nanoemulsions with low fat contents enriched with vitamin E for dietary supplement.
Article
Pharmaceuticals freeze-drying requires a careful monitoring to preserve product quality. This is a challenging task as it is not possible to measure inline the variables of interest, i.e., temperature and residual amount of ice in the product in the primary drying stage and residual unfrozen water in the secondary drying stage. Various sensors are available to estimate the state of the product, coupling experimental measures and a model of the process. Methods based on the measure of product temperature and on the pressure rise test are discussed and compared by means of experimental investigations. The former is a local intrusive method, as it requires placing thermocouples in various vials, but allows monitoring the batch taking into account its non-uniformity, while the latter is a global and non-intrusive method which permits a partial insight into process dynamics.
Article
Ice templating is able to do much more than macroporous, cellular materials. The underlying phenomenon—the freezing of colloids—is ubiquitous, at a unique intersection of a variety of fields and domains, from materials science to physics, chemistry, biology, food engineering, and mathematics. In this review, I walk through the seemingly divergent domains in which the occurrence of freezing colloids can benefit from the work on ice templating, or which may provide additional understanding or inspiration for further development in materials science. This review does not intend to be extensive, but rather to illustrate the richness of this phenomenon and the obvious benefits of a pluridisciplinary approach for us as materials scientists, and for other scientists working in areas well outside the realms of materials science.
Article
A sol-gel and a freeze-casting process are used to produce tablet-like bodies without the standard compression. The advantage is that temperature sensible materials can be produced in tablet-like forms, thus other cost intensive production processes like capsulation or freeze drying are avoided. Different ways are introduced to characterize the suspension and the tablet. Herewith the influences of parameters like composition of the materials or freezing conditions on the final products should be clarified.
Article
The tensile strength of tablets of single-component powders, such as microcrystalline cellulose (MCC), hydroxypropylmethyl cellulose (HPMC) and starch, and binary mixtures of these powder were measured at various relative densities. It was found that the tensile strength of tablets of powder blends was primarily dependent upon relative density but was independent of the tablet dimensions and compaction kinematics. It was found that the logarithm of tensile strength was proportional to the relative density. A simple model, based upon Ryshkewitch-Duckworth equation that was originally proposed for porous materials, has been developed in order to predict the relationship between the tensile strength and relative density of binary tablets based on the properties of the constituent single-component powders. The validity of the model has been verified with experimental results for various binary mixtures. It has demonstrated that the proposed model can well predict the tensile strength of binary mixtures based upon the properties of single-component powders, such as true density, and the concentrations.
European Pharmacopoeia 6.0, European Directorate for the Quality of Medicines
  • Europe Council Of
Council of Europe: European Pharmacopoeia 6.0, European Directorate for the Quality of Medicines, Deutscher Apotheker Verlag, Strasbourg 2008.
  • C.-Y Wu
C.-Y. Wu et al., Eur. J. Pharm. Sci. 2005, 25, 331.
Physikalische Pharmazie: Pharmazeutisch Angewandte Physikalisch-chemische Grundlagen
  • A N Martin
A. N. Martin, Physikalische Pharmazie: Pharmazeutisch Angewandte Physikalisch-chemische Grundlagen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2002.
  • N Pachulski
  • J Ulrich
N. Pachulski, J. Ulrich, Lett. Drug Des. Discovery 2007, 4 (1), 78.
The Association of Powder Process Industry an Engineering
  • D Donchev
  • N Walther
  • J Ulrich
D. Donchev, N. Walther, J. Ulrich, in Proc. of the 2nd Int. Symp. on Industrial Crystallization Inspiring Powder Technology, The Association of Powder Process Industry an Engineering, Tokyo 2004, 20.
Physikalische Pharmazie: Pharmazeutisch Angewandte Physikalisch-chemische Grundlagen, Wissenschaftliche Verlagsgesellschaft mbH
  • A N Martin
A. N. Martin, Physikalische Pharmazie: Pharmazeutisch Angewandte Physikalisch-chemische Grundlagen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2002.
Ulrich inProc. of the 2nd Int. Symp. on Industrial Crystallization Inspiring Powder Technology The Association of Powder Process Industry an Engineering
  • D Donchev
  • N Walther
European Pharmacopoeia 6.0 European Directorate for the Quality of Medicines Deutscher Apotheker Verlag
  • Europe Council Of