Orodispersible dosage forms are promising new approaches in drug administration. They enable an easy application, as there is no need to drink high amounts of liquids or swallow large solid dosage forms. The aim of the study was to develop an orodispersible film (ODF) as an alternative to tablets, syrups or suppositories for the treatment of vomiting and nausea, especially for the paediatric population. Formulations were investigated by x-ray-diffraction, scanning electron and polarized light microscopy. Disintegration time of the films was determined by performing petri dish, drop and clip weight method. Additionally, two commercially available electronic taste sensing systems (electronic tongues) were used to investigate the applied taste-masking strategies. Different excipients enhancing the solubility of dimenhydrinate were investigated to avoid recrystallization in the film. Furthermore, they are discussed to improve the taste attributes of the formulation by interacting with the drug substance. Results obtained from x-ray-diffraction and polarized light microscopy showed no recrystallization of dimenhydrinate in the formulation when cyclodextrin or maltodextrin were used as solubilizing agent. All ODFs disintegrated in an appropriate time (< 120 s) depending on the characterization method. In order to get information on taste, the dimenhydrinate formulations were analytically compared to pure drug and drug-free formulations by the electronic tongues. Results obtained from both systems are comparable but can also be used complementary. In addition, possible taste masking effects by reduction of the free amount of drug could be detected by both electronic tongues. Merging data of both systems by multivariate data analysis showed improved discrimination between different drug formulation. It was possible to develop an orodispersible film of dimenhydrinate that is fast disintegrating even in small amounts of liquid. Moreover, a non-human taste assessment by two electronic tongues was successfully performed.

Introduction: Development of freeze-dried protein formulations is a complex and time consuming task, complicated by the numerous excipients available, the choice of processing conditions and the number of quality attributes to evaluate. The aim of this study was to develop a high throughput screening system for evaluating the visual appearance of the freeze-dried cake based on image analysis and innovative knowledge management solutions. Materials and methods: Samples consisted of different concentrations of mannitol, sucrose, model protein and dyes. 100 µL of sample solution was filled into each well of a brass well-plate sealed on one side. After freeze drying, images were obtained and analyzed with regard to color, grayscale value, sample size and a measure of the amount of information in the image termed image-entropy. Results and discussion: Different visual characteristics were evaluated using image analysis. Cake collapse was assessed by studying sample size (shrinkage), glassiness (transparency) was evaluated through the grayscale value, surface uniformity was determined through the image-entropy value of the well, and off-coloring was analyzed with color analysis. Although these sample attributes are all important parameters, none of them could be used alone, as visual appearance as observed by a specialist consists of an intricate combination of all this information. To cope with the complexity of visual assessment, an expert system was constructed to classify the samples according to overall visual appearance. Conclusion: Quality assessment of freeze-dried cakes was effectively performed using a high throughput image analysis based expert system.

Sustained-release coated pellets with different sizes (6, 2.5 and 1 mm in diameter) were investigated using terahertz pulsed imaging (TPI). Three batches of metoprolol succinate layered sugar starter cores coated with a 75:25 (w/w) polymer blend of Kollicoat SR and Kollicoat IR (approximate coating thickness of 60 μm,according to the weight gain) were analysed to evaluate the effect of size on coating thickness and morphology (depicted by the terahertz electric field peak strength, TEFPS) Ten pellets from each batch were mapped individually using TPI. From the terahertz waveform the interface between coating and drug layer, and between drug layer and core were determined. The TPI measurements were carried out on pellet surface areas of approximately 33, 2.2 and 0.4 mm² for pellets with 6, 2.5 and 1 mm diameters, respectively. Results indicated a large variation in the average coating thickness between all pellet sizes. Smaller pellets (2.5/1 mm in diameter) showed a higher average coating thickness (81 and 70 μm, respectively) compared to 6 mm pellets (50 μm), suggesting a better coating efficiency for smaller pellets. This was also confirmed by scanning electron microcopy (SEM). Since no difference in the surface morphology could be observed using SEM, differences in the average TEFPS values between 6 mm pellets (16.2%) and 2.5/1 mm pellets (2.2 and 2.6%, respectively) are related to signal reflection loss due to the increase in curvature of smaller pellets. Although the largest pellets showed the thinnest average coating, the fastest drug release was obtained from the smallest pellets due to the larger surface area exposed to the dissolution media. Pellets of 2.5 mm in diameter showed a faster initial drug release with slower release kinetics at the end of dissolution testing compared to large pellets. TPI proved highly suitable to evaluate film coating characteristics as well as detect drug layer/core interface of different sized sustained-release coated pellets.

Tablet compaction consists of several stages and is thus challenging to describe in simple mathematical equations.¹ Various numerical approaches have been applied to try and derive a more thorough understanding of the multiple interactions that occur during compaction.^2,3 A possible way to obtain insight into the behavior of solids during compression is to perform indentation load – displacememt experiments and simulations⁴. A finite element modeling (FEM) method utilizing the axisymmetric capabilities of Comsol Multiphysics is presented. The model provides the possibility for evaluating both elastic and plastic deformation occurring during the indentation experiment. This evaluation of the elastic and plastic deformation can be obtained from the calculated load displacement versus pressure profile that provides the maximum indentation depth at the highest load and the final indentation depth after unloading. Elastic recovery can, thus, be characterized by the ratio between the final indentation depth and the maximum indentation depth. The indenter is model as a rigid object that penetrates into the specimen. A mesh is assigned to the entire geometry and a higher mesh density was assigned to the specimen area where the indentation contact occurred. Experimental verification of simulations can be performed using atomic force microscopy (AFM) measurements^5,6. It is suggested that data obtained from such indentation load – displacememt experiments are capable of deepening existing understanding of tablet compaction processes 1. Sonnergaard, J. M. A critical evaluation of the Heckel equation. International Journal of Pharmaceutics 1999, 193, 63-71. 2. Wu, C. Y.; Hancock, B. C.; Mills, A.; Bentham, A. C.; Best, S. M.; Elliott, J. A. Numerical and experimental investigation of capping mechanisms during pharmaceutical tablet compaction. Powder Technology 2008, 181, 121-129. 3. Siiria, S. M.; Antikainen, O.; Heinamaki, J.; Yliruusi, J. 3D Simulation of Internal Tablet Strength During Tableting. Aaps Pharmscitech 2011, 12, 593-603. 4. Bolshakov, A.; Pharr, G. M. Influences of pileup on the measurement of mechanical properties by load and depth sensing indentation techniques. Journal of Materials Research 1998, 13, 1049-1058. 5. Garnaes, J. Diameter measurements of polystyrene particles with atomic force microscopy. Measurement Science & Technology 2011, 22. 6. Jee, A. Y.; Lee, M. Comparative analysis on the nanoindentation of polymers using atomic force microscopy. Polymer Testing 2010, 29, 95-99.

Numerical analysis has been utilized for several decades¹ for solving problems where conventional analytical equations fail due to e.g. complex geometry of the dissolution vessel². Furthermore, numerical analysis enables the visualization of the formed concentration gradients that persist during dissolution testing. Numerical analysis utilizing finite element modeling (FEM) can thus help to elucidate the dissolution process that is occurring in highly complex geometries. The FEM method can be computationally solved by the coupling of a laminar flow problem with a transport problem. The model can be solved as a stationary study by evaluating the Navier-Stokes equation for the fluid flow and the mass balance equation for the transport problem. A FEM simulation was subsequently performed for a flow through cell geometry designed for dissolution testing and the calculated dissolution rate was compared to the experimentally obtained dissolution rate. It was found that the FEM method provided excellent agreement with the experimentally obtained data. Thus, the FEM method provides new possibilities for the investigation of dissolution processes in complex geometries and encompasses the capability to visualize various phenomena related to the dissolution mechanisms. This platform could in future also be suitable for studying more complex dissolution phenomena where micelles are present in the solvent phase. Future simulations supported by dissolution studies will also explore compounds that exhibit solvent mediated recrystallization. 1. Bredehoe.Jd; Pinder, G. F. Mass-Transport in Flowing Groundwater. Water Resources Research 1973, 9, 194-210. 2. Kaunisto, E.; Nilsson, B.; Axelsson, A. Drug dissolution rate measurements - evaluation of the rotating disc method. Pharmaceutical Development and Technology 2009, 14, 400-408.

Isomalt is frequently used in pharmaceutical formulations. This study is conducted to characterize the properties of galenIQ 801, a recently marketed isomalt grade, after roll compaction. Pure isomalt and a mixture of equal parts of isomalt and dibasic calciumphosphate are tested likewise. Different specific compactions forces from 2 to 14 kN/cm are used for roll compaction and the resulting granules are compressed to tablets with tableting forces from 3 to 15 kN. The granules are characterized in terms of flowability and particles size, whereas the tensile strength, porosity, disintegration time, and friability are used to define the tablets. FFC-values over 10 indicate excellent flowability for the granules prepared with specific compaction forces of 6 kN/cm and more for pure isomalt and at 10 kN/cm for the blend. This can be explained with the increasing particle size after roll compaction as the x₅₀-values grow from around 10 µm to at least 440 µm. The tensile strength is calculated to evaluate the impact of roll compaction on the compactibility of the granules. The tensile strength of pure isomalt is higher compared to the mixture. At the highest tableting force, pure isomalt tablets display maximum tensile strengths of 1.4 MPa at specific compaction forces of 2 kN/cm and 6 kN/cm, which decrease to 1 MPa and even lower at higher specific compaction forces. In case of the mixture, the tensile strength at 15 kN tableting force is approximately 0.8 MPa for all specific compaction forces. With increasing tableting force, the porosity decreases from over 25 % to around 16 %, whereas the disintegration time increases. The friability test was only passed by some of the pure isomalt tablets (specific compaction force < 14 kN/cm and tableting force > 9 kN), none of the tablets prepared from the blend fulfilled the requirements. In conclusion, it can be stated, that galenIQ 801 is suitable for recompression after roller compaction. Regarding tensile strength, flowability, and friability, a specific compaction force of 6 kN/cm is most adequate.

Objective. To characterize the oil-water interfacial adsorption of folded and unfolded protein using rheology and pendant drop techniques. Methods. Phosphate buffer pH 7 (ionic strength 0.05M) was used as the water phase and Miglyol 812 (coconut oil; medium chain triglycerol) as the oil phase. Bovine serum albumin (BSA) dissolved in the water phase (0.8 mM and 0.4 mM) was mixed with 0-50% (v/v) solutions of thermally unfolded BSA (0.15 mM) and interfacial properties were determined. Oscillatory shear measurements, using a rheometer with double-wall-ring geometry, were conducted at 0.1 Hz and strain of 0.1% (within the linear viscoelastic regime). Interfacial tension measurements were performed using an aqueous drop volume of 50 μL (needle diameter 1.83 mm) which was lowered into the oil phase. Results. BSA formed a viscoelastic film at the oil-water interface. The presence of thermally unfolded protein in the bulk water phase delayed the interfacial film formation but giving similar elastic and viscose moduli after 1h. After ten minutes, the surface tension for the folded protein alone [7.63±0.25 (mN/m) (0.4 mM) and 9.81±0.29 (mN/m) (0.2 mM)] was higher than for the folded protein in the presence of the unfolded protein [7.20±0.04 (mN/m) (0.4 mM) and 8.49±0.20 (mN/m) (0.2 mM)]. The magnitude and time course of the observed differences in rheological properties and interfacial tension suggest that the interfacial behaviour between BSA solution and the oil phase was not governed by the folded protein concentration alone. In fact, the presence of unfolded protein in the solution also affects the properties of the viscoelastic film. Conclusion. The combination of rheology and pendant drop techniques was shown to be useful for the characterization of the physical behavior of protein at the oil-water interface.

A typical approach to establish a Quality by Design (QbD) design space is to base it on data collected by a Design of Experiment (DoE) followed by ANOVA model building. Though the ANOVA model is useful in describing mathematically how critical quality parameters and quality attributes are linked, often the model contains higher order interaction terms, making interpretation and understanding difficult. On the other hand, the GEneralized Multiplicative ANOVA (GEMANOVA) model assumes the presence of higher order interaction term from the beginning, and typically yields a model that is intuitively easier to understand compared to the additive ANOVA models. The comparison between the two mentioned alternatives can be based on the principle of parsimony or Occam\'s razor dating back to the 14^th century. In short the principle of parsimony states that for multiple models with equal predictive performance, the model that uses the fewest number of parameters should be preferred. Though this principle might be useful from a mathematical point of view as impartial selection tool for the final model, in practice the data analyst often prioritizes the model that is easier to understand rather than the solution having the fewest parameters. In the present study two different models (ANOVA and GEMANOVA) were compared on the same data set from a DoE. Applying different model selection criteria such as the principle of parsimony, ease of model interpretation, understanding and visualization, the study discusses the strengths and limitations in selecting the suitable model from a QbD design space perspective.

The aim was to study how hot melt (HM) process parameters affect the formation of carbamazepine containing Egalet® tablets and their functionality. A fractional factorial 2⁴ design of experiment (DoE) was composed, where the investigated factors were melting temperature (90, 115 and 140 °C), melting time (10, 25 and 40 min), drug loading (15, 30 and 50 % (w/w)) and molecular weight of the polymer (PEG 35 000, PEO 100 000 and 300 000). Hot melt processing was performed on injection molding system (HAAKE MiniJet, Thermo Scientific, Germany). Powder blend was placed into a barrel, heated into given temperature and for the time period described in the DoE, which after the molten mass was injected into a mould (height 6 mm, volume 50 mm³, 25 °C). The polymorphic form of API was determined using X-ray diffractometer (X\'Pert Powder, Pan Analytical, The Netherlands, a continuous 2θ scan, range of 2 to 40°, step size 0.0263 °2θ, scanspeed of 0.0673 °2θ/s). In vitro release behaviour of the Egalet® tablets were determined by paddle method (Vankel VK 7025 Dissolution tester, Agilent Technologies, USA, 900ml, 50 rpm, 37 °C, pH 1.2) using a wavelength of 269 nm (Cary UV-Vis specthrometer, Agilent Technologies, USA). The results indicate that the HM process can induce polymorphic transition of API and the most crucial process parameters are melting temperature and molecular weight of the polymer. High process temperature and low molecular weight of the polymer induced polymorphic transition of API, which might be due to the dissolution of the API into rapidly melting polymer during the process and consequent recrystallization of API into metastable polymorphic form after the molten mass was injection molded and cooled down. Furthermore, the results indicate that the polymorphic transition can affect the release rate of the API.

In silico modeling of oral drug absorption has received widespread attention over the past few years. These models require a number of input parameters and the accurate prediction is often limited by the lack and/or inappropriate selection of reliable input data. The objective of this study was to explore the predictive properties of GastroPlus^TM simulation technology using BCS class II drug nimesulide as a model compound. Model sensitivity to the input data and accuracy to predict drug pharmacokinetic profile observed in vivo were evaluated by constructing drug specific absorption models by two independent investigators, using different presumptions regarding the key factors that govern nimesulide absorption throughout gastrointestinal tract. The first model was constructed assuming that nimesulide might be a substrate for influx transporters in the intestine. Therefore, the absorption scale factors (ASFs) were adjusted to best match the resultant profile to the in vivo observed data. Experimentally determined intrinsic solubility was used as the input value, and human jejunal permeability was in silico predicted. Drug particle radius was assumed to be 5 microns. The main premise in the second model was that nimesulide is well absorbed after oral administration mainly due to the pH-surfactant induced increase in solubility in the gastrointestinal milieu. Therefore, the ASFs were kept on default GastroPlus^TM values, and input solubility and permeability values were optimized to best match the in vivo data. Drug particle size was 25 microns. The results of the simulations were compared with actual clinical data in order to identify the model yielding the best estimation. The presented data indicate the potential of gastrointestinal simulation technology to predict oral drug absorption. However, in order to obtain meaningful in silico modeling, the necessary input data have to be carefully selected and/or experimentally verified.