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The main objective of the study was to develop artificial intelligence methods for optimization of drug release from matrix tablets regardless of the matrix type. Static and dynamic artificial neural networks of the same topology were developed to model dissolution profiles of different matrix tablets types (hydrophilic/lipid) using formulation composition, compression force used for tableting and tablets porosity and tensile strength as input data. Potential application of decision trees in discovering knowledge from experimental data was also investigated. Polyethylene oxide polymer and glyceryl palmitostearate were used as matrix forming materials for hydrophilic and lipid matrix tablets, respectively whereas selected model drugs were diclofenac sodium and caffeine. Matrix tablets were prepared by direct compression method and tested for in vitro dissolution profiles. Optimization of static and dynamic neural networks used for modeling of drug release was performed using Monte Carlo simulations or genetic algorithms optimizer. Decision trees were constructed following discretization of data. Calculated difference (f(1)) and similarity (f(2)) factors for predicted and experimentally obtained dissolution profiles of test matrix tablets formulations indicate that Elman dynamic neural networks as well as decision trees are capable of accurate predictions of both hydrophilic and lipid matrix tablets dissolution profiles. Elman neural networks were compared to most frequently used static network, Multi-layered perceptron, and superiority of Elman networks have been demonstrated. Developed methods allow simple, yet very precise way of drug release predictions for both hydrophilic and lipid matrix tablets having controlled drug release.

The compressibility and compatibility of a powder formulation is usually determined by compaction and following destructive tensile strength and relative density measurement of the final compact.In this study, a non-destructive method with Near-Infrared Spectroscopy (NIRS) was designed and evaluated for the measurement of powder compressibility and compactibility.12 different formulations with a wide range of difference in properties were investigated by compaction and analysis of the resulting tablets. Two similar tablet batches were produced with every formulation. Relative density and tensile strength were measured with the traditional, destructive method on one tablet batch while a newly developed non-destructive chemometric NIRS method was applied for the second batch. The outcomes of the two approaches were compared to validate the developed method. All data sets were applied to three established mathematical equations to calculate equation factors, which are claimed to represent the formulation compressibility and compactibility. The study focus was set on the equation factor value comparison between the traditional and the newly designed method.The results showed a high similarity between the outcomes of the two methods. An essential difference was noticed for the outcomes of the equation factors after application to the Leuenberger equation.The approach with the NIRS is suggested as a promising tool for a reliable inline quality monitoring in the tablet manufacturing process.

The purpose of this work was to investigate and evaluate the powder compressibility of binary mixtures containing a well-compressible compound (microcrystalline cellulose) and a brittle active drug (paracetamol and mefenamic acid) and its progression after a drug load increase. Drug concentration range was 0%-100% (m/m) with 10% intervals. The powder formulations were compacted to several relative densities with the Zwick material tester. The compaction force and tensile strength were fitted to several mathematical models that give representative factors for the powder compressibility. The factors k and C (Heckel and modified Heckel equation) showed mostly a nonlinear correlation with increasing drug load. The biggest drop in both factors occurred at far regions and drug load ranges. This outcome is crucial because in binary mixtures the drug load regions with higher changeover of plotted factors could be a hint for an existing percolation threshold. The susceptibility value (Leuenberger equation) showed varying values for each formulation without the expected trend of decrease for higher drug loads. The outcomes of this study showed the main challenges for good formulation design. Thus, we conclude that such mathematical plots are mandatory for a scientific evaluation and prediction of the powder compaction process.

Fluid bed granulation is a dominant method used to produce granules in the pharmaceutical industry. However, controlling the various process parameters is still challenging and granule product quality has further impacts on the tableting process and final tablet quality. Focused beam reflectance measurement (FBRM) was implemented inside the vessel of a fluid bed granulator as a tool for monitoring in-line the particle growth during the granulation process. The main objective of our study was to investigate the relationship between the FBRM measurements of the granules with the physical properties of the compacted granules (tablets). Fifteen granulation experiments were performed under different process parameters in order to vary the dimension of the granules. After granulation, the mean granule size was measured using sieve analysis. Then, the granules were compacted using an instrumented compaction simulator in order to simulate high-speed tableting conditions. The breaking force, disintegration time, compactibility and compressibility of the tablets were analyzed. The results showed that granule size has a powerful influence on the physical properties of the final tablets and, thus, on the quality of the tablets. However, the prediction of those properties exhibited its dependency on the method used to determine particle size.

Roller compaction is a dry granulation method which results in tablets with inferior tensile strength comparing to direct compaction. The effect of roller compaction on compressibility and compactibility of tablets prepared from Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate was investigated by measuring tensile strength of tablets as well as calculating compressibility and compactibility parameters by Leuenberger equation. The tablets under the same conditions were prepared by direct compaction and roller compaction. The binary mixtures of Theophylline anhydrate powder, Theophylline anhydrate fine powder, Theophylline monohydrate and microcrystalline cellulose were prepared in order to determine the optimal ratio of active material and excipients which delivers a sufficient mechanical strength of tablets. Tensile strength of MCC tablets and compactibility parameters calculated by Leuenberger equation after roller compaction was significantly decreased, while THAP, THAFP and THMO tablets showed only a minor reduction in compactibility and compressibility. Adding MCC to a mixture with Theophylline showed that the right choice and ratio of excipients can enable a sufficient mechanical strength of the tablets after roller compaction.

Dwell time mainly depends on punch geometry, so some tableting problems such as capping and lamination could occur at high speed compaction. Robust tools are required to monitor the interaction of punch tip and powder bed at these high speeds. Our aim was to investigate the effect of punch geometry (flat and standard concave) on powder compaction at high speed using radial die-wall pressure (RDWP) as a monitoring tool. Instrumented die guided by compaction simulation was applied for five materials with different compaction behaviors. Flat-faced punch showed higher residual, maximum die-wall pressures, and axial stress transmission than concave punches, p

The effect of moisture as a function of water activity (Aw) on the compaction process is important to understand particle/water interaction and deformation. Studying powder/moisture interaction under pressure with radial die-wall pressure (RDWP) tool was never done. The aim of our study was to use this tool to study this interaction at high compression pressure and speed. Moreover, the effect of changing ejection cam angle (EA) of the machine on ejection force (EF) was investigated. Also, a new tool for prediction of tablet sticking was proposed. Materials with different deformation behaviors stored at low and high moisture conditions were used. Compaction simulation guided by modeling was applied. High Aw resulted in a low residual die-wall pressure (RDP) for all materials, and a high maximum die-wall pressure (MDP) for plastic materials, p < 0.05. This was due to the lubricating and plasticizing effects of water, respectively. However, microcrystalline cellulose showed capping at high Aw and compaction pressure. By increasing compression pressure at high Aw for all materials, effective fall time (EFT) was increased, p < 0.05, showing tendency for sticking. Increasing EA caused an increase of friction and EF for powders, p < 0.05. RDWP was a useful tool to understand particle/moisture interaction under pressure.

In this study the Nano Spray Dryer B-90 (BÜCHI Labortechnik AG, Flawil, Switzerland) was evaluated with regard to the drying of proteins and the preparation of respirable powders in the size range of 1-5 μm. β-galactosidase was chosen as a model protein and trehalose was added as a stabilizer. The influence of inlet temperature, hole size of the spray cap membrane and ethanol concentration in the spray solution was studied using a 3³ full factorial design. The investigated responses were enzyme activity, particle size, span, yield and shelf life. Furthermore, the particle morphology was examined. The inlet temperature as well as the interaction of inlet temperature and spray cap size significantly influenced the enzyme activity. Full activity was retained with the optimized process. The particle size was affected by the hole size of the spray cap membrane and the ethanol content. The smallest cap led to a monodisperse particle size distribution and the greatest yield of particles of respirable size. Higher product recovery was achieved with lower inlet temperatures, higher ethanol contents and smaller cap sizes. Particle morphology differed depending on the cap size. The protein exhibited higher storage stability when spray dried without ethanol and when a larger spray cap size was used.

Paracetamol was selected as a model drug and roll compaction was examined in an attempt to improve the undesirable physical characteristics of paracetamol. Furthermore, the impact of tableting speed was investigated with respect to the tablet tensile strength and capping tendency. The results showed that roll compaction could successfully correct the poor flowability of paracetamol-containing powder blend. Roll pressure and roll speed during roll compaction had particularly significant effects on the granule and tablet properties. Tablet tensile strength was decreased but it was still in an acceptable range. No significant change was observed in compressibility, compactibility and drug release pattern. No polymorphic change occurred. The material showed the lower speed dependency in tableting after roll compaction. There was no considerable difference in capping tendency between starting powder and roll-compacted granules.

Existing treatments of onychomycosis are not satisfactory. Oral therapies have many side effects and topical formulations are not able to penetrate into the human nail plate and deliver therapeutical concentrations of active agent in situ. The purpose of the present study was to determine the amount of terbinafine, which permeates through the human nail plate, from liquid formulations containing enhancers, namely hydrophobins A–C in the concentration of 0.1% (w/v). The used reference solution contained 10% (w/v) of terbinafine in 60% (v/v) ethanol/water without enhancer. Permeability studies have been performed on cadaver nails using Franz diffusion cells modified to mount nail plates and filled with 60% (v/v) ethanol/water in the acceptor chamber. Terbinafine was quantitatively determined by HPLC. The amount of terbinafine remaining in the nail was extracted by 96% ethanol from pulverized nail material after permeation experiment and presented as percentage of the dry nail weight before the milling test. Permeability coefficient (PC) of terbinafine from reference solution was determined to be 1.52E−10 cm/s. Addition of hydrophobins improved PC in the range of 3E−10 to 2E−9 cm/s. Remaining terbinafine reservoir in the nail from reference solution was 0.83% (n = 2). An increase of remaining terbinafine reservoir in the nail was observed in two out of three tested formulations containing hydrophobins compared to the reference. In all cases, known minimum inhibitory concentration of terbinafine for dermatophytes (0.003 μg/ml) has been exceeded in the acceptor chamber of the diffusion cells. All tested proteins (hydrophobins) facilitated terbinafine permeation after 10 days of permeation experiment, however one of them achieved an outstanding enhancement factor of 13.05 compared to the reference. Therefore, hydrophobins can be included in the list of potential enhancers for treatment of onychomycosis.

The purpose of this study was development of diclofenac sodium extended release compressed matrix pellets and optimization using Generalized Regression Neural Network (GRNN). According to Central Composite Design (CCD), ten formulations of diclofenac sodium matrix tablets were prepared. Extended release of diclofenac sodium was acomplished using Carbopol (R) 71G as matrix substance. The process of direct pelletisation and subsequently compression of the pellets into MUPS tablets was applied in order to investigate a different approach in formulation of matrix systems and to achieve more control of the process factors over the principal response - the release of the drug. The investigated factors were X(1) -the percentage of polymer Carbopol (R) 71 G and X(2)- crushing strength of the MUPS tablet. In vitro dissolution time profiles at 5 different sampling times were chosen as responses. Results of drug release studies indicate that drug release rates vary between different formulations, with a range of 1 hour to 8 hours of dissolution. The most important impact on the drug release has factor X(1) -the percentage of polymer Carbopol (R) 71 G. The purpose of the applied GRNN was to model the effects of these two causal factors on the in vitro release profile of the diclofenac sodium from compressed matrix pellets. The aim of the study was to optimize drug release in manner wich enables following in vitro release of diclofenac sodium during 8 hours in phosphate buffer: 1 h: 15-40%, 2 h: 25-60%, 4 h: 35-75%, 8 h: >70%.

The aim of this study was to investigate the effect of roll compaction variables, various excipients, and tableting speed on the granule and tablet properties made of St. John’s wort dry extract. Three key process variables, such as roll pressure, roll speed, and milling speed were selected and their influences were studied using a factorial design. Bulk and tap density, particle size, tablet hardness and the disintegration time of tablets were significantly affected by these variables. The tablet properties such as hardness and disintegration time were considerably modified using different excipients. The effect of tableting speed on the final tablet hardness was reduced or eliminated by the application of roll compaction compared to direct compaction in the case of plastic material. Roll compaction could be successfully applied as a dry granulation method for St. John’s wort dry extract and it is suggested as a novel choice also for other herbal dry extracts to improve their undesirable properties.

The objective of this study was to evaluate the effects of drug load, spray rate and rotor speed and their combinations for production of lansoprazole pellets based on Balocel in a fluidized bed rotary processor and to investigate the influence of temperature and formulation factors on stability of optimum formulation. A Vertex-Centroid Design was used to find the optimal levels of factors for the chosen dependent variables, geometric mean diameter by weight and moisture content. Investigation of stability was conducted for pellets in the size range of 500 μm, prepared with a drug load of 12 %, spray rate of 10 rpm (23 g/min) and rotor speed of 65 %. The influence of alkaline agent magnesium carbonate-heavy at 7 % (w/w) and the presence of a protective coating of hydroxypropylmethyl cellulose at 4 % (w/w) on stability at temperatures of 30, 40, 55 and 60 °C at 79 % RH was investigated. The results of the study revealed that the influence of rotor speed, spray rate and inlet-air humidity should be highly controlled in preparing drug loaded microcrystalline cellulose (MCC) pellets, in terms of size, shape and dissolution. A combination of factors promoting higher powder bed moisture content had a positive effect on pellet size. Presence of MCC and sodium-carboxymethylcellulose in Balocel powder led to dissolution modifying properties depending on the powder bed moisture.

Quantitative applications for pharmaceutical solid dosage forms using near-infrared (NIR) spectroscopy are central to process analytical technology (PAT) manufacturing designs. A series of studies were conducted to evaluate the use of NIR transmission mode under various pharmaceutical settings. The spectral variability in relation to tablet physical parameters were investigated using placebo tablets with different thickness and porosity steps and both variables showed an exponential relationship with the detected transmittance signal drop. The drug content of 2.5% m/m folic acid tablets produced under extremely different compaction conditions was predicted and found to agree with UV assay results after inclusion of extreme physical outliers to the training sets. NIR transmission was also shown to traverse a wide section of the tablet by comparing relative blocking intensities from different regions of the tablet surface and >90% of the signal was detected through a central area of 7 mm diameters of the tablet surface. NIR Quantification of both film thickness and active ingredient for film-coated tablets are examined in part II of this study.

The purpose of this study was to propose a method of determining the exact value of disintegrant ratio in a binary drug‐disintegrant compacted mixture for a minimum disintegration time in the case of spherical particles. Disintegration is a limiting factor in dissolution process of compact for low water soluble active ingredients. As disintegration time is shortest at a certain ratio of disintegrant, a calculation of this value is important for solid dosage from design to enhance disintegration and dissolution process. According to percolation theory, a minimum disintegration time corresponds to the formation of a continuous water‐conducting cluster through the entire tablet. The critical volumetric ratio at which the cluster is formed is named percolation threshold and has the value of 0.16 for random close packed (RCP) sphere systems. RCP systems where chosen as the best model for compacts consisting of spherical particles. Two cases for water diffusion through the tablet were identified, according to geometrical considerations between disintegrant and drug particles. These cases determine if disintegrant particles can have a contact between each other within the compact and thus if porosity and disintegrant volume are included in the continuous cluster. An equation for both cases is presented in the form of piecewise function to determine the minimal disintegrant volumetric ratio for a binary drug/disintegrant compact in order to achieve a minimum disintegration time. Disintegration tests were performed with tablets at different ratios of modified corn starch mixed with caffeine or paracetamol powders. Estimated and experimental optimal ratio were compared showing coefficient R2 = 0.96. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:529–541, 2008

Mefenamic acid (MA), a poorly water-soluble drug, was used as a model substance to investigate granules and tablet characteristics to be optimized for the loading volume of MA (0-74.1% v/v) in the formulation including lactose monohydrate/maize starch (7/3) as excipients. The compactibility of granules increased with loading volume of MA. This was related to the brittle behavior of MA during compression and the increase of intragranular pore volume of granules. The minimum disintegration time (266+/-8.3 s) was found in the tablet that was composed of 55.1% v/v MA and 13.6% v/v maize starch. The determination of the critical concentration of disintegrant (% v/v) required for a minimum disintegration time is suggested to be useful for solid dosage form design.

A multi-unit floating drug delivery system containing pellets with lipid coating were fabricated. Coated pellets were prepared by a fluid bed hot melt coating technique with drug-lipid dispersion. Metoprolol tartrate was used as a water soluble model drug and hydrogenated soybean oil (HSO) was used as a lipid carrier. The drug was dispersed in molten HSO and the mixture was directly sprayed on inert nonpareils in a fluid bed chamber. No major interaction between drug and HSO was observed, nevertheless, the drug could be partially dissolved in the molten HSO. Increasing coating amount or adding an inert substance, Aerosil R972, in the coating mixture reduced the initial burst release as well as the total drug release. Increasing drug particle size gave a variation in the drug release due to brittle fracture induced at the nozzle by pressurized atomization air. Coated pellets presented a good floating property in vitro regardless of the coating amount. The present study shows that a drug-lipid dispersion coating prepared by a hot melt coating technique is a promising means for the development of multi-unit floating drug delivery systems.

In this study, the influence of hot melt coating condition on polymorphic change of a triglyceride base, hydrogenated soybean oil (HSO) was studied. Metoprolol tartrate was used as a water-soluble model drug. Coated pellets were prepared by spraying drug-lipid dispersion onto nonpareil seeds. A tempering process was employed in order to achieve the stable form of HSO. Differential scanning calorimetry was used to simulate the coating and tempering conditions prior to the processing and to characterize polymorphic change together with powder X-ray diffractometry and hot stage microscopy. Coated pellets possessed three polymorphic forms of HSO but only the stable form was dominant after tempering. Tempered pellets presented crystal growth of HSO with 1-2 μm microstructure elements. This morphological change led to the reduced porosity and increased surface area of the pellets as well as the increased drug release. The release profile was attributable to the tempering temperature. In order to stabilize the drug release, the tempering process was suggested to perform at the temperature below the melting point of the unstable form.

The hydrogenated soybean oil was prepared by catalytic hydrogenation process in order to be used as a pharmaceutical excipient for hot melt applications. To optimize the hydrogenation process and produce a product whose quality conforms to the hydrogenated vegetable oil type I in the US Pharmacopoeia (USP 24), a central composite design was applied. The influence of three main process parameters, i.e. amount of catalyst, hydrogen pressure and temperature on the hydrogen consumption, the time required for the completion of the reaction and the reaction rate as well as the quality of final products was studied. The increase in the amount of catalyst and temperature significantly enhanced the reaction rate. However, at higher temperature, the acid values of the final products also increased. The thermal behavior of the product showed tolerance to high temperature exposure, i.e. 80-120°C, where unchanged exothermic peaks were determined in the thermograms before and after exposure. This novel excipient is applied in a next step in the hot melt coating application for the preparation of modified release formulations.

This study was performed to elucidate the influences of process and formulation design using power consumption and temperature measurements during granulation. Power consumption was recorded “in process” using a previously introduced computer program for optimal end-point detection at an early stage. The temperature increase (Δ T ) during granulation was recorded using a temperature sensor. The temperature increase in the wet powder bed expresses the friction forces at interparticle contacts occurring during granulation. The maxima of temperature profile occurred at 130% saturation, whereas the maxima of power consumption were determined at 100% saturation. The ratio of temperature and power consumption (TPR factor) is introduced as a signature of formulation design. TPR factor was found to be dependent on particle size, particle surface, water absorption capacity and solubility of the excipient and model drug, respectively. However, TPR factor was found to be independent of process design, such as the filling level of the mixer. Understanding and controlling the granulation process is a key factor in robust dosage form design. The “in process” control fits ideally the prerequisites of a drug quality system for the 21st century and FDA’s Process Analytical Technology (PAT) initiative. The results of previous and present works of our research group will be used in a following step to develop an artificial neural network for granulation “in process” control.

This study was performed to elucidate the influences of process and formulation design on the granulation process using power consumption and tensile strength measurements. In order to record and analyze the power consumption profile ``in process`` a computer program was developed to be used for optimal end-point control in reproducible granule production. The program analyzes and calculates a characteristical point, the turning point of the S-shaped ascent of the profile. The tensile strength expresses the cohesiveness between the powder particles, which is dependent on saturation and capillary pressure. In order to investigate the influence of the amount of liquid present in the granular material on tensile strength a device was developed. The maxima of tensile strength occurred at 90 maxima of power consumption were determined at 100 measured tensile strength sigma (N/m(2)) equals to the volume specific cohesion (J/m(3)). The present work proved that the power consumption measurement is an alternative, simple and inexpensive method to determine the cohesion of powder particles. The turning point is introduced as a signature of the starting material and furthermore as a parameter for the cohesiveness of the starting material and therefore for optimal end-point detection at an early stage. (C) 2002 Elsevier Science B.V. All rights reserved.

A quasicontinuous granulation and drying process to avoid scale-up problems is introduced in this work. Consistent and reproducible granule quality is a key factor in robust dosage form design and fits ideally the prerequisites of a drug quality system for the twenty-first century and the Food and Drug Administration's Process Analytical Technology (PAT) initiative. In scale-up, factors that simulate or reproduce the laboratory scale must be considered. This system provides a new possibility for industrial manufacturing and galenical development of pharmaceutical solids. The quasicontinuous method described in the present work, and the laboratory and production batches and the granulating equipment used to produce them, are the same. Once a robust process has been defined in the laboratory, it is merely repeated as many times as necessary to achieve the desired final batch size. The quasicontinuous process gives new possibilities to simplify manufacturing procedures and to validate them faster. The quality of the resulting granules and tablets compared with classical methods is equal until better. In many cases, existing products have been transferred to the multicell process without formulation changes. The quasicontinuous production concept for high-shear granulation and fluid-bed drying offers many advantages over the classical methods used to produce pharmaceutical granules. The wet massing process may be monitored by the power consumption of the mixer motor for each subunit, as in classical high-shear granulation processes. The air volume, temperature, and humidity of each of the drying cells may be controlled individually to avoid overheating of temperature-sensitive materials. All processing variables must be precisely controlled by a computer, and the data must be collected for documentation. As such, product quality and reproducibility for each subunit is assured.

The interaction of liposome formulations consisting of Phospholipon 80 and sphingomyelin with human skin was investigated. These formulations were shown previously to have a composition-dependent effect on the penetration of Heparin into the skin. Fluorescence labelled phosphatidylethanolamine (PE-NBD) was incorporated in the liposomes and the depth in which the fluorescent phospholipid label enters into epidermal membrane and full thickness skin was studied by confocal laser scanning microscopy (CLSM). Confocal sections parallel to the surface of the skin were recorded in heat separated epidermis. An even distribution of phospholipid in the lipid matrix of the stratum corneum surrounding the corneocytes was observed with Phospholipon 80 but not when sphingomyelin was included in the formulation. The addition of Heparin which formed a coating around the liposomes, caused a strong localization of fluorescence within the epidermis. For full thickness skin, mechanical cross sections of skin were made and optical sections were recorded parallel to the plane of cut. Phospholipid penetrated and was distributed fairly homogeneously in the lower dermis layers within 30 min of application regardless of liposome composition and the presence of Heparin. This rather quick penetration process seemed to follow distinct pathways along the epidermis and the upper dermis, notably the hair follicle route. Thus, a strong and in some respects composition-dependent interaction of phospholipids with skin is evident. These observations, however, are limited to the level of phospholipid molecules, rather than of entire liposomes interacting with skin.

The aim of this study was to develop a quantitative Near-Infrared (NIR) method which monitors the homogeneity of a pharmaceutical formulation coming out of a continuous blender. For this purpose, a NIR diode array spectrometer with fast data acquisition was selected. Additionally, the dynamic aspects of a continuous blending process were studied; the results showed a well-defined cluster for the steady state, and the paths for the start-up and emptying stages were clearly identified. The end point of the start-up phase was detected by moving block of standard deviation, relative standard deviation, and principal component analysis. A partial least square (PLS) model was generated for the quantification of the drug, with a standard error of prediction of 0.2% m/m. The PLS model was successfully applied for monitoring the drug level at the outlet of the continuous blender. Furthermore, the PLS model was tested under different flow and stirring rates. Flow and stirring rate variations caused different powder flow dynamics, which were reflected on the NIR measurements. Therefore, the PLS model was sensitive to changes in mass flow and rotation speeds.

In silico simulation and percolation theory are important tools in the study of physical and mechanical behavior of pharmaceutical compacts. The aim was to generate a new in silico simulation program that describes the mechanical structure of binary compacts formed from an excipient with excellent compactibility and a drug with null compactibility.Paracetamol and microcrystalline cellulose powders were compressed under different pressures. Values for the indentation hardness and tensile strength were measured and fitted to the Leuenberger's model. On the other hand, compacts with different composition were in silico simulated. In each system, the biggest excipient cluster was identified and quantified using the Hoshen-Kopelman algorithm. Then, the size of the biggest in silico cluster was correlated with experimental compactibility values.The Leuenberger's model resulted in good fit to the experimental data for all formulations over 40% of excipient load. Formulations with high drug load (≥0.8) had reduced range for forming compacts and gave low compactibility values. The excipient percolation threshold for the simulated system was 0.3395, indicating that over this excipient fraction, a compact with defined mechanical properties will be formed. The compactibility values presented a change in the range of 0.3-0.4 of excipient fraction load, just where the in silico excipient percolation threshold was found.Physical measurements of the binary compacts showed good agreement with computational measurements. Subsequently, this in silico approach may be used for the optimization of pharmaceutical powder formulations used in tablet compression.

Fluidized bed granulation is a commonly used unit operation in the pharmaceutical industry. But still to obtain and control the desired granule size is challenging due to many process variables affecting the final product. Focused beam reflectance measurement (FBRM, Mettler-Toledo, Switzerland) is an increasingly popular particle growth analysis technique. FBRM tool was installed in two different locations inside a fluidized bed granulator (GPCG2, Glatt, Binzen) in order to monitor the granulation growth kinetics. An experimental design was created to study the effect of process variables using FBRM probe and comparing the results with the one's measured by sieve analysis. The probe location is of major importance to get smooth and robust curves. The excess feeding of binder solution might lead to agglomeration and thus to process collapse, however this phenomenon was clearly detected with FBRM method. On the other hand, the process variables at certain levels might affect the FBRM efficiency by blocking the probe window with sticky particles. A good correlation was obtained (R(2) = 0.95) between FBRM and sieve analysis mean particle size. The proposed in-line monitoring tool enables the operator to select appropriate process parameters and control the wet granulation process more efficiently.

The aim of this study was to develop a high-dose tablet formulation of the poorly soluble carbamazepine (CBZ) with sufficient tablet hardness and immediate drug release. A further aim was to investigate the influence of various commercial CBZ raw materials on the optimized tablet formulation.Hydroxypropyl cellulose (HPC-SL) was selected as a dry binder and crospovidone (CrosPVP) as a superdisintegrant. A direct compacted tablet formulation of 70% CBZ was optimized by a 3² full factorial design with two input variables, HPC (0--10%) and CrosPVP (0--5%). Response variables included disintegration time, amount of drug released at 15 and 60 min, and tablet hardness, all analyzed according to USP 31.Increasing HPC-SL together with CrosPVP not only increased tablet hardness but also reduced disintegration time. Optimal condition was achieved in the range of 5--9% HPC and 3--5% CrosPVP, where tablet properties were at least 70 N tablet hardness, less than 1 min disintegration, and within the USP requirements for drug release. Testing the optimized formulation with four different commercial CBZ samples, their variability was still observed. Nonetheless, all formulations conformed to the USP specifications.With the excipients CrosPVP and HPC-SL an immediate release tablet formulation was successfully formulated for high-dose CBZ of various commercial sources.

With high-speed compaction cycles as applied in pharmaceutical industrial presses, robust tools like radial die-wall pressure (RDWP) are required to monitor the deformation behavior of formulations under pressure and to avoid common problems such as capping. In this study, the effects of common formulation factors such as lubricant, binder, and drug loading on RDW were investigated. Compaction simulation using Presster™ was applied for five pharmaceutical fillers with different compaction behaviors. Two lubricants, two binders and paracetamol as a model drug were used. Residual die-wall (RDP) and other compaction parameters were measured. Lubricant reduced RDP for fillers with plastic/brittle behavior(s), (p0.05), while increased RDP for fillers with plastic/elastic behavior, (p0.05), leading to higher tendency for capping in the later fillers. Binder reduced RDP for the fillers, (p0.05), hence, decreased capping probability. By increasing drug loading for fillers with plastic/elastic behavior(s), RDP was increased, (p = 0.00001), leading to capping, especially at high compaction pressure and speed. Die-wall instrumentation was useful in investigating formulation variables and detecting capping during high speed tableting.

During tableting, capping is a problem of cohesion while sticking is a problem of adhesion. Sticking is a multi-composite problem; causes are either material or machine related. Nowadays, detecting such a problem is a pre-requisite in the early stages of development. The aim of our study was to investigate sticking by radial die-wall pressure monitoring guided by compaction simulation. This was done by using the highly sticking drug; Mefenamic acid (MA) at different drug loadings with different fillers compacted at different pressures and speeds. By increasing MA loading, we found that viscoelastic fillers showed high residual radial pressure after compaction while plastic/brittle fillers showed high radial pressure during compaction, p 0.05. Visually, plastic/brittle fillers showed greater tendencies for adhesion to punches than viscoelastic fillers while the later showed higher tendencies for adhesion to the die-wall. This was confirmed by higher values of axial stress transmission for plastic/brittle than viscoelastic fillers (higher punch surface/powder interaction), and higher residual die-wall and ejection forces for viscoelastic than plastic/brittle fillers, p 0.05. Take-off force was not a useful tool to estimate sticking due to cohesive failure of the compacts. Radial die-wall pressure monitoring is suggested as a robust tool to predict sticking.

In tablet manufacturing, less attention is paid to the measurement of die-wall pressure than to force-displacement diagrams.Therefore, the aim of this study was to investigate radial stress change during pharmaceutical compaction.The Presster(TM), a tablet-press replicator, was used to characterize compaction behavior of microcrystalline cellulose (viscoelastic), calcium hydrogen phosphate dihydrate (brittle), direct compressible mannitol (plastic), pre-gelatinized starch (plastic/elastic), and spray dried lactose monohydrate (plastic/brittle) by measuring radial die-wall pressure; therefore powders were compacted at different (pre) compaction pressures as well as different speeds. Residual die-wall pressure (RDP) and maximum die-wall pressure (MDP) were measured. Various tablet physical properties were correlated to radial die-wall pressure.With increasing compaction pressure, RDP and MDP (P0.0001) increased for all materials, with increasing precompaction RDP decreased for plastic materials (P0.05), whereas with increasing speed MDP decreased for all materials (P0.05). During decompression, microcrystalline cellulose and pre-gelatinized starch showed higher axial relaxation, whereas mannitol and lactose showed higher radial relaxation, calcium hydrogen phosphate showed high axial and radial relaxations. Plastic and brittle materials showed increased tendencies for friction because of high radial relaxation.Die-wall monitoring is suggested as a valuable tool for characterizing compaction behavior of materials and detecting friction phenomena in the early stage of development.

Investigating particle properties such as shape and size is important in understanding the deformation behavior of powder under compression during tableting. Particle shape and size control the pattern of powder rearrangement and interaction in the die and so the final properties of the compact. The aim of this study was to examine the effect of particle size and shape on compactability. Particle friction and adhesion were investigated through radial die-wall (RDW) pressure monitoring. To fulfill this aim, powders and granules of different sizes and shapes of materials with different compaction behaviors were used. Compaction simulation using the Presster with an instrumented die was applied. Small particle size increased residual die-wall pressure (RDP) and maximum die-wall pressure (MDP) (p

Various modeling techniques have been applied to analyze fluidized-bed granulation process. Influence of various input parameters (product, inlet and outlet air temperature, consumption of liquid-binder, granulation liquid-binder spray rate, spray pressure, drying time) on granulation output properties (granule flow rate, granule size determined using light scattering method and sieve analysis, granules Hausner ratio, porosity and residual moisture) has been assessed. Both conventional and novel modeling techniques were used, such as screening test, multiple regression analysis, self-organizing maps, artificial neural networks, decision trees and rule induction. Diverse testing of developed models (internal and external validation) has been discussed. Good correlation has been obtained between the predicted and the experimental data. It has been shown that nonlinear methods based on artificial intelligence, such as neural networks, are far better in generalization and prediction in comparison to conventional methods. Possibility of usage of SOMs, decision trees and rule induction technique to monitor and optimize fluidized-bed granulation process has also been demonstrated. Obtained findings can serve as guidance to implementation of modeling techniques in fluidized-bed granulation process understanding and control.

Roll compaction was applied for the preparation of hydroxypropyl cellulose (HPC)-based sustained-release matrix tablets. Matrix tablets made via roll compaction exhibited higher dosage uniformity and faster drug release than direct-compacted tablets. HPC viscosity grade, roll pressure, and milling speed affected tablet properties significantly. Roll compaction seems to be an adequate granulation method for the preparation of HPC-based matrix tablets due to the simplicity of the process, less handling difficulty from HPC tackiness as well as easier particle size targeting. Selecting the optimum ratio of plastic excipients and the particle size of starting materials can however be critical issues in this method.

The aim of this study was to characterize the variability of commercial carbamazepine (CBZ) samples and to investigate the influence of two commonly used tablet fillers, i.e., mannitol and microcrystalline cellulose (MCC) on the CBZ sample variability. Polymorphism and morphology of CBZ samples were analyzed by differential scanning calorimetry, X-ray powder diffraction, sieve analysis, and scanning electron microscopy. Drug release from CBZ samples and binary mixtures (30-90% drug load) was characterized by a unidirectional dissolution method measuring disk intrinsic dissolution rate (DIDR) and drug release, respectively. All CBZ samples were of p-monoclinic form but differed in their polymorphic purity, particle size, morphology and intrinsic dissolution rate. Two characteristic inflection points, determined in the DIDR profiles, characterized the specific transformation behavior of each CBZ sample. The variability in CBZ samples was also exhibited in the drug release profiles from their binary mixtures. Mannitol increased initial drug release of CBZ samples up to 10-fold in mixtures of 30% drug load. The presence of MCC resulted in reduced variability in drug release. The unidirectional dissolution method is presented as a straightforward monitoring tool to characterize variability of CBZ raw materials and effect of tablet fillers.

Near-infrared spectroscopy offers tremendous advantages for pharmaceutical manufacturing as a fast and nondestructive method of quantitative and qualitative analysis. Content uniformity (end-product analytics) and process analytics are two important applications of the method. Diffuse reflection (DR) information depth (vertical sampling span) assessment is of equal importance in content prediction applications and to understand the effect of inhomogeneities in the sample. Three experiments were conducted: (a) 0.5 to 10.0 mm incremental thickness MCC tablets with constant porosity, (b) MCC/phenylbutazone (PBZ) double-layered (DL) tablets (PBZ layer 0%-100% in 0.5 mm steps), and (c) Comparison of placebo and 30% caffeine tablet cores with incremental film coating (film thickness of 0-0.35 mm). Incremental thickness and cluster analysis of DL tablets showed that DR information depth was0.5 mm, whereas the data fitting from incremental coating showed that signal drop reached 50% at 0.05 to 0.07 mm, depending on the wavenumber and 90% signal drop (10% information content) can be seen between 0.20 and 0.25 mm without extrapolation. These results mean that DR mode for pharmaceutical tablets obtains spectral information from the very surface, and radiation is barely reflected back from beyond thin-film coatings, making it less useful than diffuse transmission mode for core content analysis, especially for thick-coated, multilayer, multicore, or highly inhomogeneous tablets.

The effect of roller compaction on disintegration time, dissolution rate and compressibility of tablets prepared from Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate was studied. In addition, the influence of adding microcrystalline cellulose, a commonly used excipient, in mixtures with these materials was investigated. Theophylline anhydrate powder was used as a model drug to investigate the influence of different compaction pressures on the tablet properties. Tablets with same porosity were prepared by direct compaction and by roller compaction/re-compaction. Compressibility was characterized by Heckel and modified Heckel equations. Due to the property of polymorphic materials to change their form during milling and compression, X-ray diffraction analysis of Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate powders and granules was carried out. After roller compaction the disintegration time and the dissolution rate of the tablets were significantly improved. Compressibility of Theophylline anhydrate powder and Theophylline anhydrate fine powder was decreased, while Theophylline monohydrate showed higher compressibility after roller compaction. Microcrystalline cellulose affected compressibility of Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate whereby the binary mixtures showed higher compressibility than the individual materials. X-ray diffraction analyses confirmed that there were no polymorphic/pseudopolymorphic changes after roller compaction.

The purpose of the study was to screen the effects of formulation factors on the in vitro release profile of diclofenac sodium from matrix pellets compressed into multiple unit pellet system (MUPS) tablets using design of experiment (DOE). Extended release of diclofenac sodium was accomplished using Carbopol (R) 71G as matrix substance. According to Fractional Factorial Design FFD 2(3-1) four formulations of diclofenac sodium MUPS matrix tablets were prepared. The process of direct pelletization and subsequently compression of the pellets into tablets was applied in order to investigate a different approach in formulation of matrix systems and to achieve a better control of the process factors over the principal response - the release of the drug. The investigated factors were X-1-the percentage of polymer Carbopol (R) 71G, X-2-crushing strength of the tablet and X-3-different batches of the diclofenac sodium. In vitro dissolution time profiles at 6 different sampling times were chosen as responses. Results of drug release studies indicated that drug release rates vary between different formulations, with a range of 1 to 8 h to complete dissolution. The most important impact on the drug release hart factor X-1-the percentage of polymer Carbopol (R) 71G. The polymer percentage is suggested as release regulator for diclofenac sodium release from MUPS matrix tablets. All other investigated factors had no significant influence on the release profile of diclofenac sodium.

The aim of the present study was to investigate the effect of the variability of commercially available carbamazepine (CBZ) samples on the intrinsic dissolution behavior in order to recommend a strategy to maintain product quality by monitoring the variability of critical parameters of the bulk drug. Extensive physical characterization of nine anhydrous CBZ samples from three different sources and their respective dihydrates showed that the commercial anhydrous CBZ samples exhibited the same polymorphic form, but different morphology and particle size distribution which led to a variation in the kinetics of conversion from anhydrous to the dihydrate CBZ and therefore to variation in the kinetics of solubility. Disc intrinsic dissolution rate (DIDR) tests showed different intrinsic dissolution behavior of the samples, whereby the transition points of anhydrous to dihydrate conversion varied between 15 and 25 min. On the other hand, converting the anhydrous CBZ's to dihydrate eliminated the variation in intrinsic dissolution behavior. Tablets of the different CBZs and Ludipress were prepared by direct compression. The amount of CBZ dissolved after 15 min showed the same rank order as the rank order of the transition points determined by intrinsic dissolution test. Therefore, the intrinsic dissolution test with specific acceptance criteria can be a valuable and simple tool for monitoring, respectively reducing the variability of the CBZ bulk material.

Topical therapies for nail diseases are limited by keratinized cells in the human nail plate. An optimal permeation enhancer would not only improve drug delivery through the nail plate, but would also open new possibilities for treating neighboring target sites if systemic circulation is reached. The aim of the present work was to identify permeation enhancers and to improve the understanding of physicochemical parameters that influence drug permeation. Caffeine served as the model drug, and formulations were prepared in water and 20% (v/v) ethanol/water solutions. Tested enhancers were urea, dimethyl sulfoxide (DMSO), methanol, N-acetyl- l -cysteine (NAC), docusate sodium salt (DSS), boric acid, and fungal proteins, such as hydrophobins. Permeability studies employed cadaver nails in modified Franz-type diffusion cells. The permeability coefficient of caffeine in ethanol/water was determined to be 1.56E−08 cm/s and was improved to 2.27E−08 cm/s by the addition of NAC. Formulations containing either methanol or DMSO showed the highest permeability coefficients in the range of 5–7.5E−08 cm/s. Enhancers could be classified according to their permeation enhancement: methanol > class II hydrophobins > DMSO > followed by class I hydrophobins and urea. Ethanol at a concentration of 20% (v/v) in water did not influence swelling of nail samples. Hydrophobins are suggested to be efficient in drug delivery through the nail plate.

The main objective of this study was to demonstrate the possible use of dynamic neural networks to model diclofenac sodium release from polyethylene oxide hydrophilic matrix tablets. High and low molecular weight polymers in the range of 0.9-5 x 10(6) have been used as matrix forming materials and 12 different formulations were prepared for each polymer. Matrix tablets were made by direct compression method. Fractions of polymer and compression force have been selected as most influential factors on diclofenac sodium release profile. In vitro dissolution profile has been treated as time series using dynamic neural networks. Dynamic networks are expected to be advantageous in the modeling of drug release. Networks of different topologies have been constructed in order to obtain precise prediction of release profiles for test formulations. Short-term and long-term memory structures have been included in the design of network making it possible to treat dissolution profiles as time series. The ability of network to model drug release has been assessed by the determination of correlation between predicted and experimentally obtained data. Calculated difference (f(1)) and similarity (f(2)) factors indicate that dynamic networks are capable of accurate predictions. Dynamic neural networks were compared to most frequently used static network, multi-layered perceptron, and superiority of dynamic networks has been demonstrated. The study also demonstrated differences between the used polyethylene oxide polymers in respect to drug release and suggests explanations for the obtained results.

The moist agglomeration process, i.e., the wet massing, screening and subsequent drying is often a critical unit operation. The correct amount of granulating liquid and the correct monitoring and detection of the granulation kinetics are important issues. The method to monitor the kinetics needs to be robust and should be applicable for any batch size. In this context, the theory of scale-up and the monitoring of the moist agglomeration process are reviewed. It has to be kept in mind that the production of granules in the pharmaceutical industry is still based on a batch concept. This concept offers many advantages with respect to quality assurance as a batch can be accepted or rejected. From experience, it is well known, however, that the scale-up of the batch size may lead to problems. This fact is due to the variety of the equipment involved and to the fact that there is a lack of well-known “scale-up invariant” parameters. A survey of the granulation endpoint detection procedure shows that the majority of the equipment manufacturers offer mixer/kneaders for the moist agglomeration process instrumented with a power consumption device. In the following chapter, this and other approaches are discussed and emphasis is put on how to best use the power consumption method. The question of robust formulations leads to the conclusion that, for a robust dosage form design, new concepts such as percolation theory have to be applied. A typical example is presented, which illustrates the effect of a percolation phenomenon.

Since 2001, the Institute of Pharmaceutical Technology (IPT) at the University of Basel and the Mendeleyev University of Chemical Technology of Russia (MUCTR) have established an institutional partnership (IP), which is supported by the Swiss National Science Foundation (SNF) in the framework of the SCOPES (Scientific Cooperation between Eastern Europe and Switzerland) project. The results of this collaboration are the new teaching technologies that were introduced at the MUCTR and the IPT. The former include multimedia lectures in pharmaceutical technology, which are held in parallel at University of Basel and MUCTR, and the educational web-portal 'Pharmacy online', which was awarded a medal at the 4th Moscow International Salon of Innovations. The multimedia lectures are popular with and helpful for MUCTR students, because they can compensate to a certain extent the lack of equipment at the MUCTR. However, multimedia lectures can never replace hands-on training and therefore the continuation of the collaboration is ongoing. In this respect SNF decided in 2005 to give continuous support for this cooperation through the grant entitled 'New Concepts in Training Industrial Pharmacists and Pharmaceutical Engineers to Be Developed and Implemented at the Russian-Swiss Scientific and Education Centre in MUCTR'. This centre was established as a result of the previous grant. The development and implementation of a unique and innovative learning concept on the basis of the Russian-Swiss scientific and educational centre involving the Russian pharmaceutical and biotechnological industry, is an ongoing activity.

The interaction of liposome formulations, prepared with phospholipids of different origins (egg and soya), with skin were compared in terms of their effects on skin water content, skin barrier function, and skin elasticity. Short-term effect of four different liposome formulations and two references during 3.5 h was investigated non-occlusively on the volar side of the forearm of 10 volunteers, ranging in age from 24 to 32 years. Liposomes composed of different phospholipids showed differing effects on skin humidity. The maximal effect was achieved within 30 min and constant values were reached after 1.5 h for all formulations, however values remained significantly higher than without treatment (p

The large and varied multigene families of tissue kallikreins of rat and mouse are considered to selectively release as many bioactive peptides. In order to determine whether a similar family of enzymes is expressed in the organs of the guinea pig purification studies were performed. Tissue kallikreins from the submandibular gland, coagulating gland/prostate complex and the pancreas were separated by affinity chromatography on benzamidine-Sepharose. Amino-terminal sequences, the patterns of hydrolysis rates of a number of peptide p-nitroanilides, inactivation rates by active site-directed irreversible inhibitors, specific kininogenase activities and types of kinin released were used to probe the identity of the isolated enzymes. Guinea pig tissue kallikreins 1 and 2 have been reported previously. In the present study we have identified a third type, designated tissue kallikrein 1a because of its sequence similarity to kallikrein 1, which differs from the latter in the catalytic properties. The inferred occurrence of not more than two or three independent tissue kallikrein genes in the guinea pig contrasts with the varied family of enzymes expressed by the large number of such genes present in rats and mice. Expression in the guinea pig (and also in humans) of only a small number of tissue kallikreins makes specific processing of a multitude of biologically active peptides by such enzymes unlikely.