Research Interests: Engineering, Image Analysis, Response Surface Methodology, Process Engineering, Process Analytical Technology, and 14 moreProfitability, Statistical Significance, Impeller, Robustness (evolution), Pharmaceutical Innovation, Taguchi method, Temperature Dependence, Particle Size, Process Development, Flow Rate, Process Parameters, Particle Size Distribution, Response Surface Method, and Pharmacology and pharmaceutical sciences
Research Interests: Materials Science, Rheology, Pharmaceutical Technology, Scanning Electron Microscopy, Medicine, and 15 moreIn Vitro, Excipient, Albendazole, Powder, Particle Size, Scanning Electron Microscope, Shear, Powders, Lactose, Materials Testing, Flow Properties, Excipients, Theoretical Model, Fine Particles, and Pharmacology and pharmaceutical sciences
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Lipid-based systems have many advantages in formulation of poorly water-soluble drugs but issues of a limited solvent capacity are often encountered in development. One of the possible solubilization approaches of especially basic drugs... more
Lipid-based systems have many advantages in formulation of poorly water-soluble drugs but issues of a limited solvent capacity are often encountered in development. One of the possible solubilization approaches of especially basic drugs could be the addition of fatty acids to oils but currently, a systematic study is lacking. Therefore, the present work investigated apparently neutral and basic drugs in medium chain triglycerides (MCT) alone and with added either caproic acid (C6), caprylic acid (C8), capric acid (C10) or oleic acid (C18:1) at different levels (5 - 20%, w/w). A miniaturized solubility assay was used together with X-ray diffraction to analyze the residual solid and finally, solubility data were modeled using the conductor-like screening model for real solvents (COSMO-RS). Some drug bases had an MCT solubility of only a few mg/ml or less but addition of fatty acids provided in some formulations exceptional drug loading of up to about 20% (w/w). The solubility changes were in general more pronounced the shorter the chain length was and the longest oleic acid even displayed a negative effect in mixtures of celecoxib and fenofibrate. The COSMO-RS prediction accuracy was highly specific for the given compounds with root mean square errors (RMSE) ranging from an excellent 0.07 to a highest value of 1.12. The latter was obtained with the strongest model base pimozide for which a new solid form was found in some samples. In conclusion, targeting specific molecular interactions with the solute combined with mechanistic modeling provides new tools to advance lipid-based drug delivery.
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The scope of the present article is to study formulation parameters of micellar and of lipid delivery systems on the exposure of a new drug compound A in Wistar rats. A statistical analysis is to be performed a posteriori from a data set... more
The scope of the present article is to study formulation parameters of micellar and of lipid delivery systems on the exposure of a new drug compound A in Wistar rats. A statistical analysis is to be performed a posteriori from a data set of all rat studies that were conducted during the preclinical development of the drug. Several formulations were evaluated mainly in view of sufficient exposure in toxicological studies. Because of the low solubility and high lipophilicity of compound A, the preclinical formulation development focused on micellar solutions and different kinds of lipid drug delivery systems. Candidate formulations were first tested for their dilution in artificial intestinal fluids before they were evaluated in the rat. A partial least square model was applied to the entire pharmacokinetic data set, and the type of delivery system, as well as excipients, were investigated in view of effects on the area under the plasma level curve. The results showed that self-emulsifying systems and in particular self-microemulsifying drug delivery systems were most effective in pushing the exposure of compound A. Another significant factor was the dose. A data subset showed nonlinearity in the pharmacokinetics with respect to the dose. However, the most important findings of the multivariate data analysis were overall effects of excipients on the exposure. These effects are considered as a sum of several influences so that the underlying mechanism is essentially complex and is not fully understood. Cremophor and lecithin exhibited a positive effect, whereas TPGS containing systems reached only below average exposure. No significant effect was observed with polysorbate 80 or Solutol HS. The model indicated the favorable use of a cosurfactant, in particular Capmul MCM. Similarly the use of a cosolvent showed a positive coefficient and ethanol was here best in class. No marked effects were observed for the oil selection, but a tendency toward below average exposure was displayed when long-chain triglycerides were in the formulation. The a posteriori analysis of the pharmacokinetic data using multivariate statistical models was very helpful to clarify effects of drug delivery systems as well as of general effects of excipients. Guidance was provided for the formulator, but further studies are needed to better understand the complex effects on a mechanistic level.
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Research Interests: Chemistry, Analytical Chemistry, Pharmaceutical Technology, Drug Delivery System, Medicine, and 15 moreCalibration, Optical fiber sensor, Drug Delivery Systems, Prediction error, High Pressure Liquid Chromatography, High Resolution, Analytical Method, Emulsions, Capsules, Fenofibrate, Molecular Structure, Indomethacin, Pharmaceutical preparations, Pharmacology and pharmaceutical sciences, and limit of detection
The aim of the present study was to analyze the impact of lipid-based formulation (LBF) dispersion and digestion on the precipitation behavior of weakly basic drugs. Loratadine and carvedilol were formulated in a range of LBFs and drug... more
The aim of the present study was to analyze the impact of lipid-based formulation (LBF) dispersion and digestion on the precipitation behavior of weakly basic drugs. Loratadine and carvedilol were formulated in a range of LBFs and drug solubilization was analyzed under simulated dispersive and digestive conditions (fasted state). The extent of supersaturation and drug precipitation as well as the solid-state properties and redissolution behavior of precipitated drugs were assessed. X-ray powder diffraction indicated that carvedilol precipitated in a crystalline form upon dispersion, but interestingly, this drug gave an amorphous precipitate during lipolysis. In contrast, loratadine precipitated as crystalline material during both formulation dispersion and digestion. No influence of the formulation composition on the type of precipitation was observed. These results suggested that in vitro conditions (dispersive versus digestive) largely influenced the solid-state properties of precipitating weak bases. Solid-state characterization of precipitated drugs under different experimental conditions should be routinely performed in formulation screening to better understand the biopharmaceutical behavior of LBFs. Hence, these findings are of high practical importance for the pharmaceutical development and in vitro assessment of LBFs using weakly basic drugs.
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Research Interests: Chemistry, Water, Pharmaceutical Chemistry, Medicine, Pharmacology and Clinical pharmacy, and 15 moreDrug Delivery Systems, Excipient, Solubility, Precipitation, Chemical Precipitation, X ray diffraction, Surface Active Agents, Excipients, Pulmonary Surfactant, Fenofibrate, Solvents, Pharmaceutical preparations, Dilution, Pharmacology and pharmaceutical sciences, and Supersaturation
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Research Interests: Materials Science, Modeling, Polymers, Medicine, Dosage Form, and 14 morePolymer, Porosity, Pharmaceutical Sciences, Temperature, Pressure, Compression, Theoretical Models, Compaction, Tablets, Bulk Density, Excipients, Physical Properties, Equation of State, and Pharmacology and pharmaceutical sciences
Quality by design is an important concept, but only limited research has been invested in concentrated pharmaceutical suspensions. A need exists for novel analytical tools to thoroughly characterize the drug as well as its aggregated... more
Quality by design is an important concept, but only limited research has been invested in concentrated pharmaceutical suspensions. A need exists for novel analytical tools to thoroughly characterize the drug as well as its aggregated particle structure in suspension. This work focuses on lipid-based pharmaceutical suspensions for filling of capsules. A rheological approach, namely the fractal concept of flocculation, is introduced to the pharmaceutical field. The model drug mebeverine hydrochloride was first physicochemically analyzed. A special aim was to study the surface energy profiles using inverse gas chromatography as a critical characteristic for the suspension's rheological behavior. Suspensions were manufactured in laboratory process equipment while applying different homogenization speeds. Flow curves of the final suspensions were measured using a cone-and-plate rheometer. As a result, surface energy profiles revealed differences from one mebeverine lot to another. Different homogenization intensities greatly affected the viscosity and the Mooney model was able to predict experimental values as a function of the drug volume fraction. The fractal concept of flocculation characterized mebeverine in suspension and a slight increase of fractal dimension was noted when homogenization speed was increased. It was concluded that the introduced concepts have large potential for designing quality into concentrated pharmaceutical suspensions.
Research Interests: Materials Science, Chromatography, Rheology, Fractals, Medicine, and 13 moreLipids, Pharmaceutical Sciences, Flocculation, Viscosity, Suspensions, Particle Size, Surface Properties, Parasympatholytics, Fractal Dimension, Capsules, Rheometer, Phenethylamines, and Pharmacology and pharmaceutical sciences
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The purpose of this investigation was to analyze the modified Young's modulus of microcrystalline cellulose tablets at comparatively low relative densities, based on concepts of percolation theory. Tablets were prepared and tested... more
The purpose of this investigation was to analyze the modified Young's modulus of microcrystalline cellulose tablets at comparatively low relative densities, based on concepts of percolation theory. Tablets were prepared and tested using a Zwick 1478 universal testing instrument. For statistical evaluation a new method is introduced for power laws, which exhibits highly correlated model parameters. According to our results the model Leuenberger, Leu is consistent with an Effective Medium Approximation which exhibits an exponent equal to one far away from the percolation threshold. In addition, the results show that it is essential to evaluate the elastic behavior of tablets close to the percolation threshold. For the different types of MCC a critical exponent q = 3.95 +/- 0.14 was obtained. This result is very essential, as it is in good agreement with the theoretically expected value of 3.9 from an elastic network (central force model). The proposed model describes the modified Young's modulus better than former model equations taking into account the relative density. Thus, the process during uniaxial compaction can be imagined as a directed continuum percolation and the relative density of compacts can be identified as a space-occupation probability density phi yielding reasonable percolation thresholds.
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During the last decade the evolution of the pharmaceutical dosage form design has been important. In controlled release matrix tablets, the tensile strength is an essential parameter to consider, because a minimal mechanical strength is... more
During the last decade the evolution of the pharmaceutical dosage form design has been important. In controlled release matrix tablets, the tensile strength is an essential parameter to consider, because a minimal mechanical strength is needed for tablet production, handling and avoidance of any dose dumping during its use. Recent developments in percolation theory led to the theoretical proposal of lattice strength that was applied to the tensile strength of tablets. This mechanical property was described as a power law of the relative density involving a critical value that corresponds to the percolation threshold. The objective of the present work is to estimate these mechanical thresholds in KCl-Ethocel100 tablets that were manufactured from different sieve fractions (100-150, 150-200, 250-300 microm). Three power law models are compared regarding the best fit of the tensile strength-relative density profiles. The main criteria for this choice are the Akaike's Information Criterion (AIC), the analysis of the residuals in conjunction with the soundest physical meaning of the models. Accordingly, a power law model was chosen that assumes an initial strength parameter. No correlation could be established between the different mixture ratios or sieve fractions with the critical relative densities. The study showed that an equation based on percolation theory can adequately model tablet strength-density profiles from matrix tablets.
Research Interests: Mathematics, Algorithms, Medicine, Cellulose, Controlled release, and 15 morePower Law, Mathematical Model, Relative Density, Percolation threshold, Particle Size, Tablets, Tensile Strength, Drug Compounding, Percolation Theory, Potassium Chloride, Ultimate Tensile Strength, Mechanical Property, Mechanical strength, Critical value, and Pharmacology and pharmaceutical sciences
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Research Interests: Chemistry, Microstructure, Small angle X-ray and neutron scattering, Rheology, Small Angle X Ray Scattering, and 15 moreStarch, Pharmaceutical Chemistry, Medicine, Dosage Form, Pharmaceutical, Gelatin, X ray diffraction, Polyvinyl alcohol, Particle Size, Emulsions, Capsule, Capsules, Delayed-Action Preparations, Fenofibrate, and Pharmacology and pharmaceutical sciences
Oral delivery of biologicals is a thriving field in pharmaceutics and the first challenge is to achieve a stable drug product. Interesting is prilling of a drug-containing polymeric solution as microgel into an aqueous hardening bath... more
Oral delivery of biologicals is a thriving field in pharmaceutics and the first challenge is to achieve a stable drug product. Interesting is prilling of a drug-containing polymeric solution as microgel into an aqueous hardening bath where crosslinking occurs. However, to deliver a final dosage form, for example, soft gelatin capsules, the aqueous hardening bath must be removed, thus leading to manufacturing processes that are potentially harmful for the active. The current work introduces a prilling method with a lipid-based hardening bath, which could theoretically be filled directly into capsules. Bovine serum albumin (BSA) and mono-N-carboxymethyl chitosan (MCC) were selected as model biological and encapsulating polymer, respectively. Several nonaqueous formulations of the receiving bath were investigated; calcium chloride was added to these formulations to allow the MCC gelling. The obtained microgels had average diameters of ∼300 μm and spherical to toroidal shapes, according to the hardening bath composition. Along with a high encapsulation efficiency (>85%), the microgels protected the BSA from any denaturing effect of the hardening bath. The release study showed a rather fast BSA release within the first 10 min from most microgels. This novel approach demonstrated technical viability for encapsulation of biologicals using lipid formulations regarding oral delivery.
Research Interests: Chemistry, Kinetics, Chitosan, Drug delivery, Medicine, and 15 morePharmaceutics, Lipids, Circular Dichroism, Pharmaceutical Sciences, Hardness, Gels, Pharmaceutical Formulation Technology, Bovine Serum Albumin, Aqueous Solution, Capsules, Drug Carriers, Drug Stability, Protein Denaturation, Pharmacology and pharmaceutical sciences, and Biological products
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Research Interests: Materials Science, Principal Component Analysis, Rheology, Starch, Medicine, and 15 moreQuality Control, Anisotropy, Cellulose, Switzerland, Particle Size, Surface Properties, Direct Shear Test, Powders, Lactose, Materials Testing, Excipients, Drug Compounding, Mannitol, Methylcellulose, and Pharmacology and pharmaceutical sciences
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There is a growing interest in drug-phospholipid complexes and similar formulations that are mostly solid dispersions with high drug load. This study aims to explore the feasibility of such phospholipid-based solid dispersions as well as... more
There is a growing interest in drug-phospholipid complexes and similar formulations that are mostly solid dispersions with high drug load. This study aims to explore the feasibility of such phospholipid-based solid dispersions as well as to characterize them. A particular aim was to compare monoacyl phosphatidylcholine (PC) with the diacyl excipient. The solid dispersions were manufactured using a solvent evaporation technique and characterized by means of differential scanning calorimetry and X-ray diffractometry. Density functional theory was used to calculate molecular frontier orbitals of the different compounds. Finally, the dissolution properties were analyzed in a flow-through cell by means of UV imaging. It was found that the ability to form solid dispersions with the phospholipids containing amorphous or solubilized drug (at equimolar ratio with the lipid) was dependent on the drug's frontier orbital energy, the enthalpy of fusion, as well as the log P value. In a subsequent dissolution study, UV imaging revealed pronounced surface swelling of the solid dispersions. Only the monoacyl PC was found to substantially enhance in vitro dissolution compared to pure drug. The gained understanding will support a future development of solid drug dispersions using phospholipids as matrix components.
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Research Interests: Chemistry, Biochemical Engineering, Pharmacokinetics, Drug delivery, Pharmaceutical Chemistry, and 15 moreMedicine, Drug, Lipids, Humans, Pharmaceutical Sciences, Drug Delivery Systems, Bioavailability, Solubility, Intestinal absorption, Chemical Precipitation, Drug Carriers, Biological Availability, Pharmaceutical preparations, Pharmacology and pharmaceutical sciences, and Supersaturation
Research Interests: Chemistry, Viscoelasticity, Rheology, Pharmaceutical Technology, Drug delivery, and 15 moreMedicine, Pharmaceutics, Lipids, Microrheology, Viscosity, Motion, Spectrum analysis, Emulsions, Elastic Modulus, Capsules, Drug Carriers, Rheometer, Excipients, Dynamic Mechanical Analysis, and Pharmacology and pharmaceutical sciences
This article focuses on the process analytical technology (PAT) of pharmaceutical dry milling. The first objective is to compare different modes of dynamic image analysis namely, on-line, in-line and at-line for monitoring powder milling.... more
This article focuses on the process analytical technology (PAT) of pharmaceutical dry milling. The first objective is to compare different modes of dynamic image analysis namely, on-line, in-line and at-line for monitoring powder milling. The second objective is to introduce time evolving size and shape analysis (TESSA). Thus, a conical mill was equipped with a dynamic image analysis system which consisted of a xenon flash light and charge-coupled device (CCD) camera. Different pharmaceutical excipients and granulates were chosen as models. The results from the on-line, in-line and the at-line measurement modes showed similar size distributions for the various materials studied, however differences were observed that were mainly attributed to sampling and dispersion. A high correlation of 0.975 (p<0.001) was observed between on-line d(50) and at-line d(50) when compared to 0.917 (p<0.001) between in-line d(50) and at-line d(50). The concept of TESSA was found to be useful in detecting changes in milling conditions including the successful detection of a damaged screen when intentionally introduced in the milling process. This monitoring approach of particle size and shape has potential to reduce product variability, facilitates process development, and ultimately helps in establishing quality by design concept for the manufacture of solid dosage forms.
Research Interests: Materials Science, Pharmaceutical Technology, Image Analysis, Medicine, Quality Control, and 11 morePharmaceutics, Process Analytical Technology, Quality by Design, Particle Size, Pharmaceutical Formulation Technology, Time Factors, Powders, Excipients, Drug Compounding, Shape Factor, and Pharmacology and pharmaceutical sciences
The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or... more
The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of approximately 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40 degrees C/ 50 degrees C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.