Miriam Pein

Development of a Taste-Masked Orodispersible Film Containing Dimenhydrinate

Orodispersible dosage forms are promising new approaches for drug delivery. 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 pediatric population. Formulations were investigated by X-ray diffraction, scanning electron and polarized light microscopy. Additionally, two commercially available electronic taste sensing systems were used to investigate the applied taste-masking strategies. 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 and complexing agent. All ODFs showed fast disintegration depending on the characterization method. In order to get taste information, the dimenhydrinate formulations were analytically compared to pure drug and drug-free formulations by electronic tongues. Results obtained from both systems are comparable and were used together for the first time. It was possible to develop an ODF of dimenhydrinate that is fast disintegrating even in small volumes of liquid. Furthermore, in vitro taste assessment by two electronic tongues revealed taste-masking effects by the excipients.

Taste-masking assessment of solid oral dosage forms--a critical review.

Approaches to improve the taste of oral dosage forms that contain unpleasant tasting drugs are versatile. Likewise, the analytical in vitro and in vivo methods to assess taste-masking efficacy are diverse. Taste-masking has gained in importance since the EU legislation on medicines for children came into force in 2007, and taste-masking attributes are often required by regulatory authorities. However, standardized guidance for the analytical evaluation is still poor. Published protocols rarely consider real conditions, such as the volume of saliva or the residence time of solid oral dosage forms in the mouth. Methodological limitations and problems regarding time point of evaluation, sampling or sample pretreatment are hardly ever addressed. This critical review aims to evaluate and discuss published strategies in this context.

Reverse Fosmidomycin Derivatives against the Antimalarial Drug Target IspC (Dxr).

Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot experiments have demonstrated in vivo potential.

α-Substituted β-Oxa Isosteres of Fosmidomycin: Synthesis and Biological Evaluation

Specific inhibition of enzymes of the non-mevalonate pathway is a promising strategy for the development of novel antiplasmodial drugs. α-Aryl-substituted β-oxa isosteres of fosmidomycin with a reverse orientation of the hydroxamic acid group were synthesized and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of Plasmodium falciparum and for their in vitro antiplasmodial activity against chloroquine-sensitive and resistant strains of P. falciparum . The most active derivative inhibits IspC protein of P. falciparum (PfIspC) with an IC(50) value of 12 nM and shows potent in vitro antiplasmodial activity. In addition, lipophilic ester prodrugs demonstrated improved P. falciparum growth inhibition in vitro.

New protocol for αAstree electronic tongue enabling full performance qualification according to ICH Q2.

Performance qualification (PQ) of taste sensing systems is mandatory for their use in pharmaceutical industry. According to ICH Q2 (R1) and a recent adaptation for taste sensing systems, non-specificity, log-linear relationships between the concentration of analytes and the sensor signal as well as a repeatability with relative standard deviation (RSD) values <4% were defined as basic requirements to pass a PQ. In the present work, the αAstree taste sensing system led to a successful PQ procedure by the use of recent sensor batches for pharmaceutical applications (sensor set #2) and a modified measurement protocol. Log-linear relationships between concentration and responses of each sensor were investigated for different bitter tasting active pharmaceutical ingredients (APIs). Using the new protocol, RSD values <2.1% were obtained in the repeatability study. Applying the visual evaluation approach, detection and quantitation limit could be determined for caffeine citrate with every sensor (LOD 0.05-0.5 mM, LOQ: 0.1-0.5 mM). In addition, the sensor set marketed for food applications (sensor set #5) was proven to show beneficial effects regarding the log-linear relationship between the concentration of quinine hydrochloride and the sensor signal. By the use of our proposed protocol, it is possible to implement the αAstree taste sensing system as a tool to assure quality control in the pharmaceutical industry.

Roll compaction of mannitol: Compactability study of crystalline and spray-dried grades

Purpose of this project was to investigate the roll compaction behavior of various mannitol grades. Therefore, five spray-dried grades as well as unprocessed β-d-mannitol were roll compacted with different compaction forces. The resulting granules were characterized with regard to their particle size distribution, flow properties, and BET surface area and compressed to tablets. Granules of unprocessed mannitol, even when applying high compaction forces during dry granulation, were characterized by a high amount of fines (about 21%), a small surface area (0.83 m(2)/g), and solely fair flowability (ffc=7.2). Tablets revealed either high friability or insufficient disintegration behavior. However, the use of spray-dried mannitol led to better results. Granules showed improved flow properties and a reduced amount of fines. Robust tablets with low friability were produced. Within the various spray-dried grades huge differences concerning the compactability were observed. Large BET surface areas of the granules resulted in advanced tensile strengths of the tablets, but acceptable disintegration behavior was maintained. These findings are relevant for the development of mannitol based drug formulations, in particular (oro)dispersible tablets containing a low dose or poor flowing active pharmaceutical ingredient, where direct compression is inappropriate and a granulation process prior to tableting is mandatory.

Interlaboratory testing of Insent e-tongues

The first interlaboratory testing of electronic taste sensing systems was performed within five participating centers, each working with the Insent (Insent Inc., Atsugi-Shi, Japan) e-tongue. Preparation of the samples for the comprised four experiments, shipping of the samples and evaluation of the results was performed at the University of Duesseldorf. The sensitivity (in this case the difference between lowest and highest sensor response) and slope of the regression line values, obtained within Experiment 1 and 2, have been found to serve as applicable evaluation criterions for interlaboratory comparability. Modified sensor responses could be attributed to aged sensors, but did not influence the results of either Experiment 3, dealing with the evaluation of film formulations, or Experiment 4, dealing with the evaluation of minitablet formulations, in a great amount. Presented PCA Score and Loading Scatter Plots as well as Euclidean distance patterns based on the raw sensor responses confirmed the comparable performance of Insent e-tongues of the participating centers.

Lean production of taste improved lipidic sodium benzoate formulations

Sodium benzoate is a highly soluble orphan drug with unpleasant taste and high daily dose. The aim of this study was to develop a child appropriate, individually dosable, and taste masked dosage form utilizing lipids in melt granulation process and tableting. A saliva resistant coated lipid granule produced by extrusion served as reference product. Low melting hard fat was found to be appropriate as lipid binder in high-shear granulation. The resulting granules were compressed to minitablets without addition of other excipients. Compression to 2mm minitablets decreased the dissolved API amount within the first 2 min of dissolution from 33% to 23%. The Euclidean distances, calculated from electronic tongue measurements, were reduced, indicating an improved taste. The reference product showed a lag time in dissolution, which is desirable for taste masking. Although a lag time was not achieved for the lipidic minitablets, drug release in various food materials was reduced to 2%, assuming a suitable taste masking for oral sodium benzoate administration.

Spheronization of solid lipid extrudates: A novel approach on controlling critical process parameters.

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

Applicability of two automated disintegration apparatuses for rapidly disintegrating (mini)tablets

Abstract Objectives: Orally disintegrating (mini)tablets (OD(M)Ts) are of interest in the field of pharmaceutics. Their orodispersible character is defined by the disintegration time, which is measured with a basket apparatus according to the European Pharmacopoeia. This method, however, lacks applicability for ODTs and especially ODMTs. New disintegration apparatuses have been described in literature, but a qualification to assess the applicability has not been described. A qualification procedure for two automated disintegration apparatuses, OD-mate and Hermes apparatus, is introduced. Methods: Aspects of the operational qualification as well as precision and accuracy regarding a performance qualification were evaluated for both apparatuses analog to the ICH guideline Q2. While the OQ study is performed separately for each apparatus, accuracy and precision were performed following the same protocol for both testers. Key findings: Small RSDs (16.9% OD-mate; 15.2% Hermes compared to 32.3% for the pharmacopeial method) were found despite very fast disintegration times (1.5 s for both apparatuses). By comparing these RSDs to practical examples, the authors propose threshold values for repeatability depending on the mean disintegration time. Obtained results from the qualification were used to assess the applicability of both apparatuses.