Methods for Estimating the Detection and Quantification Limits of Key Substances in Beer Maturation with Electronic Noses.

To evaluate the suitability of an analytical instrument, essential figures of merit such as the limit of detection (LOD) and the limit of quantification (LOQ) can be employed. However, as the definitions k nown in the literature are mostly applicable to one signal per sample, estimating the LOD for substances with instruments yielding multidimensional results like electronic noses (eNoses) is still challenging. In this paper, we will compare and present different approaches to estimate the LOD for eNoses by employing commonly used multivariate data analysis and regression techniques, including principal component analysis (PCA), principal component regression (PCR), as well as partial least squares regression (PLSR). These methods could subsequently be used to assess the suitability of eNoses to help control and steer processes where volatiles are key process parameters. As a use case, we determined the LODs for key compounds involved in beer maturation, namely acetaldehyde, diacetyl, dimethyl sulfide, ethyl acetate, isobutanol, and 2-phenylethanol, and discussed the suitability of our eNose for that dertermination process. The results of the methods performed demonstrated differences of up to a factor of eight. For diacetyl, the LOD and the LOQ were sufficiently low to suggest potential for monitoring via eNose.

Critical View on the Qualification of Electronic Tongues Regarding Their Performance in the Development of Peroral Drug Formulations with Bitter Ingredients.

In this review, we aim to highlight the advantages, challenges, and limitations of electronic tongues (e-tongues) in pharmaceutical drug development. The authors, therefore, critically evaluated the performance of e-tongues regarding their qualification to assess peroral formulations containing bitter active pharmaceutical ingredients. A literature search using the keywords 'electronic', 'tongue', 'bitter', and 'drug' in a Web of Science search was therefore initially conducted. Reviewing the publications of the past decade, and further literature where necessary, allowed the authors to discuss whether and how e-tongues perform as expected and whether they have the potential to become a standard tool in drug development. Specifically highlighted are the expectations an e-tongue should meet. Further, a brief insight into the technologies of the utilized e-tongues is given. Reliable protocols were found that enable (i) the qualified performance of e-tongue instruments from an analytical perspective, (ii) proper taste-masking assessments, and (iii) under certain circumstances, the evaluation of bitterness.

A Machine Learning Approach to Qualitatively Evaluate Different Granulation Phases by Acoustic Emissions.

Wet granulation is a frequent process in the pharmaceutical industry. As a starting point for numerous dosage forms, the quality of the granulation not only affects subsequent production steps but also impacts the quality of the final product. It is thus crucial and economical to monitor this operation thoroughly. Here, we report on identifying different phases of a granulation process using a machine learning approach. The phases reflect the water content which, in turn, influences the processability and quality of the granule mass. We used two kinds of microphones and an acceleration sensor to capture acoustic emissions and vibrations. We trained convolutional neural networks (CNNs) to classify the different phases using transformed sound recordings as the input. We achieved a classification accuracy of up to 90% using vibrational data and an accuracy of up to 97% using the audible microphone data. Our results indicate the suitability of using audible sound and machine learning to monitor pharmaceutical processes. Moreover, since recording acoustic emissions is contactless, it readily complies with legal regulations and presents Good Manufacturing Practices.

Compression Density as an Alternative to Identify an Optimal Moisture Content for High Shear Wet Granulation as an Initial Step for Spheronisation.

Pellet production is a multi-step manufacturing process comprising granulation, extrusion and spheronisation. The first step represents a critical control point, since the quality of the granule mass highly influences subsequent process steps and, consequently, the quality of final pellets. The most important parameter of wet granulation is the liquid requirement, which can often only be quantitatively evaluated after further process steps. To identify an alternative for optimal liquid requirements, experiments were conducted with a formulation based on lactose and microcrystalline cellulose. Granules were analyzed with a Powder Vertical Shear Rig. We identified the compression density (ρpress) as the said alternative, linking information from the powder material and the moisture content (R2 = 0.995). We used ρpress to successfully predict liquid requirements for unknown formulation compositions. By means of this prediction, pellets with high quality, regarding shape and size distribution, were produced by carrying out a multi-step manufacturing process. Furthermore, the applicability of ρpress as an alternative quality parameter to other placebo formulations and to formulations containing active pharmaceutical ingredients (APIs) was demonstrated.

Implementation of real-time and in-line feedback control for a fluid bed granulation process.

The application of process analytical technologies (PAT) to monitor critical quality attributes (CQAs) provides an important approach to enhance process understanding and improve the reliability of pharmaceutical production processes. The present study focuses on the first PAT based feedback control system for a fluid bed granulation batch process. Real-time particle size measurement by in-line spatial filtering technique (SFT) using a modified time-based buffer system was applied to define a target particle size after spraying a specific amount of binder solution. After identifying an appropriate control variable, a suitable strategy for feedback control was established, followed by tuning of the control loop to obtain best performance of the integrated system. By adapting the final target particle size within a specified range good functionality of the system could be demonstrated. Investigations of the robustness further showed that the implemented system enables the production of a predefined target particle size also by varying process and formulation parameters. The effect of increasing spray rates and binder concentrations on the particle size could be compensated in a given range by feedback control ensuring a predefined product quality. The study provides an advanced approach for quality assurance of fluid bed granulation.

Evaluation of in-line particle measurement with an SFT-probe as monitoring tool for process automation using a new time-based buffer approach.

The Process Analytical Technology (PAT) initiative published by the Food and Drug administration (FDA) describes PAT systems as important tools to optimize pharmaceutical processes in order to ensure the final product quality. Real-time particle size measurements provide a promising approach for process automation of fluid bed granulation processes. This work focuses on the introduction and evaluation of a new time-based buffer approach for in-line spatial filtering technique (SFT) in order to provide a minimum time delay of the real-time measurement. Comparing the new buffer system to the conventionally used number-based approach, a reduced influence of the particle rate and a constant response time was found. A performance qualification of the Parsum probe IPP 80 using this buffer approach according to the ICH guideline Q2 was performed to investigate whether common variations of process parameters influence the real-time particle size measurement. Focussing on the main requirements for process control, hereby a good precision and specificity as well as an adequate robustness was found. Summarized, this study identified the time-based buffer system as more suitable buffer system for process automation.

Using 3D Printing for Rapid Prototyping of Characterization Tools for Investigating Powder Blend Behavior.

There is an increasing need to provide more detailed insight into the behavior of particulate systems. The current powder characterization tools are developed empirically and in many cases, modification of existing equipment is difficult. More flexible tools are needed to provide understanding of complex powder behavior, such as mixing process and segregation phenomenon. An approach based on the fast prototyping of new powder handling geometries and interfacing solutions for process analytical tools is reported. This study utilized 3D printing for rapid prototyping of customized geometries; overall goal was to assess mixing process of powder blends at small-scale with a combination of spectroscopic and mechanical monitoring. As part of the segregation evaluation studies, the flowability of three different paracetamol/filler-blends at different ratios was investigated, inter alia to define the percolation thresholds. Blends with a paracetamol wt% above the percolation threshold were subsequently investigated in relation to their segregation behavior. Rapid prototyping using 3D printing allowed designing two funnels with tailored flow behavior (funnel flow) of model formulations, which could be monitored with an in-line near-infrared (NIR) spectrometer. Calculating the root mean square (RMS) of the scores of the two first principal components of the NIR spectra visualized spectral variation as a function of process time. In a same setup, mechanical properties (basic flow energy) of the powder blend were monitored during blending. Rapid prototyping allowed for fast modification of powder testing geometries and easy interfacing with process analytical tools, opening new possibilities for more detailed powder characterization.

In vivo and in vitro palatability testing of a new paediatric formulation of valaciclovir.

AIMS: The palatability of a new paediatric formulation of valaciclovir was assessed in children and their parents: non-inferiority of the new paediatric formulation (test formulation) compared to the reference formulation was investigated. METHODS: In vivo palatability testing was performed in a randomized, two-period, multicentre, cross-over study. Children and their parents scored the liking of the new paediatric valaciclovir formulation and the reference formulation on a 100 mm visual analogue scale (VAS). To support formulation development and palatability testing, electronic tongue measurements were applied. RESULTS: The electronic tongue measurement indicated taste-masking capabilities for three different formulations in the developmental phase. A glycerol-based formulation was further tested and compared to the reference formulation prepared out of crushed and suspended tablets. The mean difference (95% CI) in VAS scores between both formulations, as indicated by the children (n = 20), was 2.4 (-8.5, 13) mm, in favour of the new paediatric valaciclovir formulation. The mean (95% CI) difference in VAS scores indicated by the parents (n = 20) was -0.9 (-12, 9.8) mm. CONCLUSION: The palatability of the new paediatric valaciclovir formulation was considered non-inferior to the reference formulation prepared out of crushed tablets. We were able to optimize the study design and number of children to be included in the palatability testing by using electronic tongue measurements.

Early pediatric formulation development with new chemical entities: Opportunities of e-tongue besides human taste assessment.

The palatability of a pediatric drug formulation is one of the key prerequisites for therapeutic success. Liquid formulations are often chosen for pediatric drug products, and they require special attention regarding their taste, as they have direct contact to the taste buds and a relatively long residence time in the oral cavity. For ethical reasons, the role of electronic tongues in the development of oral drug formulations with new chemical entities (NCEs) for pediatric use is growing, however, little is known about the strategies how this instrumental taste assessment can be performed. The present study illustrates two possibilities to combine in-vitro and in-vivo data for the characterization of the palatability of the new drug candidates CSE3104 and CSE3165. As a first step, the implementation and suitability of electronic tongue measurements has been demonstrated by comparison of in-vivo and in-vitro data. In alignment with the taste assessment results during a single-center, double-blinded, randomized, placebo-controlled, single ascending dose (SAD) study in healthy subjects, the bitter taste perception of CSE3104 was assessed with e-tongue measurements. Moreover, the sensor response pattern showed comparable results of the e-tongue measurements to the human taste study of CSE3165: With increasing concentration, the bitterness values were increased. In addition, the human taste pattern showed increasing values for sourness due to higher volumes of the citric acid buffer. Results of the hedonic descriptor "unpleasant" within the human taste assessments could be related to bitterness in the instrumental taste assessment. For the second step in electronic tongue guided formulation development two possibilities are depicted in the article focusing on the effect of different excipients on the formulation on the one hand and on the assessment and comparison of two drug formulations on the other hand. Based on these results, the low number of healthy volunteers for the taste assessment in a Phase 1 study led to a meaningful interpretation, by applying in addition the electronic tongue. Using this instrumental approach led to reproducible data versus the human taste assessment, without ethical concerns, and with a reduction in time and costs.

Critical view on drug dissolution in artificial saliva: A possible use of in-line e-tongue measurements.

Proper monitoring of drug's dissolution is a prerequisite for assessing of taste masking efficacy of pharmaceuticals. Corresponding dissolution procedure is likely to be performed with water. Since the objective of these tests is to examine fate of a pharmaceutical formulation in oral cavity, this choice of solvent seems unsuitable because physical and chemical properties of human saliva are quite far from those of water. Obviously, dissolution profiles registered in water may differ significantly from what really happens with a drug in a mouth cavity. In order to address this discrepancy we examined three different compositions of artificial saliva in dissolution test context in present study. It was found that certain compositions preclude the employment of traditional UV-vis spectroscopy as a detection tool due to strong light scattering in the media caused by viscosity and protein composition modifiers. This issue was circumvented by the use of in-line applied potentiometric multisensor system (e-tongue) and the potential of this new approach for more biorelevant dissolution tests was demonstrated with two model formulations of quinine and ibuprofen.

Suitability of E-tongue Sensors to Assess Taste-Masking of Pediatric Liquids by Different Beverages Considering Their Physico-chemical Properties.

Manipulation of liquid oral drugs by mixing them into foodstuff is a common procedure for taste-masking of OTC pharmaceuticals when administered to children. However, the taste-masking capability of such application media is not systematically evaluated, and recommendations for suitable media are hardly published. In this study, a sensor array of commercially available and self-developed electronic tongue sensors was employed to assess the taste-masking efficiency of eight different beverages (tap water, apple juice, carrot juice, fennel tea, fruit tea, milk, cocoa, and Alete meal to drink) on the OTC pharmaceuticals Ambroxol-ratiopharm®, Cetirizin AL, and Laxoberal® by multivariate data analysis. The Euclidean distances between each pure application medium and its corresponding drug mixture were used as an indicator for the taste-masking efficiency and correlated to the physico-chemical properties of the beverages. Thus, the pH value, the viscosity, as well as the fat and sugar content of the beverages were included, whereas only the viscosity appeared to be insignificant in all cases. The sugar content as well as the fat content and pH value emerged to be a significant variable in taste-masking efficiency for some of the tested drug products. It was shown that the applied electronic tongue sensors were capable to demonstrate the impact of the physico-chemical properties of the application media on their taste-masking capacity regardless of their non-selectivity towards these characteristics.

Data for a pre-performance test of self-developed electronic tongue sensors.

This article presents data, which can be applied for a pre-performance test of self-developed electronic tongue sensors. Contained data is related to the research article "Impact of Sodium Lauryl Sulfate in oral liquids on E-Tongue Measurements" (http://dx.doi.org/10.1016/j.ijpharm.2016.10.045; (L.I. Immohr, R. Turner, M. Pein-Hackelbusch, 2016) [1]). Sensor responses were obtained from 10 subsequent measurements and four different concentrations of quinine hydrochloride by electronic tongue (TS-5000Z, Insent Inc., Atsugi-Shi, Japan) measurements. Based on the data for the pre-performance testing, which were calculated based on the fluctuation range of the sensor responses around the median, stability criteria and required preconditions cycles were defined.

Impact of sodium lauryl sulfate in oral liquids on e-tongue measurements.

During development of oral liquid medicines taste assessment is often required to evaluate taste and taste masking. Electronic tongue analysis can provide taste assessment of medicinal products but should only be conducted with medicines that interact with the instrument without damaging the sensor membranes or interfering with their electrical output so that robust data is generated. To explore the impact of a substance deemed unsuitable for electronic tongue analysis the influence of the anionic surfactant sodium lauryl sulfate (SLS), on the performance of the electronic tongue was conducted using electronic tongues equipped with self-developed PVC based sensors. The results showed a significant impact of SLS on all applied sensor types and an alteration of the sensor's sensitivity. Nevertheless, concentration dependent sensor responses could still be obtained and the sensor performance was not impacted negatively. Assessment of unsuitable substances should therefore be evaluated prior to performing electronic tongue analysis so that their impact is understood fully.

Taste-masking properties of solid lipid based micropellets obtained by cold extrusion-spheronization.

Taste-masked properties of micropellets based on hard fat and/or solid lipid mixtures (prepared by solvent-free cold extrusion/spheronization), containing metformin hydrochloride were investigated. An in-line and an on-line drug release profile evaluation of the pellets was performed and further correlated with an electronic tongue investigation. The pellets based on more than 30% of lipid binders showed metformin HCl releases below 10% after 30s of dissolution. Micropellets based on 20 and 30% of lipids showed immediate drug release profiles. Likewise, the electronic tongue assay showed a decrease in the sensor responses related to the increase of lipid amount in the formulations denoting a significant improvement in the taste masking properties of pellets based on more than 30% of lipid binders. A slight difference between pellets based on hard fat only and pellets based on ternary lipid mixtures was evidenced. Solvent-free cold extrusion/spheronization using solid lipids showed to be a robust method to obtain high drug loaded metformin HCl micropellets with adequate taste-masked properties and immediate drug release profile.

A new biorelevant dissolution method for orodispersible films.

Specific knowledge about the dissolution behavior under biorelevant conditions is of high interest for the rational development of orodispersible films (ODFs). As the conditions in the oral cavity strongly differ from those in the gastrointestinal tract and from those performed with the pharmacopoeial test setups, a biorelevant dissolution setup was developed in this work, considering the mechanical force of the tongue, the saliva flow, the small fluid volume and the saliva composition. Especially in the initial phase, dissolution profiles of KTP (ketoprofen) ODFs observed by the new method showed a slower drug release than obtained with setups based on conventional dissolution methods. 27.47% KTP release after 100s was detected using the new method, compared to 59.29-82.55% detected without considering the in vivo conditions. Furthermore, an influence of the simulated in vivo conditions on the dissolution profile was observed. By simulating either saliva flow or mechanical force, the KTP release after 100s was two to three times higher (18.78% and 14.18%) compared to the profiles, measured without considering one of the parameters (6.76%). Further studies have to show, whether obtained data are comparable to in vivo data to predict drug release profiles of ODFs in the oral cavity.