Ultra-high-resolution optical coherence tomography for the investigation of thin multilayered pharmaceutical coatings.

Optical Coherence Tomography (OCT) has recently gained attention as a promising technology for in-line monitoring of pharmaceutical film-coating processes for (single-layered) tablet coatings and end-point detection with commercial systems. An increasing interest in the investigation of multiparticulate dosage forms with mostly multi-layered coatings below 20 µm final film thickness demands advancement in OCT technology for pharmaceutical imaging. We present an ultra-high-resolution (UHR-) OCT and investigate its performance based on three different multiparticulate dosage forms with different layer structures (one single-layered, two multi-layered) with layer thicknesses in a range from 5 to 50 µm. The achieved system resolution of 2.4 µm (axial) and 3.4 µm (lateral, both in air) enables the assessment of defects, film thickness variability and morphological features within the coating, previously unattainable using OCT. Despite the high transverse resolution, the provided depth of field was found sufficient to reach the core region of all dosage forms under test. We further demonstrate an automated segmentation and evaluation of UHR-OCT images for coating thicknesses, where human experts struggle using today's standard OCT systems.

Ascertain a minimum coating thickness for acid protection of enteric coatings by means of optical coherence tomography.

Enteric coatings are designed to protect active pharmaceutical ingredients (APIs) against untimely release in the stomach. Acid protection of such coatings depends on the coating layer thickness and integrity, which must be determined in an accurate and reliable way to ensure the final product's desired performance. Our work addresses the use of optical coherence tomography (OCT) for characterizing the coating thickness and variability of an enteric-coated drug product and linking them to resistance against gastric fluid. In this study, three batches of enteric-coated tablets drawn during the manufacturing process were investigated. An industrial OCT system was used to establish the coating thickness variability of single tablets (intra-tablet), all tablets in a batch (inter-tablet) and between the batches (inter-batch). Based on the large amount of OCT data, we calculated a critical coating thickness for the investigated film coating, which was found to be 27.4 µm. The corresponding distribution has a mean coating thickness of 44.3 µm ± 7.8 µm. The final coated product has a final mean coating thickness of 63.4 µm ± 8.7 µm, guaranteeing that all tablets meet the quality criterion (i.e., acid protection). Based on the measured thickness distributions, already known distribution functions were considered and an additional, new function was proposed for characterizing the coating thickness distributions in the early stages of industrial coating processes. The proposed approach can be transferred to in-line monitoring of the tablet coating processes, which could drastically improve the production efficiency by ultimately allowing real-time release testing (RTRT).

Near-Infrared Hyperspectral Imaging as a Monitoring Tool for On-Demand Manufacturing of Inkjet-Printed Formulations.

This study evaluates the potential use of near-infrared hyperspectral imaging (NIR-HSI) for quantitative determination of the drug amount in inkjet-printed dosage forms. We chose metformin hydrochloride as a model active pharmaceutical ingredient (API) and printed it onto gelatin films using a piezoelectric inkjet printing system. An industry-ready NIR-HSI sensor combined with a motorized movable linear stage was applied for spectral acquisition. Initial API-substrate screening revealed best printing results for gelatin films with TiO2 filling. For calibration of the NIR-HSI system, escalating drug doses were printed on the substrate. After spectral pre-treatments, including standard normal variate (SNV) and Savitzky-Golay filtering for noise reduction and enhancement of spectral features, principal component analysis (PCA) and partial least squares (PLS) regression were applied to create predictive models for the quantification of independent printed metformin hydrochloride samples. It could be shown that the concentration distribution maps provided by the developed HSI models were capable of clustering and predicting the drug dose in the formulations. HSI model prediction showed significant better correlation to the reference (HPLC) compared to on-board monitoring of dispensed volume of the printer. Overall, the results emphasize the capability of NIR-HSI as a fast and non-destructive method for the quantification and quality control of the deposited API in drug-printing applications.

Deep convolutional neural networks: Outperforming established algorithms in the evaluation of industrial optical coherence tomography (OCT) images of pharmaceutical coatings.

This paper presents a novel evaluation approach for optical coherence tomography (OCT) image analysis of pharmaceutical solid dosage forms based on deep convolutional neural networks (CNNs). As a proof of concept, CNNs were applied to image data from both, in- and at-line OCT implementations, monitoring film-coated tablets as well as single- and multi-layered pellets. CNN results were compared against results from established algorithms based on ellipse-fitting, as well as to human-annotated ground truth data. Performance benchmarks used include, efficiency (computation speed), sensitivity (number of detections from a defined test set) and accuracy (deviation from the reference method). The results were validated by comparing the output of several algorithms to data manually annotated by human experts and microscopy images of cross-sectional cuts of the same dosage forms as a reference method. In order to guarantee comparability for all results, the algorithms were executed on the same hardware. Since modern OCT systems must operate under real-time conditions in order to be implemented in-line into manufacturing lines, the necessary steps are discussed on how to achieve this goal without sacrificing the algorithmic performance and how to tailor a deep CNN to cope with the high amount of image noise and alterations in object appearance. The developed deep learning approach outperforms static algorithms currently available in pharma applications with respect to performance benchmarks, and represents the next level in real time evaluation of challenging industrial OCT image data.

At-line validation of optical coherence tomography as in-line/at-line coating thickness measurement method.

Optical Coherence Tomography (OCT) is a promising technology for monitoring of pharmaceutical coating processes. However, the pharmaceutical development and manufacturing require a periodic validation of the sensor's accuracy. For this purpose, we propose polyethylene terephthalate (PET) films as a model system, to periodically validate the measurements during manufacturing. This study proposes a new approach addressing the method validation requirement in the pharmaceutical industry and presents results for complementary methods. The methods investigated include direct measurement of the layer thickness using a micrometer gauge as reference, X-ray micro computed tomography, transmission and reflectance terahertz pulsed imaging, as well as 1D- and 3D-OCT. To quantify the significance of OCT for pharmaceutical coatings, we compared the OCT results for commercial Thrombo ASS and Pantoloc tablets with direct measurements of coating thickness via light microscopy of microtome cuts. The results of both methods correlate very well, indicating high intra- and inter-tablet variations in the coating thickness for the commercial tablets. The light microscopy average measured coating thickness of Thrombo ASS (Pantoloc) was 71.0 µm (83.7 µm), with an inter-coating variability of 8.7 µm (6.5 µm) and an intra-coating variability of 2.3 µm to 9.4 µm (2.1 µm to 6.7 µm).

Shedding light on coatings: Real-time monitoring of coating quality at industrial scale.

Optical Coherence Tomography (OCT) is increasingly being used for studies of pharmaceutical film coating. OCT allows fast and non-destructive analysis of the coating thickness and quality via high-resolution cross-sectional images. Information about both the coating thickness and the coating quality can be extracted. Most studies and OCT applications performed to date have been limited to off-line measurements and off-line computations of coating features based on data acquired in-line. This study examines OCT's applicability to an industrial-scale pan coating process. Automated layer detection, classification and thickness calculation were executed in real time. To evaluate the system's performance, runs with various tablet size, coating solution concentration and operating parameters were carried out and monitored. Our results indicate that, in addition to correct end-point determination, OCT enables real-time monitoring of the coating processes (thickness, homogeneity and roughness) and can support active process control by supplying information about the coating thickness and quality.

Photoluminescence from GeSn nano-heterostructures.

We investigate the distribution of Sn in GeSn nano-heteroepitaxial clusters deposited at temperatures well exceeding the eutectic temperature of the GeSn system. The 600 °C molecular beam epitaxy on Si-patterned substrates results in the selective growth of GeSn nano-clusters having a 1.4 ± 0.5 at% Sn content. These nano-clusters feature Sn droplets on their faceted surfaces. The subsequent deposition of a thin Ge cap layer induced the incorporation of the Sn atoms segregated on the surface in a thin layer wetting the nano-dots surface with 8 ± 0.5 at% Sn. The presence of this wetting layer is associated with a relatively strong photoluminescence emission that we attribute to the direct recombination occurring in the GeSn nano-dots outer region.

Reduction of Argon Consumption to Less than 2 L min(-1) by Gas Recycling in Inductively Coupled Plasma Optical Emission Spectrometry.

An innovative interface between the torch and the entrance optics for inductively coupled plasma optical emission spectrometry (ICP-OES) is proposed. This system is capable of collecting all argon which was initially supplied to the torch, cooling and cleaning it and feeding most of the argon back to the outer gas port of the torch. Thereby, the total argon consumption could be reduced from 14 to 1.4 L min(-1) using a standard torch and without restricting the rf power. The excitation- and rotational temperature of the plasma were identical when comparing the traditional setup with the enclosed plasma interface. However, the limits of detection (LOD) and limits of quantification (LOQ) of 27 elements investigated were degraded about 5-fold, though this fact can be expected to stem from a change of the observed zone in the plasma caused by the slight overpressure of 2000 Pa within the interface. Though the enclosed plasma interface was located close to the load coil, the rf power coupled to the interface was well below 1 W and no rf arcing was observed for two different rf generator designs.

Laparoscopic transperitoneal sublay mesh repair: a new technique for the cure of ventral and incisional hernias.

BACKGROUND: Incisional hernia is a frequent complication after abdominal surgery. Today open sublay mesh repair and the laparoscopic intraperitoneal onlay mesh repair are the most widely used techniques for its cure. We developed a laparoscopic transperitoneal sublay mesh repair for the treatment of small- and medium-size ventral and incisional hernias. Outcomes of the new technique and the Rives-Stoppa repair were compared. METHODS: This prospective cohort study with a control group involved 93 patients. Between 2008 and 2010, 43 patients underwent the laparoscopic transperitoneal sublay mesh repair. During the same period of time, a control group of 50 patients underwent an open sublay repair after Rives and Stoppa. In 2011, all patients were invited for follow-up. This included pain assessments and physical examinations with use of ultrasound. RESULTS: The two groups were comparable in terms of patient characteristics and hernia data. The operating time was slightly longer for the laparoscopic technique. The hospital stay was shorter in the laparoscopy group. There was less chronic pain in the laparoscopy group, but this difference was not statistically significant. There was no significant difference in postoperative complications, use of analgetics, foreign body sensation, and paresthesia between the two groups. We found one long-term hematoma in the laparoscopy group and one seroma in the open group. In this series, there were no recurrences and no wound infections. CONCLUSIONS: Our initial results indicate that the new laparoscopic transperitoneal sublay mesh repair is a safe and effective method for the treatment of small- and medium-size ventral and incisional hernias.

Nerve management and chronic pain after open inguinal hernia repair: a prospective two phase study.

INTRODUCTION: This prospective cohort study involved 781 elective primary inguinal hernia operations performed on 736 patients at the Hernia Centre of Reinbek Hospital from April 2000 to April 2002. MATERIAL AND METHODS: Small hernias were fixed by the Shouldice repair, and large defects by the Lichtenstein repair with conventional polypropylene mesh. Pain was assessed before the operation, on day 0, 1, 2, 7, 6 months and 5 years after the operation by the visual analogue scale (VAS). The follow-up was 90.1% after 6 months and 82.6% after 5 years. Chronic pain (CP) was assessed in relation to preoperative pain, nerve anatomy and intraoperative nerve management. The anatomy of the iliohypogastric nerve (IHN), ilioinguinal nerve (IIN), and genital branch of the genitofemoral nerve (GB) before and after surgery was recorded in every operation. RESULTS: The preoperative pain rate was 41.0%. The CP and sensory disorder rate after 6 months were 16.4% and 15.9, respectively. The only independent significant parameters for CP after 6 months were preoperative pain (P < 0.002) and sensory disorder of the groin after 6 months (P < 0.0001). After 5 years 16.1% of patients reported pain and 20.3% sensory disorder of the groin. Independent significant predictors of CP were: Preoperative pain (P < 0.024), IIN neurolysis in Lichtenstein repair (=IIN mobilization from its natural bed and nerve preservation; P < 0.002), CP after 6 months (P < 0.006) and a sensory disorder after 5 years (P < 0.0001). Eleven of 12 patients with relevant CP (VAS > 3) after 5 years had had a Lichtenstein repair with IIN neurolysis. The CP population of preoperative pain free patients changed with time: 65% of the patients with CP after 6 months were pain free after 5 years, and 69% of the patients with CP after 5 years were asymptomatic after 6 months. CONCLUSION: Mesh contact with a nerve removed from its natural bed may cause chronic long-term pain. The combination of IIN neurolysis and the Lichtenstein repair should be avoided.