The Influence of Equipment Design and Process Parameters on Granule Breakage in a Semi-Continuous Fluid Bed Dryer after Continuous Twin-Screw Wet Granulation.

The drying unit of a continuous from-powder-to-tablet manufacturing line based on twin-screw granulation (TSG) is a crucial intermediate process step to achieve the desired tablet quality. Understanding the size reduction of pharmaceutical granules before, during, and after the fluid bed drying process is, however, still lacking. A first major goal was to investigate the breakage and attrition phenomena during transport of wet and dry granules, the filling phase, and drying phase on a ConsiGma-25 system (C25). Pneumatic transport of the wet granules after TSG towards the dryer induced extensive breakage, whereas the turbulent filling and drying phase of the drying cells caused rather moderate breakage and attrition. Subsequently, the dry transfer line was responsible for additional extensive breakage and attrition. The second major goal was to compare the influence of drying air temperature and drying time on granule size and moisture content for granules processed with a commercial-scale ConsiGma-25 system and with the R&D-scale ConsiGma-1 (C1) system. Generally, the granule quality obtained after drying with C1 was not predictive for the C25, making it challenging during process development with the C1 to obtain representative granules for the C25.

In-line temperature measurement to improve the understanding of the wetting phase in twin-screw wet granulation and its use in process development.

Wetting is the initial stage of wet granulation processes during which the first contact between the powder and the liquid occurs. Wetting is a critical step to allow granule growth and consolidation, but also to ensure uniform active pharmaceutical ingredient (API) distribution over all granule size fractions. A physical understanding of the wetting stage is therefore crucial to design a robust granulation process. In twin-screw granulation, wetting is physically separated from granule consolidation, growth, breakage and attrition. The present study used this particularity to investigate the wetting step in such a way that the fundamental mechanisms governing the wetting can be linked and understood. A modified granulator barrel was used allowing the collection of granules immediately after the wetting. A low drug-loaded pharmaceutical formulation containing a poorly soluble and poorly wettable API was used for this investigation. Granules obtained after the wetting zone were analysed for granule size distribution, API distribution over the different size fractions and granule temperature. It was found that "wetting efficiency" (i.e., fraction of powder being nucleated during the wetting stage) could be predicted using an energy balance based on in-line measurement of the granule temperature. Wetting efficiency could moreover be linked to final granule quality attributes (i.e., granule size distribution) at the outlet of the granulator. It was further demonstrated that granule growth and consolidation could only be achieved when complete wetting was achieved in the wetting zone of the granulator. This study suggested a methodology based on in-line temperature measurements to quickly determine wetting efficiency. The described methodology could therefore be used as a tool to gain more fundamental understanding of the wetting stage during twin-screw granulation as well as to define suitable formulation and process ranges for further granulation process development.

Heat Transfer Evaluation During Twin-Screw Wet Granulation in View of Detailed Process Understanding.

During the last decade, the pharmaceutical industry has shown a growing interest in continuous twin-screw granulation (TSG). Despite flourishing literature on TSG, limited studies focused on fundamental process understanding on its mechanisms. In current study, granule quality attributes along the length of the TSG barrel were evaluated together with heat transfer in order to achieve a more fundamental understanding of the granulation process. An experimental setup was developed allowing the collection of granules at the different TSG compartments. In addition to the determination of typical granule attributes, mechanical energy, barrel and granule temperature (measured using an in-line implemented infra-red camera) were measured to evaluate heat transfer occurring at the different compartments and to relate them to granulation mechanisms. Collected data identified wetting enthalpy and friction forces as the main sources of heat along the granulator length. Wetting occurred in the wetting zone and generated temperature increase depending on liquid-to-solid ratio and powder wettability. In the kneading zones, granule temperature increase was proportional to mechanical energy. While it is usually admitted that granule consolidation and reshaping are the consequence of the high shear experienced by the granules, it was highlighted that most of the mechanical energy is converted into thermal energy with no correlation between mechanical energy and granule size distribution. Combined mass and energy balance of the granulation process are therefore necessary to capture the interaction between granule properties and physico-chemical and mechanical phenomena occurring in each compartment.

Diagnostic approach to localised organising pneumonia--A case report.

INTRODUCTION: Localised organising pneumonia, radiologically presented with oval or round shadows mimicing lung cancer or metastases, is a major issue in differential diagnosis. CASE REPORT: A female patient was hospitalized to clarified the etiology of multiple nodular lung lesions. The chest X-ray and the chest computed tomography (CT) revealed bilateral patchy and nodular shadows, and round lung lesions, respectively. Neither sputum analyses, nor histology of bronchoscopy samples clarified the etiology of these lung lesions. As secondary deposits in the lungs were suspected, video-assisted thoracoscopy and anterolateral right minithoracotomy with atypical upper and lower lobe resection were performed. The frozen-section analysis suggested the benign nature of the lesion, and the definite histopathological finding of localised organising pneumonia was established. Due to bilateral lung lesions, corticosteroids were applied. Seven weeks later, the chest CT finding revealed a total regression of the lesions. CONCLUSION: A surgical resection was necessary to diagnose the localised organising pneumonia which mimiced secondary malignant lesions, thus establishing the definite etiology of lung lesions. Bronchoscopic cryobiopsy, recently introduced in order to obtain peripheral lung biopsy samples, has provided new possibilities in the diagnosis and treatment of neoplastic and non-neoplastic lung diseases.

Modeling of an Active Tablet Coating Process.

Tablet coating is a common unit operation in the pharmaceutical industry, during which a coating layer is applied to tablet cores. The coating uniformity of tablets in a batch is especially critical for active coating, that is, coating that contains an active pharmaceutical ingredient. In recent years, discrete element method (DEM) simulations became increasingly common for investigating tablet coating. In this work, DEM was applied to model an active coating process as closely as possible, using measured model parameters and non-spherical particles. We studied how operational conditions (rotation speed, fill level, number of nozzles, and spray rate) influence the coating uniformity. To this end, simulation runs were planned and interpreted according to a statistical design of (simulation) experiments. Our general goal was to achieve a deeper understanding of the process in terms of residence times and dimensionless scaling laws. With that regard, the results were interpreted in light of analytical models. The results were presented at various detail levels, ranging from an overview of all variations to in-depth considerations. It was determined that the biggest uniformity improvement in a realistic setting was achieved by increasing the number of spray nozzles, followed by increasing the rotation speed and decreasing the fill level.

Semi-Fowler vs. lateral decubitus position for thoracoscopic sympathectomy in treatment of primary focal hyperhidrosis.

BACKGROUND AND OBJECTIVE: The aim of this study is to compare usefulness of Semi-Fowler position vs. lateral decubitus position for thoracoscopic sympathectomy in treatment of primary focal hyperhidrosis. MATERIALS AND METHODS: From January 2009 to January 2010, 263 consecutive patients with palmar and axillar hyperhidrosis underwent thoracoscopic sympathectomy Th2-Th4. Patients were divided into two groups: group A (n=133) underwent thoracoscopic sympathectomy through lateral decubitus using double lumen endotracheal intubation, and group B (n=130) underwent thoracoscopic sympathectomy through Semi-Fowler supine position (semi sitting with arm abducted) using single lumen endotracheal intubation without insufflation of CO2, but with short apnea period. All operations were performed through two 5 mm operating ports, videothoracoscopic camera 0° and endoscopic ultrasound activated harmonic scalpel. RESULTS: There were 107 males and 156 females with median age 30.31±8.35 years. Two groups were comparable in gender, age, severity of sweating. All operations were successfully performed with no complications or perioperative morbidity. For group A average operation time for both sides was 31.2±3.87 min and for group B average time was 14.19±4.98 min. In group B apnea period per one lung lasts 2.86±1.15 min and during that period observed saturation was 92.65%±5.66% without significant cardiorespiratory disturbances. Pleural drains were taken off on operation table after forced manually lung reexpansion. Patients were discharged from hospital for few hours, after the operation and radiologic confirmation of complete lung reexpansion. CONCLUSIONS: Based on this data (shorter operating time, lack of incomplete lung collapse, insignificant apnea and better reexpansion of lungs) we concluded that thoracoscopic sympathectomy through Semi-Fowler supine position is highly effective and easy to perform for primary hyperhidrosis.

[Parapneumonic effusions: features, diagnostics and treatment options].

INTRODUCTION: Parapneumonic effusions, as a complication of inflammatory processes in the lungs, usually have a good course, but they sometimes progress into pulmonary empyema, thus becoming a significant clinical problem. OBJECTIVE: To review clinical and radiological features, as well as diagnostic and therapeutic options in parapneumonic effusions. METHODS: The analysis included 130 patients with parapneumonic effusions hospitalized at the General Pulmonology Clinic of the Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica during 2013. RESULTS: Of 385 patients with pneumonia, 130 (33.8%) had parapneumonic effusion, 78 (60.0%) of whom were males. Most patients (361; 27.7%) were 60-69 years of age. The most common symptoms included fever (92; 70.8%) and cough (91; 70.0%). Hypertension was the most common comorbidity registered in 81 (62.3%) patients, and chronic obstructive pulmonary disease present in 33 (25.4%) patients. Pleural puncture was performed in 62 (47.7%) patients. Macroscopically, effusion was clear in most cases (31; 50.0%), and cytologically the mixed type was most frequently established (26; 41.9%). Bronchoscopy was performed in 52 (40.0%) patients, and video-assisted thoracoscopy in 9 (6.9%) patients. Empyema signs were registered in 13 (10.0%) patients; in all a thoracic drainage with administration of intrapleural streptokinase was performed. CONCLUSION: Patients with a parapneumonic effusion have the symptoms of acute respiratory infection and frequent concomitant diseases. Further diagnostic and therapeutic treatment depends on pleural fluid features and chest CT finding.

Optimization of the inter-tablet coating uniformity for an active coating process at lab and pilot scale.

The objective of this study was to enhance the inter-tablet coating uniformity in an active coating process at lab and pilot scale by statistical design of experiments. The API candesartan cilexetil was applied onto gastrointestinal therapeutic systems containing the API nifedipine to obtain fixed dose combinations of these two drugs with different release profiles. At lab scale, the parameters pan load, pan speed, spray rate and number of spray nozzles were examined. At pilot scale, the parameters pan load, pan speed, spray rate, spray time, and spray pressure were investigated. A low spray rate and a high pan speed improved the coating uniformity at both scales. The number of spray nozzles was identified as the most influential variable at lab scale. With four spray nozzles, the highest CV value was equal to 6.4%, compared to 13.4% obtained with two spray nozzles. The lowest CV of 4.5% obtained with two spray nozzles was further reduced to 2.3% when using four spray nozzles. At pilot scale, CV values between 2.7% and 11.1% were achieved. Since the test of uniformity of dosage units accepts CV values of up to 6.25%, this active coating process is well suited to comply with the pharmacopoeial requirements.

Experimental analysis of tablet properties for discrete element modeling of an active coating process.

Coating of solid dosage forms is an important unit operation in the pharmaceutical industry. In recent years, numerical simulations of drug manufacturing processes have been gaining interest as process analytical technology tools. The discrete element method (DEM) in particular is suitable to model tablet-coating processes. For the development of accurate simulations, information on the material properties of the tablets is required. In this study, the mechanical parameters Young's modulus, coefficient of restitution (CoR), and coefficients of friction (CoF) of gastrointestinal therapeutic systems (GITS) and of active-coated GITS were measured experimentally. The dynamic angle of repose of these tablets in a drum coater was investigated to revise the CoF. The resulting values were used as input data in DEM simulations to compare simulation and experiment. A mean value of Young's modulus of 31.9 MPa was determined by the uniaxial compression test. The CoR was found to be 0.78. For both tablet-steel and tablet-tablet friction, active-coated GITS showed a higher CoF compared with GITS. According to the values of the dynamic angle of repose, the CoF was adjusted to obtain consistent tablet motion in the simulation and in the experiment. On the basis of this experimental characterization, mechanical parameters are integrated into DEM simulation programs to perform numerical analysis of coating processes.

Soluplus® as an effective absorption enhancer of poorly soluble drugs in vitro and in vivo.

As many new active pharmaceutical ingredients are poorly water soluble, solubility enhancers are one possibility to overcome the hurdles of drug dissolution and absorption in oral drug delivery. In the present work a novel solubility enhancing excipient (Soluplus®) was tested for its capability to improve intestinal drug absorption. BCS class II compounds danazol, fenofibrate and itraconazole were tested both in vivo in beagle dogs and in vitro in transport experiments across Caco-2 cell monolayers. Each drug was applied as pure crystalline substance, in a physical mixture with Soluplus®, and as solid solution of the drug in the excipient. In the animal studies a many fold increase in plasma AUC was observed for the solid solutions of drug in Soluplus® compared to the respective pure drug. An effect of Soluplus® in a physical mixture with the drug could be detected for fenofibrate. In vitro transport studies confirm the strong effect of Soluplus® on the absorption behavior of the three tested drugs. Furthermore, the increase of drug flux across Caco-2 monolayer is correlating to the increase in plasma AUC and C(max)in vivo. For these poorly soluble substances Soluplus® has a strong potential to improve oral bioavailability. The applicability of Caco-2 monolayers as tool for predicting the in vivo transport behavior of the model drugs in combination with a solubility enhancing excipient was shown. Also the improvement of a solid dispersion compared to physical mixtures of the drugs and the excipient was correctly reflected by Caco-2 experiments. In the case of fenofibrate the possible improvement by a physical mixture was demonstrated, underscoring the value of the used tool as alternative to animal studies.

Autofluorescence imaging videobronchoscopy in the detection of lung cancer: from research tool to everyday procedure.

Autofluorescence imaging videobronchoscopy (AFI) is one of the new systems of autofluorescence bronchoscopy designed for thorough examination of bronchial mucosa. The integration of autofluorescence and videobronchoscopy provides clear images of normal and pathologically altered bronchial mucosa. Major indications for AFI include evaluation of early-stage lung cancer and detection of precancerous lesions. However, in recent years, the indications for AFI are widening, and this tool might find its place in routine daily bronchoscopic practice. With new indications for AFI, such as evaluation of tumor extension or follow-up after surgical resection, this tool might be more often used by bronchoscopists. A sharp learning curve and clear distinction between healthy and pathologically altered mucosa make this technology acceptable for young and inexperienced bronchoscopists. One of the major disadvantages of AFI is low specificity in the detection of premalignant lesions and early-stage lung cancer. This disadvantage could be overcome with the appearance of new and improved technologies in autofluorescence, such as the addition of backscattered light analysis, ultraviolet spectra, fluorescence-reflectance or dual digital systems. Quantitative image analysis is also one of the ways to improve objectivity and minimize observer errors. However, one of the most appropriate solutions would be the addition of AFI to narrow band imaging, and merging the two technologies into one videobronchoscope.

Role of surface free energy and spreading coefficient in the formulation of active agent-layered pellets.

Formulation of layered pellets can be a useful method for the preparation of multiparticulate systems. The aims of this work were to study the properties of hydrophilic active agent (pirenzepine dihydrochloride) layers formed on different pellet cores, the efficacy of layering and the connection between the core and the layers. The carrier pellets were prepared from mixtures of a hydrophilic (microcrystalline cellulose) and a hydrophobic (magnesium stearate) component in different ratios. These cores were coated in a fluid bed apparatus with an aqueous solution of active agent, with or without the addition of hydroxypropyl methyl cellulose (HPMC) as an adhesive component. The wettability of the pharmaceutical powders was assessed by means of Enslin number and contact angle measurements, and the surface energy was determined. Spreading coefficients of the components were also calculated and correlated with pellet properties such as the content of active agent, the friability and the morphological appearance of the layered product. An increased friability of the layer formed and the lower effectiveness of the process were experienced with a reduction in the wetting of the core. The efficiency of layering on a less polar core could be increased by the addition of HPMC, but the sensitivity of these pirenzepine layers to mechanical stress was higher. The type of the abrasion of these particles was dissimilar to that for samples prepared without HPMC. Peeling of the layers containing HPMC was observed for hydrophobic cores, but this phenomenon was not detected for the hydrophilic ones. These results can be explained by the spreading coefficients, which revealed an insufficient adhesion of layers for the samples that exhibited peeling.

Continuous granulation with a twin-screw extruder: impact of material throughput.

Agglomeration behavior of a twin-screw extruder at different material throughputs was investigated. Water insoluble dicalcium phosphate and the binder povidone were agglomerated with demineralized water with five different screw configurations using conveying-, kneading- or combing mixer elements. Increasing material throughput mainly had an effect on the particle size of granules. Due to a higher filling degree of the barrel, the particle size was higher at increased material throughput. Granule porosity was generally influenced by screw element type. With a higher element dispersivity granule porosity and friability decreased. Compression of the different granule batches led to comparable tablet properties. A simple scale up in order to increase batch size can be realized by increasing either production time at given material throughput or material throughput.

Impact of screw elements on continuous granulation with a twin-screw extruder.

The influence of different screw element types on wet granulation process with a twin-screw extruder was investigated. Lactose granules were prepared with different screw configurations such as conveying, combing mixer and kneading elements. The use of kneading blocks led to an almost complete agglomeration of lactose, whereas kneading and combing mixer elements resulted in smaller granules in comparison. Granule porosity varied between 17.4% and 50.6%. Granule friability values ranged from 1.2% to 38.5%. Conveying elements led to the most porous and friable granules, whereas kneading blocks produced the densest and least friable granules. Combing mixer elements produced granules with median properties. A linear correlation between granule porosity and the natural logarithm of granule friability was detected. Flowability of granules was also influenced by the element type. Compressed granules with higher granule porosities resulted in tablets with higher tensile strength values and vice versa. Twin-screw extruders proved to be a versatile tool for wet granulation. By the choice of a suitable screw element granule and tablet characteristics were influenced.

Postoperative morbidity and mortality after induction chemoradiotherapy for locally advanced lung cancer: an analysis of 350 operated patients.

OBJECTIVE: The purpose of this study was to evaluate the frequency and risk of postoperative cardiopulmonary and bronchial complications in patients with locally advanced lung cancer after induction chemoradiotherapy and definitive surgery. METHODS: We reviewed the charts of 350 patients who underwent thoracotomy in the course of two phase II and one phase III studies with preoperative chemotherapy (three cycles of split- dose cisplatin/etoposide in 261 patients and cisplatin/paclitaxel in 89 patients) followed in all 350 patients by concurrent chemoradiotherapy (one cycle cisplatin/etoposide combined with 45 Gy hyperfractionated accelerated radiotherapy) and operation from March 1991 to December 2000. Univariate and multivariate analysis was used to identify predictors of complications. RESULTS: Of 350 consecutive patients 278 (79%) had a non-small cell lung cancer (154 stage IIIA and 124 IIIB) and 72 (21%) a small cell lung cancer (12 stage IIA/B, 35 stage IIIA and 25 stage IIIB). Resections included 125 pneumonectomies (35%), 15 bilobectomies (4.3%), 37 sleeve lobectomies (11%), 157 lobectomies (45%), and two segmentectomies (0.6%); 14 patients (4%) had an exploration only. Additionally to pulmonary resection 32 patients underwent a partial chest wall resection. One hundred and fifty-four patients (44%) developed early or late complications; the hospital mortality rate was 4.9% (17 patients). The causes of death were sepsis (n=5), pneumonia and respiratory failure (n=4), adult respiratory distress syndrome (n=3), cardiac failure (n=3) and lung embolism (n=2). Multivariate analysis extracted increased age, lower Karnofsky status, abnormal echocardiographic findings and no bronchial stump covering technique to be risk factors for perioperative morbidity. Lower Karnofsky status and increased age were significant risk factors for postoperative mortality. CONCLUSION: This retrospective analysis demonstrates that in patients with locally advanced lung cancer and induction chemoradiotherapy, surgery can be feasible with acceptable mortality but increased morbidity. Accurate cardiopulmonary evaluation before surgery and standard operative techniques with protection of bronchial stump or anastomosis can contribute to a reduced complication rate with this intensive approach.