The Use of a Closed Feed Frame for the Development of Near-Infrared Spectroscopic Calibration Model to Determine Drug Concentration.

PURPOSE: This study evaluates the use of the closed feed frame as a material sparing approach to develop near-infrared (NIR) spectroscopic calibration models for monitoring blend uniformity. The effect of shear induced by recirculation on NIR spectra was also studied. METHODS: Calibration models were developed using NIR spectra obtained in the closed feed frame for two cases. For case 2, blends that flowed through the open feed frame were predicted with the model. The shear effect of the feed frame on the blends was assessed through the characterization of powder properties before and after recirculation. RESULTS: The physical characterization of the blends confirmed that the powder properties were not altered after recirculation within the closed feed frame. Both calibration models provided highly accurate predictions of the test sets with low bias (0.03% w/w and -0.06% w/w) and relative standard error of prediction (1.9% and 3.7%), respectively. The predictive performance of the calibration models was not affected by the shear effect. CONCLUSION: Recirculation within the closed feed frame did not change the physical properties of the blends studied. The prediction of blends flowing through the open feed frame was possible with a calibration model developed in the closed feed frame. The closed feed frame could reduce the materials needed to develop calibration models by more than 90%.

Cleaning of direct compression continuous manufacturing equipment through displacement of API residues by excipients.

This feasibility study evaluates a cleaning process designed to avoid the use of detergents and reduce operator exposure to the active pharmaceutical ingredient (API). The continuous manufacturing equipment was cleaned using excipients to displace ibuprofen residues from the system. The cleaning process was performed using 3.0 kg of Prosolv® and 3.0 kg of Tablettose® 70. The impact of different volumetric feed rates of the cleaning excipient was assessed. The displacement of API and blend residues was evaluated with in-line near infrared (NIR) spectroscopy. Principal component analysis (PCA) was performed to evaluate the cleaning progress as the Prosolv® flowed through the feeder, mixer and stream sampler. In-place Raman spectra were acquired from the material sticking to detect the ibuprofen residues. The study showed that Prosolv® and Tablettose® can remove ibuprofen residues effectively from the hopper, feeder screw, mixer paddles, shaft and stream sampler. The Process Analytical Technology (PAT) system can be utilized to detect API displacement during the cleaning process. However, dismantling and manual cleaning was required to remove material sticking at the surfaces adjacent to the rotating feeder screws and mixer paddles.

Blend uniformity monitoring in a continuous manufacturing mixing process for a low-dosage formulation using a stream sampler and near infrared spectroscopy.

Continuous manufacturing has the potential to offer several benefits for the production of oral solid dosage forms, including reduced costs, low-scale equipment, and the application of process analytical technology (PAT) for real-time process control. This study focuses on the implementation of a stream sampler to develop a near infrared (NIR) calibration model for blend uniformity monitoring in a continuous manufacturing mixing process. Feeding and mixing characterizations were performed for three loss-in-weight feeders and a commercial continuous mixer to prepare powder blends of 2.5-7.5 % w/w ibuprofen DC 85 W with a total throughput of 33 kg/h. The NIR spectral acquisition was performed after the mixing stage using a stream sampler for flowing powders. A continuous mixer shaft speed of 250 RPM was selected to operate the mixing process based on a variability analysis developed with in-line spectral data acquired using the stream sampler at 6 RPM. A partial least squares regression (PLS-R) model was performed and evaluated, yielding a root-mean-square error of prediction (RMSEP) of 0.39 % w/w and a bias of 0.05 % w/w. An independent experimental run conducted two days later revealed that the continuous mixing process and the NIR calibration model presented low day-to-day variation. The minimum practical error (MPE) and sill values through variographic analysis showed low variance associated with the sampling process using the stream sampler. Results demonstrated the promising capacity of the stream sampler coupled to an NIR probe to be implemented within continuous manufacturing processes for the real-time determination of API concentration.

Burkholderia caballeronis sp. nov., a nitrogen fixing species isolated from tomato (Lycopersicon esculentum) with the ability to effectively nodulate Phaseolus vulgaris.

During a survey of Burkholderia species with potential use in agrobiotechnology, a group of 12 strains was isolated from the rhizosphere and rhizoplane of tomato plants growing in Mexico (Nepantla, Mexico State). A phylogenetic analysis of 16S rRNA gene sequences showed that the strains are related to Burkholderia kururiensis and Burkholderia mimosarum (97.4 and 97.1 %, respectively). However, they induced effective nitrogen-fixing nodules on roots of Phaseolus vulgaris. Based on polyphasic taxonomy, the group of strains represents a novel species for which the name Burkholderia caballeronis sp. nov. is proposed. The type species is TNe-841(T) (= LMG 26416(T) = CIP 110324(T)).

Assessment of blend uniformity in a stream sampler device using Raman spectroscopy.

This study describes the first implementation of Raman spectrometer in a stream sampler for the in-line monitoring of low drug concentration in poor flowability powder blends. Raman spectra were continuously acquired as the powder blends flowed through the stream sampler operating with a paddle wheel speed of 10 RPM and used to develop the calibration models. A calibration model was developed to quantify caffeine concentration from 1.50 to 4.50% w/w using Partial Least Squares Regression (PLS-R). Three test set blends were used to assess the prediction errors of the calibration model. Caffeine concentration was predicted for the test set blends with a root mean square error of prediction of 0.21% w/w and a low bias of -0.03% w/w. The calibration model showed good prediction performance with an estimated sample mass of 83 mg. Variographic analysis demonstrated the low process variance of the real-time spectral acquisition through minimum practical error and sill values. The results showed the ability of the Raman spectrometer coupled with the stream sampler to monitor low drug concentration for poor flowability blends.

Isolation of the opdE gene that encodes for a new hydrolase of Enterobacter sp. capable of degrading organophosphorus pesticides.

Microbial enzymes that can hydrolyze organophosphorus compounds have been isolated, identified and characterized from different microbial species in order to use them in biodegradation of organophosphorus compounds. We isolated a bacterial strain Cons002 from an agricultural soil bacterial consortium, which can hydrolyze methyl-parathion (MP) and other organophosphate pesticides. HPLC analysis showed that strain Cons002 is capable of degrading pesticides MP, parathion and phorate. Pulsed-field gel electrophoresis and 16S rRNA amplification were performed for strain characterization and identification, respectively, showing that the strain Cons002 is related to the genus Enterobacter sp. which has a single chromosome of 4.6 Mb and has no plasmids. Genomic library was constructed from DNA of Enterobacter sp. Cons002. A gene called opdE (Organophosphate Degradation from Enterobacter) consists of 753 bp and encodes a protein of 25 kDa, which was isolated using activity methods. This gene opdE had no similarity to any genes reported to degrade organophosphates. When kanamycin-resistance cassette was placed in the gene opdE, hydrolase activity was suppressed and Enterobacter sp. Cons002 had no growth with MP as a nutrients source.

Quantitative analysis of blend uniformity within a Three-Chamber feed frame using simultaneously Raman and Near-Infrared spectroscopy.

This study reports the use of Raman and Near-infrared (NIR) spectroscopy to simultaneously monitor the drug concentration in flowing powder blends within a three-chamber feed frame. The Raman probe was located at the top of the dosing chamber, while the NIR probe was located at the top of the filling chamber. The Raman and NIR spectra were continuously acquired while the powder blends flowed through the feed frame. Calibration models were developed with spectra from a total of five calibration blends ranging in caffeine concentration among 3.50 and 6.50% w/w. These models were optimized to predict three test set blends of 4.00, 5.00, and 6.00% w/w caffeine. The results showed a high predictive ability of the models based on root mean square error of predictions of 0.174 and 0.235% w/w for NIR and Raman spectroscopic models, respectively. Concentration profiles with higher variability were observed for the Raman spectroscopy predictions. An estimate of the mass analyzed by each spectrum showed that a NIR spectrum analyzes approximately 4.5 times the mass analyzed by a Raman spectrum; despite these differences in the mass analyzed, blend uniformity results are equivalent between techniques. Variographic analysis demonstrated that both techniques have significantly low sampling errors for the real-time monitoring process of drug concentration within the feed frame.

Evaluation of strain-induced hydrophobicity of pharmaceutical blends and its effect on drug release rate under multiple compression conditions.

OBJECTIVE: The purpose of this study was to investigate the effect of mechanical shear on hydrophobicity of pharmaceutical powder blends as a function of composition and particle size, and to determine the impact on drug release from tablets. METHODS: Four powder formulations were subjected to three different shear strain conditions (40 rev, 160 rev, and 640 rev) in a controlled shear environment operating at a shear rate of 80 rpm. A total of 12 blends were tested for hydrophobicity. Subsequently, sheared blends were compressed into tablets at 8 kN and 12 kN in a rotary tablet press. During tablet compression, powder samples were collected after the feed frame and their hydrophobicity was again measured. RESULTS: Results indicated that increase in shear strain could significantly increase hydrophobicity, predominantly as an interacting function of blend composition. Blends with both colloidal silica and magnesium stearate (MgSt) were found to show higher hydrophobicity with shear than other blends. Additional shear applied by the tablet press feed frame was found to change the powder hydrophobicity only in the absence of MgSt. CONCLUSIONS: Studies showed that the drug release rates dropped with shear more for the blends with both colloidal silica and MgSt than the other blends. Furthermore, the rate of drug release dropped with a decrease in particle size of the main excipient. Surprisingly, the relationship between the relative increase in hydrophobicity and a corresponding drop in the drug release rate was not found when either MgSt or colloidal silica was mixed alone in the blends.

Monitoring of high-load dose formulations based on co-processed and non co-processed excipients.

This work presents the evaluation of a co-processed material for high-load dose formulations and its real-time monitoring by near-infrared (NIR) spectroscopy at the tablet press feed frame. The powder and tableting properties of co-processed material blends were evaluated and compared to the blend of the individual excipients. The formulations with the co-processed material showed excellent flow properties and were superior to the physical blend of individual excipients. Two NIR spectroscopic methods were developed to monitor ibuprofen concentration between 40.0 and 60.0% w/w, one method using a co-processed material as the main excipient and the other using the blend of the individual excipients. The NIR spectra were obtained while the powder blends flowed within a three-chamber feed frame from a Fette 3090 tablet press. The NIR spectroscopic method with the co-processed material presented better performance with significantly lower prediction error. Variographic analysis demonstrated that using the co-processed material considerably reduces the sampling and analytical errors in the in-line determination of ibuprofen. The authors understand that this is the first study where the sampling errors are evaluated as a function of the excipients used in the pharmaceutical formulation. This study demonstrated that selecting a suitable excipient for the formulation helps optimize the manufacturing process, reducing the magnitude of the total measurement error.

An innovative sampling interface for monitoring flowing pharmaceutical powder mixtures.

A chute was designed following the principles of the Theory of Sampling to minimize the variations in powder flow and provide all particles in the flowing blends with the same opportunity of being selected as a sample. The design also reduces the thickness of the chute to allow the analysis of a higher portion of the flowing blends by a near infrared spectrometer. The blends that flowed through the chute had Carr's index values that fluctuated between 23 and 25 percent, indicating passable flowability. A powder fowling evaluation demonstrated that there was no powder accumulation at the inspection window of the chute. The mass flow rate profiles indicated that the system achieves mass steady-state in approximately 30 s and a throughput of 30 kg/h which makes it suitable for continuous manufacturing operations. An in-line NIR calibration model was developed to quantify caffeine concentrations between 1.51 and 4.52 % w/w. The spectra obtained from each experiment had minimal baseline variation. The developed NIR method was robust to throughput changes up to approximately ±7 %. The test blends in the caffeine concentration range between 2.02 % w/w and 4.02 % w/w met the dose uniformity requirements of the Ph.Eur. 9.0, chapter 2.9.47. Variographic analysis was done to estimate the analytical and sampling errors which yielded values below 0.01 (%w/w)2. The obtained results showed that this chute could also be used in a continuous manufacturing line or other applications with flowing powders.

Utility of endoscopic ultrasound in idiopathic acute recurrent pancreatitis.

Idiopathic acute recurrent pancreatitis (IARP) is defined as at least two episodes of acute pancreatitis with the complete or near-complete resolution of symptoms and signs of pancreatitis between episodes, without an identified cause. There is a paucity of information about the usefulness of endoscopic ultrasound (EUS) in IARP. OBJECTIVES: To determine the diagnostic yield of EUS in IARP. DESIGN: A retrospective study was performed in patients with IARP evaluated by EUS between January 2009 and December 2016. Follow-up assessments of acute pancreatitis recurrence were carried out. RESULTS: Seventy-three patients with 102 EUS procedures were included. EUS was able to identify the cause of IARP in 55 patients (75.3%). The most common findings were chronic pancreatitis in 27 patients (49.1%), followed by lithiasic pathology in 24 patients (43.6%), and intraductal papillary mucinous neoplasm in four patients (7.3%). A directed treatment against EUS findings had a protective tendency associated with the final resolution of recurrence. There were no complications reported. CONCLUSION: EUS performed in patients with IARP helped to identify a possible cause in 2/3 of the cases. The majority of patients have a treatable disease.

[Intraabdominal mass with difficult diagnosis: Solitary fibrous tumor]. / Masa intraabdominal de difícil diagnóstico: tumor fibroso peritoneal solitario.

Solitary fibrous tumor (SFT) is a rare neoplasm of mesenchymal origin. The most commonly reported locations are the pleura and meninges. Less frequently, SFT manifests as an asymptomatic mass in the pancreas, liver, peritoneum or kidney. Clinical and radiological findings have failed to provide any specific diagnostic pattern but allow malignant development to be suspected due to infiltration or metastasis. In addition, preoperative cytology often yields inconclusive or misleading results. Therefore the definitive diagnosis is achieved after both surgical resection and immunohistochemical analysis, with markers such as CD34, vimentin and desmin. We present a case of SFT, which was difficult to diagnose, even after an extensive battery of tests based on imaging techniques.

Real-time quantification of low-dose cohesive formulations within a sampling interface for flowing powders.

This study investigates the performance of a sampling interface for monitoring cohesive, flowing powder formulations with Hausner's Ratio and Carr's Index higher than 1.5 and 35%, respectively. The sampler device was operated in combination with near-infrared (NIR) spectroscopy to quantify ibuprofen concentrations between 1.5 and 4.5% w/w. NIR spectra also provided essential information to study the process dynamics within the sampler. The 200 spectra per blend obtained demonstrated a continuous powder flow with no evidence of agglomerates or segregation within the sampler for a blend of 6 kg. A NIR calibration model was optimized to predict independent test blends, delivering root mean square error of predictions and bias under 0.1% w/w. The test blends were within specifications according to the requirements of European Pharmacopeia. Variographic analysis demonstrated that the sampler device may determine low drug concentration in cohesive powder blends, presenting sampling errors below 0.011 (%w/w)2. This analysis also demonstrated that an increase in the blend compressibility leads to a slight rise in sampling errors within the sampler device. The sampler device offers statistical robustness in the evaluation of blend uniformity, providing greater confidence in the quality determination of the cohesive powder blends without significantly affecting its flow properties.

In-line monitoring of low drug concentration of flowing powders in a new sampler device.

A novel sampler device for flowing powders was tested to quantify drug concentrations as low as 0.76% w/w in pharmaceutical powder blends. The sampler device was developed based on the powder flow behavior within a tablet press feed frame, following the principles laid down in the Theory of Sampling. Two Near-Infrared (NIR) spectroscopic calibration models were developed with powder blends that varied from 0.52 to 2.52% w/w and 1.51-4.52% w/w. The calibration models were able to determine caffeine concentration in test set blends with root mean square error of predictions and bias below 0.1% w/w. Samples were collected from the sampler device and analyzed by ultraviolet-visible (UV-Vis) to determine the caffeine concentration. A high agreement between the in-line NIR predictions and the sampled UV-Vis results was found. The paddle wheel speed in the sampler can be varied up to ±10% without affecting NIR predictions; however, the models did not respond adequately to a 25% increase in this speed. Variographic analysis showed that the sampler device may quantify low drug concentrations with nugget effects below 0.0050 (%w/w)2. This study demonstrate that the sampler device may handle throughputs up to 45 kg/h, without significantly affecting the physical properties of powder blends.

A sampling system for flowing powders based on the theory of sampling.

An innovative chute and stream sampler system for flowing powders has been developed and tested. The system is designed for representative sampling based on the principles of the Theory of Sampling (TOS). The sampling system was used in combination with near infrared (NIR) spectroscopy to determine the drug concentration of flowing powders. The system is comprised of three parts: a chute, a stream sampler and a sample collection port. The NIR spectra were obtained at the chute, before entering the sampler, and as the powder flowed through the stream sampler. Samples were also collected from the sample collection port to be analyzed using an ultraviolet-visible (UV-Vis) reference method to determine drug content. A total of eight pharmaceutical powder blends, ranging in concentration from 10.5(%w/w) to 19.5(%w/w) of caffeine, were used to test the sampling system. Materials were characterized before blends were made to provide information on flow properties. The throughput of the system was between 30 and 35 kg/h based on the flow properties of the blend. Drug concentration was effectively determined at the chute and stream sampler. The NIR calibration models showed low root mean squared errors of prediction, 0.65(%w/w) and 0.51(%w/w), for the chute and stream sampler respectively. The NIR calibration models also showed low bias values -0.36(%w/w) at the chute and 0.057(%w/w) at the stream sampler. Significant agreement was obtained between the results from the nondestructive NIR versus the destructive UV-Vis method. Variographic analysis was performed to estimate the analytical and sampling errors when determining the drug concentration at the chute and stream sampler respectively. The variographic analysis showed low analytical errors, 0.103(%w/w)2 and 0.181(%w/w)2 at the chute and stream sampler respectively. The analysis also showed that the minimum practical error (MPE) was around 0.2(%w/w)2 at both chute and stream sampler.

Feed frame: The last processing step before the tablet compaction in pharmaceutical manufacturing.

The feed frame is a force-feeding device used in the die filling process. The die filling process is crucial within pharmaceutical manufacturing to guarantee the critical quality attributes of the tablets. In recent years, interest in this unit has increased because it can affect the properties of the powder blend and tablets, and because of the success in real time monitoring of powder blend uniformity potential for Process Analytical Technology as described in this review. The review focuses on the recent advances in understanding the powder flow behavior inside the feed frame and how the residence time distribution of the powder within the feed frame is affected by the operating conditions and design parameters. Furthermore, this review also highlights the effect of the paddle wheel design and feed frame process parameters on the tablet weight, the principal variable for measuring die filling performance.

Development of near infrared spectroscopic calibration models for in-line determination of low drug concentration, bulk density, and relative specific void volume within a feed frame.

This study describes the development of a near infrared (NIR) calibration model for real time determination of drug concentration, powder density, and porosity or relative specific void volume (RSVV) of 3.00%w/w acetaminophen blends within a feed frame. The NIR calibration model was developed from 1.50 to 4.50%w/w of acetaminophen, using a high variability of major excipients (from 12.92 to 81.95%w/w) which facilitates the prediction of powder density and RSVV based on near infrared calibration spectra. The model using second derivative as spectral preprocessing explained the changes related to acetaminophen concentration in the first latent variable. The second latent variable was related to changes in concentration of microcrystalline cellulose and lactose in the powder blends. NIR calibrations were also developed based on the bulk density and RSVV of the powder blends using the same design as the API model, due to the physical properties of the particles and their effects on the NIR spectra. The RSVV was predicted for the independent set blends with an RSEP(%) below 4% with a significantly low bias (0.04 cm3/g) from reference values of 1.33 to 1.58 cm3/g. The bulk density model also exhibited excellent predictions with RSEP(%) below 2.6% and significantly low bias (0.01 g/cm3) from reference values of 0.45 to 0.51 g/cm3. The excellent results obtained show the potential of near infrared spectroscopic measurements within the feed frame for a Process Analytical Technology method to control the critical properties such as tablet mass, hardness and dissolution in batch and continuous manufacturing processes.

Assessment of blend uniformity in a continuous tablet manufacturing process.

Blend uniformity was monitored throughout a continuous manufacturing (CM) process by near infrared (NIR) spectroscopic measurements of flowing blends and compared to the drug concentration in the tablets. The NIR spectra were obtained through the chute after the blender and within the feed frame, while transmission spectra were obtained for the tablets. The CM process was performed with semi-fine acetaminophen blends at 10.0% (w/w). The blender was operated at 250 RPM, for best performance, and 106 and 495 rpm where a lower mixing efficiency was expected. The variation in blender RPM increased the variation in drug concentration at the chute but not at the feed frame. Statistical results show that the drug concentration of tablets can be predicted, with great accuracy, from blends within the feed frame. This study demonstrated a mixing effect within the feed frame, which contribute to a 60% decrease in the relative standard deviation of the drug concentration, when compared to the chute. Variographic analysis showed that the minimum sampling and analytical error was five times less in the feed frame than the chute. This study demonstrates that the feed frame is an ideal location for monitoring the drug concentration of powder blends for CM processes.

Stacked traits conferring multiple resistance to imazamox and glufosinate in soft wheat.

BACKGROUND: Conventional crossing of soft wheat cultivars resistant to imazamox and glufosinate resulted in two (Rados and Helter) lines resistant to both herbicides. Stacked traits conferring this dual herbicide resistance in these lines, compared with a susceptible (S) cultivar, were characterized. RESULTS: Rados and Helter lines were ∼ 18-fold more resistant (R) to glufosinate, and between 15.1 and 19.8-fold more resistant to imazamox than the S cultivar. Resistance to glufosinate and imazamox decreased up to 12% and 50%, respectively, when the herbicides were applied sequentially. The basal activities of the acetolactate and glutamine synthases were similar between R and S plants. Rados and Helter lines were 11.7- and 17.7-fold more resistant to imazamox than the S cultivar, due to the Ser653-Asn mutation in their imi-ALS genes. R lines, susceptible to glufosinate at the target site level, showed lower ammonia accumulation evidencing the activity of the phosphinothricin acetyl transferase. Absorption and translocation patterns for 14 C-imazamox and 14 C-glufosinate were similar between R and S cultivars and so do not contribute to resistance. CONCLUSION: Stacked traits conferring dual herbicide resistance to the lines Rados and Helter come from the resistant parents. These R lines are potential tools for weed management in wheat production, mainly via herbicide rotation. © 2018 Society of Chemical Industry.

The evolving notion of "senior" kidney transplant recipients.

The maximum age of recipients expected to benefit with a kidney transplant has increased in the past three decades. In 1980, patients older than age 50 were not listed for a transplant. In 2004, almost 90% aged 50-60 yr with end-stage renal disease were listed, and some were even older than age 80. We summarize previous articles to illustrate how the notion of "senior" has evolved for kidney transplantation, and using data reported to the Organ Procurement Transplant Network, describe characteristics, treatments and outcomes in recipients older than 50 yr. Fractions of male, white, non-obese, unsensitized recipients and use of expanded criteria donors increased in cohorts with increasing recipient age. The percentage of recipients with hypertension or diabetes decreased, but the percentage with cancer increased. The fraction spared steroids increased with increasing age, but other aspects of immunosuppression were not remarkably different. No differences in early outcomes were notable, and elderly recipients likely did not return to dialysis. However, both graft and patient survival rates decreased with increasing age. Although a small fraction was selected, and survival rates were lower, patients older than 80 yr received kidney transplants.