Challenges, opportunities and recent advances in near infrared spectroscopy applications for monitoring blend uniformity in the continuous manufacturing of solid oral dosage forms.

Near infrared (NIR) spectroscopy has been widely recognized as a powerful PAT tool for monitoring blend uniformity in continuous manufacturing (CM) processes. However, the dynamic nature of the powder stream and the fast rate at which it moves, compared to batch processes, introduces challenges to NIR quantitative methods for monitoring blend uniformity. For instance, defining the effective sample size interrogated by NIR, selecting the best sampling location for blend monitoring, and ensuring NIR model robustness against influential sources of variability are challenges commonly reported for NIR applications in CM. This article reviews the NIR applications for powder blend monitoring in the continuous manufacturing of solid oral dosage forms, with a particular focus on the challenges, opportunities for method optimization and recent advances with respect three main aspects: effective sample size measured by NIR, probe location and method robustness.

Multicomponent granular mixing in a Bohle bin Blender-Experiments and simulation.

Study of mixing and segregation of granular materials was performed in a Bohle bin blender using both computational modeling and experiments. A multicomponent mixture of pharmaceutical excipients and coated theophylline granules, an active pharmaceutical ingredient (API) was considered as the blend formulation. A DEM (Discrete Element Method) Model was developed to simulate the flow and mixing of the multicomponent blend to compare with the experimental data. DEM is a numerical modeling technique which incorporates all the material properties (such as Particle size, density, elastic modulus, yield strength, Poisson's ratio, work function etc.)to simulate granular flow (such as mixing, conveying) of particles. In simulation, the degree (Relative standard deviation) of mixing in a Bohle bin blender was assessed as a function of critical processing parameters (loading pattern, rotational rate, and fill percentage). Numerical simulation results reveal radial mixing in a Bohle bin blender is faster than axial mixing due to symmetric geometry limitation. This study investigates a numerical model-based approach to study the effect of the critical process parameters on the mixing dynamics in Bohle bin blender for a moderately cohesive pharmaceutical formulation. The DEM model can be used to provide crucial insights to developed optimized mixing protocols to ascertain the best mixing conditions for different formulation. As for example, as we try to develop a mixing protocol for another formulation with different operational parameters such as loading pattern, rotational speed, and fill percentage, one can device an optimized mixing protocol of the formulation with the help of this DEM model.

A robust quantitative near infrared modeling approach for blend monitoring.

This study demonstrates a material sparing Near-Infrared modeling approach for powder blend monitoring. In this new approach, gram scale powder mixtures are subjected to compression loads to simulate the effect of scale using an Instron universal testing system. Models prepared by the new method development approach (small-scale method) and by a traditional method development (blender-scale method) were compared by simultaneously monitoring a 1kg batch size blend run. Both models demonstrated similar model performance. The small-scale method strategy significantly reduces the total resources expended to develop Near-Infrared calibration models for on-line blend monitoring. Further, this development approach does not require the actual equipment (i.e., blender) to which the method will be applied, only a similar optical interface. Thus, a robust on-line blend monitoring method can be fully developed before any large-scale blending experiment is viable, allowing the blend method to be used during scale-up and blend development trials.

Prediction of dissolution profiles by non-destructive near infrared spectroscopy in tablets subjected to different levels of strain.

This study describes how the strain on formulation components affects dissolution and how near infrared spectroscopy can be used to predict dissolution. Strain (exposure to shear stress) applied during powder mixing affects the interaction between formulation components. Particles experience shear strain when they move relative to each other in a process affecting the properties of the final product. This stress affects the dissolution of oral solid dosages forms. However, dissolution testing destroys the entire tablet, making it impossible to further evaluate tablet properties when an out of specification result is obtained. Thus, a nondestructive technique such as near infrared spectroscopy is desirable to predict dissolution. The aim of this study was to predict dissolution on tablets with different levels of strain (shear) using near infrared spectroscopy in combination with multivariate data analysis. Shear was induced using a modified Couette cell on the powder mixture and tablets from these mixtures were produced using a tablet press emulator. Tablets produced with different strain levels were measured using near infrared spectroscopy. Spectra were obtained in diffuse reflectance mode and pretreated with baseline correction to maintain the physical and chemical information of the tablets. Dissolution profiles were obtained using USP Apparatus 2 as a reference method. Principal component analysis was used to study the sources of variation in the spectra obtained. Partial least squares 2 was used to predict dissolution on tablets with different levels of strain.

In-line near-infrared (NIR) and Raman spectroscopy coupled with principal component analysis (PCA) for in situ evaluation of the transesterification reaction.

Biodiesel was synthesized from different commercially available oils while in-line Raman and near-infrared (NIR) spectra were obtained simultaneously, and the spectral changes that occurred during the reaction were evaluated with principal component analysis (PCA). Raman and NIR spectra were acquired every 30 s with fiber optic probes inserted into the reaction vessel. The reaction was performed at 60-70 °C using magnetic stirring. The time of reaction was 90 min, and during this time, 180 Raman and NIR spectra were collected. NIR spectra were collected using a transflectance probe and an optical path length of 1 mm at 8 cm(-1) spectral resolution and averaging 32 scans; for Raman spectra a 3 s exposure time and three accumulations were adequate for the analysis. Raman spectroscopy showed the ester conversion as evidenced by the displacement of the C=O band from 1747 to 1744 cm(-1) and the decrease in the intensity of the 1000-1050 cm(-1) band and the 1405 cm(-1) band as methanol was consumed in the reaction. NIR spectra also showed the decrease in methanol concentration with the band in the 4750-5000 cm(-1) region; this signal is present in the spectra of the transesterification reaction but not in the neat oils. The variations in the intensity of the methanol band were a main factor in the in-line monitoring of the transesterification reaction using Raman and NIR spectroscopy. The score plot of the first principal component showed the progress of the reaction. The final product was analyzed using (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy and using mid-infrared spectroscopy, confirming the conversion of the oils to biodiesel.

Incidencia y principales causas de cesárea en pacientes atendidas en la maternidad Enrique C. Sotomayor, período comprendido entre julio 2005 a septiembre 2005 / Incidence and principal causes of cesarean section of patients at Enrique C. Sotomayor Maternity Hospital during the period from June to September 2005

Debido a una variedad de factores médicos y sociales, el índice de cesáreas ha aumentado; se deduce que dicho aumento se debe a procesos que no son justificados. Tipo de estudio: descriptivo y prospectivo. Objetivos: determinar la incidencia y las causas de las cesáreas realizadas en el Hospital maternidad “Enrique C. Sotomayor”, para comprobar si esta intervención quirúrgica esta justificada. Promover alternativas para reducir el índice de cesáreas injustificadas. Resultados: El universo fue de 563 pacientes cesareadas. La principal causa de cesárea en pacientes sin antecedentes de cesárea fue la desproporción cefalopélvica. En los pacientes con antecedente(s) de cesárea, la cicatriz uterina previa (CUP) fue la principal causa por la cual se realizó la siguiente cesárea. Conclusión: Las cesáreas realizadas en pacientes sin antecedentes de cesárea son justificadas. Las cesáreas realizadas en pacientes con antecedentes de cesárea no son justificadas en su totalidad. Existen casos en este estudio de pacientes que pudieron ser sometidos a diferentes opciones de parto y no acudir a la cesárea.

According to a variety of medical and social factors, the cesarean rate has increased; this increase might be due to unjustified processes. Type of study: descriptive and prospective. Objective: to determine the incidence and the causes of cesarean practiced at “Enrique C. Sotomayor” Maternity hospital, to check if the surgery is justified. To promote alternatives to reduce unjustified cesarean rate. Results: the sample group was of 563 patients. The main cause of cesarean in patients without history of cesarean was a cephalopelvic disproportion. In patients with history of cesarean, previous uterine scar (PUS) was the main cause of another cesarean. Conclusions: the cesarean sections carried out in patients without history of cesarean are justified. All the cesarean sections carried out in patients with history of cesarean are not totally justified. In this study there are cases of patients who could have undergone different options of labour instead of the cesarean.