Jukka-Pekka Mannermaa

On-line monitoring of moisture content in an instrumented fluidized bed granulator with a multi-channel NIR moisture sensor

The applicability of a near-infrared reflectance spectroscopic method was tested. The set-up used was constructed for the determination of water during different unit operations performed in a fluidized bed granulator. The granulation of three different formulations and the drying of one pellet formulation were investigated. The pellets were prepared by the continuous extrusion spheronisation technique. It proved possible to measure the moisture content of granules with a standard error of performance of 0.2%. The reference method used was based on the measurement of loss on drying (infrared dryer, wet basis). The applicability of the near-infrared method in pharmaceutical formulation and process development work was investigated using different liquid flow rates and drying end points. Combining the continuous measurement of moisture content and the product temperature measurement creates a novel tool for observing both the granule spraying and the drying phase. Different moisture profiles of the granules were clearly distinguished as well as the different drying end points.

In-line moisture measurement during granulation with a four-wavelength near infrared sensor: an evaluation of particle size and binder effects.

Factors affecting in-line near infrared (NIR) moisture measurement with a four-wavelength sensor were evaluated (choice of binder used in granulation liquid and the increase in particle size). An entire NIR spectrum is not necessary for the measurement of water, and often the use of only a few NIR wavelengths around the water band enables reliable and high-speed detection of moisture. Glass ballotini and microcrystalline cellulose (MCC) were used as model test materials. The binders studied were poly[1-(2-oxo-1-pyrrolidinyl)ethylene] (PVP) and gelatin. Full off-line NIR spectra of test materials at different levels of binder solutions were measured. The major spectral features for both the binders were bands around 1700 nm (first overtones CH related stretches) and 2200 nm (combination bands). Gelatin also had an NH band around 1500 nm (first overtones of NH stretches) and combination bands at about 2050 nm. Particle size effects were observed as an increase in spectra baseline. All these factors should be considered when choosing NIR wavelengths used for detection of water with a fixed wavelength set-up. A robust calibration model enables the development of in-process control of wet granulation processes.

In-line moisture measurement during granulation with a four-wavelength near-infrared sensor: an evaluation of process-related variables and a development of non-linear calibration model

Abstract The near-infrared set-up based on simultaneous detection of four wavelengths was applied for in-line moisture measurement during fluid bed granulation. In addition to the spectral response, several other process measurements describing the state of the granulation were evaluated. The near-infrared moisture measurement is disturbed by the variation in physical properties of the sample (e.g., temperature, particle size, bulk density). The factors explaining the non-linearity of spectral response during different phases of granulation could be extracted. Combining all this process information improved the prediction capability of the multivariate calibration models tested (partial least squares and artificial neural network (ANN)). The back-propagation neural network approach was found to have most predictive power with the independent test data.

Electrostatic measurements on a miniaturized fluidized bed

In the pharmaceutical industry fluidization is often used in drying, coating and granulation processes. During fluidization powder particles contact other particles as well as the walls of the vessel and this leads to generation of electric charges. These charges may result in sparks, dust explosions, fires, reduced process efficiency and particle accumulation on the walls. However, the mechanism of the charging is not well understood. In this paper, an inductive method for charge generation measurement is presented. The system consists of an electrostatic ring probe, which allows charge scanning across the miniaturized fluidized bed without disturbing the fluidization process. The charge coupling from the system to the probe has been modelled and the experimental data have been simulated using an advanced field solving software. Experiments on lactose monohydrate, microcrystalline cellulose and glass beads have been performed and these results are presented.

Next generation fluidized bed granulator automation

1bstract1 system for fluidized bed granulator automation with in-line multichannel near infrared (NIR) moisture measurement and a unique air flow rate measurement design was assembled, and the information gained was investigated. The multivariate process data collected was analyzed using principal component analysis (PCA). The test materials (theophylline and microcrystalline cellulose) were granulated and the calibration behavior of the multichannel NIR set-up was evaluated against full Fourier Transform (FT) NIR spectra. Accurate and reliable process air flow rate measurement proved critical in controlling the granulation process. The process data describing the state of the process was projected in two dimensions, and the information from various trend charts was outlined simultaneously. The absorbence of test material at correction wavelengths (NIR region) and the nature of material-water interactions affected the detected in-line NIR water signal. This resulted in different calibration models for the test materials. Development of process analytical methods together with new data visualization algorithms creates new tools for in-process control of the fluidized bed granulation.

Water-soluble β-Cyclodextrins in Paediatric Oral Solutions of Spironolactone: Preclinical Evaluation of Spironolactone Bioavailability from Solutions of β-Cyclodextrin Derivatives in Rats

Water‐soluble derivatives of β‐cyclodextrin have been considered for solubilization of spironolactone in the formulation of a safe liquid preparation for premature infants. The oral absorption of spironolactone was studied in rats to evaluate the need to adjust spironolactone dosage in prospective clinical studies. Spironolactone was administered in solutions of sulphobutyl ether β‐cyclodextrin (SBE7) or dimethyl‐β‐cyclodextrin (DM‐β‐CyD) and also as spironolactone‐containing powder papers (reference preparation). Spironolactone in SBE7 solution was administered intravenously to assess the extent of intestinal absorption from the different formulations.

Visualization of fluid-bed granulation with self-organizing maps

The degree of the instrumentation of pharmaceutical unit operations has increased. This instrumentation provides information of the state of the process and can be used for both process control and research. However, on-line process data is usually multidimensional, and is difficult to study with traditional trends and scatter plots. The Self-Organizing Map (SOM) is a recognized tool for dimension reduction and process state monitoring. The basics of the SOM and the application to on-line data collected from a fluid-bed granulation process are presented. As a batch process, granulation traversed through a number of process states, which was visualized with SOM as a two-dimensional map. In addition, it is demonstrated how the differences between granulation batches can be studied. The results suggest that SOM together with new in-line process analytical solutions support the in-process control of the pharmaceutical unit operations. Further, a novel research tool for understanding the phenomena during processing is achieved.

High-performance liquid chromatography methods for the separation and quantitation of spironolactone and its degradation products in aqueous formulations and of its metabolites in rat serum

HPLC assays have been developed for the determination of spironolactone and its degradation products 7 alpha-thiospirolactone and canrenone in aqueous solutions of beta-cyclodextrins and for the determination of spironolactone and its metabolites 7 alpha-thiospirolactone, 7 alpha-thiomethylspirolactone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone and canrenone in rat serum samples. Both methods were well suited for their respective applications, i.e., studying the stability of spironolactone in liquid formulations of beta-cyclodextrins and the oral absorption of spironolactone in rats. The HPLC method developed for spironolactone and its metabolites in rat serum requires very small volumes of serum making it possible to take several blood samples over a period of time.

Water-soluble β-cyclodextrins in paediatric oral solutions of spironolactone: solubilization and stability of spironolactone in solutions of β-cyclodextrin derivatives

Abstract Water-soluble β -cyclodextrins, hydroxypropyl- β -cyclodextrin (HP β CD), dimethyl- β -cyclodextrin (DM β CD) and sulphobutyl ether β -cyclodextrin (SBE7), were evaluated as potential solubilizers of spironolactone (SP) in paediatric enteral formulations. 1 H-NMR was used to verify the formation of inclusion complexes and to detect possible degradation of spironolactone through deacetylation. The effect of temperature on spironolactone stability was studied in solutions of HP β CD and SBE7 to estimate shelf-lives of possible liquid preparations. HP β CD, DM β CD and SBE7 formed true inclusion complexes with spironolactone with a stoichiometry of 1:2 (SP: β CD). No degradation of spironolactone could be detected in the presence of DM β CD, whereas spironolactone degraded through deacetylation according to pseudo-first order kinetics in the presence of HP β CD and SBE7. Spironolactone degradation was slower in solutions of SBE7 than in HP β CD, with the slowest degradation at 6°C in SBE7 solution. Estimated shelf-lives ( t 90% ) for solutions containing 3 mg/ml of spironolactone were, even at 6°C, below 2 h in the presence of HP β CD. The t 90% -values in the presence of SBE7 were 4.1, 8.3 and 24.5 h at 22, 13 and 6°C, respectively. According to these results, SBE7 could be considered for the solubilization of spironolactone in paediatric enteral solutions, if the solution were to be prepared and stored at 6°C or below.

Microscale granulation in a fluid bed powder processor using electrostatic atomisation

The aim of this study was to use the electrostatic atomisation in miniaturised fluid bed granulation process and define the effect of process parameters. The process parameters included in the study were granulation liquid flow rate, atomisation voltage and binder concentration in the granulation liquid. Altogether 22 batches were granulated in Multichamber Microscale Fluid bed powder Processor (MMFP). Granule size distributions were measured with both sieves and image analyses. With these process conditions, the atomisation liquid flow rate had a strong positive correlation with the granule size. Increasing the atomisation voltage increased the granule size, which is contradictory with the expectations. The effect of the binder concentration remained unclear. Although it is challenging to model the fluid bed granulation process in micro-scale, multivariate methods such as principal component analysis (PCA) are helpful in studying the most important phenomena.