Eetu Räsänen

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.

Hydrate Formation During Wet Granulation Studied by Spectroscopic Methods and Multivariate Analysis

AbstractPurpose. The aim was to follow hydrate formation of two structurally related drugs, theophylline and caffeine, during wet granulation using fast and nondestructive spectroscopic methods. Methods. Anhydrous theophylline and caffeine were granulated with purified water. Charge-coupled device (CCD) Raman spectroscopy was compared with near-infrared spectroscopy (NIR) in following hydrate formation of drugs during wet granulation (off-line). To perform an at-line process analysis, the effect of water addition was monitored by NIR spectroscopy and principal components analysis (PCA). The changes in the crystal arrangements were verified by using X-ray powder diffraction (XRPD). Results. Hydrate formation of theophylline and caffeine could be followed by CCD Raman spectroscopy. The NIR and Raman spectroscopic results were consistent with each other. NIR revealed the state of water, and Raman spectroscopy gave information related to the drug molecule itself. The XRPD confirmed the spectroscopic results. PCA with three principal components explained 99.9of the spectral variation in the second derivative NIR spectra. Conclusions. Both CCD Raman and NIR spectroscopic methods can be applied to monitoring of hydrate formation processes. However, NIR is more suitable for monitoring solid-water interactions.

Novel Identification of Pseudopolymorphic Changes of Theophylline During Wet Granulation Using Near Infrared Spectroscopy

The purpose of this study was to demonstrate the efficiency of near infrared (NIR) spectroscopy in studying the pseudopolymorphic changes and the state of water during the wet granulation process. Anhydrous theophylline was granulated in a planetary mixer using water as granulation liquid. NIR spectra and differential scanning calorimetric (DSC) and wide-angle X-ray scattering (WAXS) patterns of theophylline granules, anhydrous theophylline, and theophylline monohydrate were measured. At a low level of granulation liquid (0.3 mol of water per mole of anhydrous theophylline), water absorption maxima in the NIR region occurred first at around 1475 and 1970 nm. These absorption maxima were identical to those of theophylline monohydrate. At higher levels of granulation liquid (1.3-2.7 mol of water per mole of anhydrous theophylline), the increasing absorption maxima occurred at 1410 and 1905 nm due to OH vibrations of free water molecules. X-ray diffraction patterns confirmed the transformation of anhydrous theophylline to theophylline monohydrate during wet granulation. NIR spectroscopy was able to detect different states of water molecules during the wet granulation process faster and in a more flexible manner than conventional methods.

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.

Near infrared spectroscopy in the development of solid dosage forms.

The use of near infrared (NIR) spectroscopy has rapidly grown partly due to demands of process analytical applications in the pharmaceutical industry. Furthermore, newest regulatory guidelines have advanced the increase of the use of NIR technologies. The non‐destructive and non‐invasive nature of measurements makes NIR a powerful tool in characterization of pharmaceutical solids. These benefits among others often make NIR advantageous over traditional analytical methods. However, in addition to NIR, a wide variety of other tools are naturally also available for analysis in pharmaceutical development and manufacturing, and those can often be more suitable for a given application. The versatility and rapidness of NIR will ensure its contribution to increased process understanding, better process control and improved quality of drug products. This review concentrates on the use of NIR spectroscopy from a process research perspective and highlights recent applications in the field.

Process analysis of fluidized bed granulation.

This study assesses the fluidized bed granulation process for the optimization of a model formulation using in-line near-infrared (NIR) spectroscopy for moisture determination. The granulation process was analyzed using an automated granulator and optimization of the verapamil hydrochloride formulation was performed using a mixture design. The NIR setup with a fixed wavelength detector was applied for moisture measurement. Information from other process measurements, temperature difference between process inlet air and granules (Tdiff), and water content of process air (AH), was also analyzed. The application of in-line NIR provided information related to the amount of water throughout the whole granulation process. This information combined with trend charts of Tdiff and AH enabled the analysis of the different process phases. By this means, we can obtain in-line documentation from all the steps of the processing. The choice of the excipient affected the nature of the solid-water interactions; this resulted in varying process times. NIR moisture measurement combined with temperature and humidity measurements provides a tool for the control of water during fluid bed granulation.

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.

Characterization of Wet Massing Behavior of Silicified Microcrystalline Cellulose and α-Lactose Monohydrate Using Near-Infrared Spectroscopy

The purpose of this study was to investigate the energetic state of water in silicified microcrystalline cellulose (SMCC) and α-lactose monohydrate wet masses using near-infrared (NIR) spectroscopy. The applicability of NIR spectroscopy to studying pharmaceutical wet masses at a wide moisture range was evaluated in comparison with mixer torque rheometry (MTR). With increasing moisture content changes in the physical properties of the samples resulted in an apparent increase in log (1/R) throughout the whole spectrum. The upward displacement of baseline and the relative height of water bands were greatest with materials that had a poor liquid-retention capacity. In the case of SMCC and 1:1 mixture of SMCC and α-lactose monohydrate, the height of the baseline-corrected water bands increased linearly at low moisture contents, thereafter achieving a plateau stage. According to the MTR results, the plateau stage of the band heights indicated a capillary state of liquid saturation. The second derivative spectrum was capable of distinguishing monohydrate, absorbed, and adsorbed water, which overlapped in the absorbance spectrum. When water was absorbed to the internal structure of the material (SMCC), the water bands were first seen at higher wavelengths, then followed by a shift to lower wavelengths. When water was only adsorbed onto the surface of the particles (glass ballotini), the water bands were seen directly in the region of bulk water.

Visualization of particle size and shape distributions using self-organizing maps

In pharmaceutical process technology, characterization of the sizes and shapes of different particles is essential. However, comparisons and analysis of different size and shape characteristics of particles are very difficult. In this investigation, we used the self-organizing map (SOM) to visualize the size and shape distributions obtained with image analysis (IA) of a series of model particles and particles created by fluidized bed granulation. Thereafter, the SOM visualization was compared to principal component analysis (PCA) results of the same data. This study shows that the self-organizing map is a useful and interpretive method for analysis of large data sets of particle size and shape distributions. The results indicate that the self-organizing map was capable of creating an intuitive presentation of the differences in the studied particle populations. The choice of data analysis tools should always be made with great consideration.

A New Method to Predict Flowability Using a Microscale Fluid Bed

The purpose of this research was to develop a new method to predict the flow behavior of pharmaceutical powders using a multichamber microscale fluid bed. Different amounts of poorly flowing paracetamol were added to various grades of microcrystalline celluloses and silicified microcrystalline cellulose powders. Magnesium stearate was used as a lubricant. Experimental minimum fluidization velocities (umf) were defined using 2 to 4 g (equal to 10 mL) of material (Video 1). The reference flowability of the powders was determined using a specific flow meter. Also, the weight variation of the compressed powders, using a single-punch press, was measured. When the amount of paracetamol in the excipients was increased, the experimentalumf increased and the fluidization behavior grew worse (Video 2). Principal component analysis (PCA) established that the pressure difference over the bed as a function of fluidization velocity could be used to characterize the behavior of powders. The increase in poor fluidization behavior of the powders was in accordance with the increasing amount of paracetamol and with the increasing weight variation of the tablets. Furthermore, the angle of repose and the flow rate of silicified microcrystalline cellulose powders were predicted using a partial least squares (PLS) model. The developed method to predict flowability is a promising approach for use in the preformulation and formulation stages of new drug candidates, for example.