Sari Airaksinen

Excipient Selection Can Significantly Affect Solid-State Phase Transformation in Formulation During Wet Granulation

Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The influences of formulation design on the optimal dosage forms should be specified. The aim here was to investigate whether excipients with different water sorption behavior affect hydrate formation of nitrofurantoin in wet masses. Nitrofurantoin anhydrate was used as a hydrate-forming model drug, and 4 excipients with different water-absorbing potential (amorphous low-substituted hydroxypropylcellulose, modified maize starch, partially amorphous silicified microcrystalline cellulose, and crystalline α-lactose monohydrate) were granulated with varying amounts of purified water. Off-line evaluation of wet masses containing nitrofurantoin anhydrate and excipient (1∶1) was performed using an X-ray powder diffractometer (XRPD) and near-infrared spectroscopy, and drying phase was evaluated by variable temperature XRPD. Only amorphous excipient in the formulation retarded hydrate formation of an active pharmaceutical ingredient (API) at high water contents. Hygroscopic partially crystalline excipient hindered hydrate formation of API at low water contents. Crystalline excipient was unable to control hydrate formation of API. The character of excipient affects the stability of formulation. Thus, correct selection of excipients for the formulation can control processing-induced phase transitions and improve the storage stability of the final dosage form.

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.

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.

Rapid Particle Size Measurement Using 3D Surface Imaging

The present study introduces a new three-dimensional (3D) surface image analysis technique in which white light illumination from different incident angles is used to create 3D surfaces with a photometric approach. The three-dimensional features of the surface images created are then used in the characterization of particle size distributions of granules. This surface image analysis method is compared to sieve analysis and a particle sizing method based on spatial filtering technique with nearly 30 granule batches. The aim is also to evaluate the technique in flowability screening of granular materials. Overall, the new 3D imaging approach allows a rapid analysis of large amounts of sample and gives valuable visual information on the granule surfaces in terms of surface roughness and particle shape.

Granule size control and targeting in pulsed spray fluid bed granulation

The primary aim of the study was to investigate the effects of pulsed liquid feed on granule size. The secondary aim was to increase knowledge of this technique in granule size targeting. Pulsed liquid feed refers to the pump changing between on- and off-positions in sequences, called duty cycles. One duty cycle consists of one on- and off-period. The study was performed with a laboratory-scale top-spray fluid bed granulator with duty cycle length and atomization pressure as studied variables. The liquid feed rate, amount and inlet air temperature were constant. The granules were small, indicating that the powder has only undergone ordered mixing, nucleation and early growth. The effect of atomizing pressure on granule size depends on inlet air relative humidity, with premature binder evaporation as a reason. The duty cycle length was of critical importance to the end product attributes, by defining the extent of intermittent drying and rewetting. By varying only the duty cycle length, it was possible to control granule nucleation and growth, with a wider granule size target range in increased relative humidity. The present study confirms that pulsed liquid feed in fluid bed granulation is a useful tool in end product particle size targeting.

Effect of fluidisation activity on end-point detection of a fluid bed drying process

The influence of inlet air humidity variations on fluid bed drying end-point detection was the primary focus here. Various drying end-point criteria based on temperature and humidity measurements were compared. Seasonally changing inlet air humidity affects the moisture content of the finished granules, as long as the drying process remains unchanged. However, a specific moisture content of the finished granules is commonly desired after fluid bed drying. When experimental batches of varying inlet air humidity were compared at the beginning of the drying phase, the temperature of the granules increased linearly as the humidity of the inlet air increased. This effect causes variation in moisture contents of the final granules of different batches when the fixed temperature of the mass is used as an end-point criterion. With varying inlet air humidity, the often used DeltaT temperature difference method resulted in more precise estimation of the drying end-point than the constant temperature criterion. In this study new insights were found into the correlation between moisture content and temperature of the fluidising mass. Fluidisation activity greatly affected detection of drying end-point. Use of the DeltaT criterion requires proper fluidisation throughout the process.

New insights into segregation during tabletting

The aim of this study was to evaluate how different granule size distributions affect the tablet compression process. The emphasis was on developing new analytic methods for compression data for entire batch. In all, 18 batches of granules containing theophylline and lactose were tabletted, using an instrumented eccentric tabletting machine. During tablet compression, upper and lower punch forces were recorded. Mathematical methods were developed for analysing the compression data during tabletting. The results suggested two types of undulation in the tabletting data: (1) short-time scale variation or tablet-to-tablet changes in force data and (2) long-time scale undulation describing the changes occurring throughout the tabletting process, such as segregation. These undulation phenomena were analysed, using various mathematical methods. In addition the results suggest that smaller particles have better tabletting properties, to a certain limit. However particle size alone cannot explain the tabletability of granules.

Evaluating optimal combination of clodronate and bioactive glass for dental application

Both clodronate and bioactive glass are mostly used alone as treatment in various bone diseases but, they are also known to have beneficial effects in dental application. The same processes that lead to loss of bone can also result in alveolar bone loss. The object of this study was to define the optimal combination of clodronate and bioactive glass (BAG) to be used locally in dentistry. The evaluation was based on measurements and solid state properties obtained with pH, scanning electron microscopy (SEM), differential scanning calorimetric (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and Focused-ion beam (FIB) and energy dispersive X-ray spectroscopic (EDS) mapping. The results indicate that if too much calcium clodronate precipitation is formed, the activity of BAG is affected negatively. As there is more reaction surface to form calcium clodronate, similar to the amount of clodronate present, this reduces the bioactivity of BAG. Therefore, in dental treatment the most suitable BAG and clodronate combination product would have apatite (HA, hydroxyapatite) formation ability and amount of clodronate enough to enhance the bioactivity of BAG allowing HA formation. Based on combinations investigated, the one with 200mg clodronate and 1 g BAG with particle size 0.5-0.8 mm was chosen to be the most promising for local dental application.

Interaction of bioactive glass with clodronate.

Bone tissue engineering is a rapidly growing area of research involving the use of bioactive glass (BG) alone and in combination with different materials. The objective of this study was to investigate the interaction of BG with clodronate. Characterisation of the interaction between BG and clodronate was undertaken using; scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), Fourier transform Raman spectroscopy and Fourier transform infrared spectroscopy (FTIR). The interaction was examined in vitro with respect to the ion exchange and surface modification on the surface of the bioactive glass in the combination product. The results showed clear ion exchange enhancement by clodronate. Additionally, this ion exchange was more extensive and long lasting in the combination product than in BG alone. Clodronate promotes the activity of the BG and a calcium clodronate precipitation is formed. It can be assumed that this solid combination could be used in clinical applications. Therefore, it can be concluded that clodronate makes a beneficial environment for BG and could enhance also the apatite formation of BG.

Difficulties in administration of oral medication formulations to pet cats: an e-survey of cat owners

The purpose here was to determine the problems cat owners encounter in medicating their cats with orally administered drugs at home. The study was carried out as an open e-questionnaire survey addressed to cat owners in which the authors focused on the oral administration route. A total of 46 completed questionnaires were included in the survey. In the study, 46 cats received 67 orally administered drugs. Approximately half of the drugs were registered for use in cats by the European Medicines Agency (54 per cent), and there were also off-label drugs registered for human (36 per cent) and canine medication (7.4 per cent) and an ex tempore drug (3.0 per cent). The owners were unable to give the doses as prescribed for their cats for one-fourth of the medications (16/67). Drugs that were registered for feline medication were significantly more palatable than drugs registered for other species (odds ratio (OR) 4.9), and liquid formulations were significantly more palatable than solid formulations (OR 4.8). However, most of the owners (22/38) preferred a solid dosage form, while few (4/38) chose a liquid formulation. The results indicate that there is still a need for more palatable and easily administered oral drugs for cats.