Rapid formulation screening with a Multipart Microscale Fluid bed Powder processor.

The aim of this study was to investigate early formulation screening in small scale with a miniaturized fluid bed device. Altogether eight different batches were granulated in a Multipart Microscale Fluid bed Powder processor (MMFP) with constant process conditions using electrostatic atomization. Atomization voltage and granulation liquid flow rate were kept constant. Acid acetylsalicylic was used as model active pharmaceutical ingredient (API), lactose monohydrate, microcrystalline cellulose and polyvinylpyrrolidone were used as excipients. Granule size distributions were measured with spatial filtering technique. Friability test was performed by spinning granules in the mixer with glass beads. Compressibility of the granules was evaluated by tableting and the breaking force of the tablets was measured. Multivariate analysis, namely partial least squares regression and multilinear regression were applied to the data. It was possible to generate granules of different compositions rapidly employing MMFP with electrostatic atomization fast and acquire reliable and logical results with only small amount of material. However, a major challenge was to find suitable analytical methods for such small batches.

Image-based characterization of powder flow to predict the success of pharmaceutical minitablet manufacturing.

Powder flowability plays an important role in die filling during tablet manufacturing. The present study introduces a novel small-scale measuring technique for powder flow. Based on image analysis, the flow was defined depending on the variation of luminous intensity and the movement of powder inside the measurement cuvette. Using quantities around 100 mg it was possible to characterize a wide range of common pharmaceutical powders, especially in distinguishing subtle differences in flow caused by minor changes in samples characteristics. The method was compared with powder rheometry, which is widely used in the pharmaceutical literature, and showed a significant improvement in predicting the success of pharmaceutical minitablet manufacture (d = 5 mm). Tablet weight variation (RSD) was defined as the most efficient way to assess relevant powder flow behaviour in tablet production when using the novel device. The proposed method was distinguished from others by its ability to classify different grades of microcrystalline cellulose in the die-filling process. Subsequently, eight common pharmaceutical powders, both excipients and APIs, were properly ranked as a function of flowability based on their physical properties. The method showed a high repeatability, with a relative standard deviation not more than 10%.

Compatibility of chewing gum excipients with the amino acid L-cysteine and stability of the active substance in directly compressed chewing gum formulation.

Using L-cysteine chewing gum to eliminate carcinogenic acetaldehyde in the mouth during smoking has recently been introduced. Besides its efficacy, optimal properties of the gum include stability of the formulation. However, only a limited number of studies exist on the compatibility of chewing gum excipients and stability of gum formulations. In this study we used the solid-state stability method, Fourier transform infrared spectroscopy and isothermal microcalorimetry to investigate the interactions between L-cysteine (as a free base or as a salt) and excipients commonly used in gum. These excipients include xylitol, sorbitol, magnesium stearate, Pharmagum S, Every T Toco and Smily 2 Toco. The influence of temperature and relative humidity during a three-month storage period on gum formulation was also studied. Cysteine alone was stable at 25 degrees C/60% RH and 45 degrees C/75% RH whether stored in open or closed glass ambers. As a component of binary mixtures, cysteine base remained stable at lower temperature and humidity but the salt form was incompatible with all the studied excipients. The results obtained with the different methods corresponded with each other. At high temperature and humidity, excipient incompatibility with both forms of cysteine was obvious. Such sensitivity to heat and humidity during storage was also seen in studies on gum formulations. It was also found that cysteine is sensitive to high pressure and increase in temperature induced by compression. The results suggest that the final product should be well protected from temperature and humidity and, for example, cooling process before compression should be considered.

Atomic layer deposition-A novel method for the ultrathin coating of minitablets.

We introduce atomic layer deposition (ALD) as a novel method for the ultrathin coating (nanolayering) of minitablets. The effects of ALD coating on the tablet characteristics and taste masking were investigated and compared with the established coating method. Minitablets containing bitter tasting denatonium benzoate were coated by ALD using three different TiO2 nanolayer thicknesses (number of deposition cycles). The established coating of minitablets was performed in a laboratory-scale fluidized-bed apparatus using four concentration levels of aqueous Eudragit® E coating polymer. The coated minitablets were studied with respect to the surface morphology, taste masking capacity, in vitro disintegration and dissolution, mechanical properties, and uniformity of content. The ALD thin coating resulted in minimal increase in the dimensions and weight of minitablets in comparison to original tablet cores. Surprisingly, ALD coating with TiO2 nanolayers decreased the mechanical strength, and accelerated the in vitro disintegration of minitablets. Unlike previous studies, the studied levels of TiO2 nanolayers on tablets were also inadequate for effective taste masking. In summary, ALD permits a simple and rapid method for the ultrathin coating (nanolayering) of minitablets, and provides nanoscale-range TiO2 coatings on porous minitablets. More research, however, is needed to clarify its potential in tablet taste masking applications.

Measurement of pharmaceutical particles using a time-of-flight particle sizer.

The Aerosizer is an instrument for time-of-flight measurement, which is widely used in particle size determinations. The results of various studies indicate that there are still some problems related to the optimization of the analysis conditions. In this study, the behaviour of a set of different kinds of pharmaceutical particles during Aerosizer measurements was studied. An Aerosizer LD equipment with an Aero-Disperser was validated with particle size standards. Volume particle size distributions of particles with different size and shape characteristics were determined (PVP, Celphere, lactose, a drug substance, PHB microparticles). The aim was to investigate the effects of the shear force and deagglomeration levels during the dispersion of the particles on the particle size distributions that were obtained. The results of this study indicate that the ability of the instrument to disperse particles is highly dependent on the properties of the materials. According to the validation measurements, the instrument gives accurate results for spherical, uncohesive particles. The capability of the dispersing unit to separate particles aerodynamically was well observed with PVP. Time-of-flight measurements were uncomplicated for relatively large particles, such as Celphere, which have little interaction with each other and with the instrument housing. For lactose, increasing shear force rates resulted in size distributions with larger particle sizes. In the case of the PHB microparticles the results indicated that the aggregates became smaller and particles were partly separated to primary particles with all shear force levels.

Evaluation of solid dispersion particles prepared with SEDS.

Formation of solid solution particles in the Solution Enhanced Dispersion by Supercritical fluids (SEDS) process from a model drug and two different types of carriers, mannitol and Eudragit E100 was evaluated. The crystal properties of samples and molecular interactions were investigated with DSC and FTIR, respectively. The effect of co-crystallisation of drug and mannitol on dissolution rate was studied. Even if a true one-phase solid dispersion was not obtained, the crystal structure of both drug and mannitol was mutually affected by the presence of the other. The drug was not in highly crystalline form in the co-precipitates. The interactions between the drug and mannitol could also be identified as hydrogen bonding between the amine or hydroxyl groups of the drug and the hydroxyl groups of mannitol. These interactions and changes in the crystal structure are probably directly related to the increase in the dissolution rate observed. A true solid solution was obtained when the drug was co-processed with Eudragit E100. A clear interaction between the acid hydroxyl group of the drug and the basic carbonyl group on the Eudragit E100 was observed. SEDS was shown to be an effective process for forming intimate blends and solid solutions for the drug and two different types of carriers.

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.