Monitoring of Pentoxifylline Thermal Behavior by Novel Simultaneous Laboratory Small and Wide X-Ray Scattering (SWAXS) and Differential Scanning Calorimetry (DSC).

The thermal and structural evolutions associated to active pharmaceutical ingredient (API) purity are monitored using a laboratory instrument (S3-MicroCaliX) allowing simultaneous time-resolved X-ray scattering at both wide and small angles (SWAXS) as a function of temperature. This is performed simultaneously with differential scanning calorimetric (DSC) that is carried out in the same apparatus at scanning rate of 2 K/min on the same sample in the range from 20° to 200°C. We have studied simultaneous thermal and structural properties of pentoxifylline, as an active pharmaceutical ingredient (API), for its purity quality control. We have found a satisfying API purity, due to obtained melting temperature and enthalpy values, which are in a well agreement with literature. We have also found that the combination of these techniques allows the thermal monitoring of scanning rates of 2 K/min, continuously without the need for static thermal equilibration, particularly for X-ray spectra. Hence, DSC and SWAXS allowing better identification of the structural thermal events recorded by following of the phase transitions simultaneously. This interpretation is much better possible when X-ray scattering at small and wide angles is coupled with DSC from the same sample. Hence, as a laboratory tool, the method presents a reproducible thermal and crystallographic API purity quality control of non-complex samples, as crucial information for pharmaceutical technology.

Pore blocking: An innovative formulation strategy for the design of alcohol resistant multi-particulate dosage forms.

In this work calcium stearate (CaSt) multi-particulates loaded with codeine phosphate (COP) were developed in an attempt to provide extended release (ER) combined with alcohol dose dumping (ADD) resistance. The pellets were prepared via wet/extrusion spheronization and ER characteristics were obtained after fluid bed drying at 30°C. Pore blockers (i.e., xanthan, guar gum and TiO2) were integrated to control the uptake of ethanolic media, the CaSt swelling and consequently, the COP release. While all three pore blockers are insoluble in ethanol, xanthan dissolves, guar gum swells and TiO2 does not interact with water. The incorporation of 10 and 15% TiO2 still provided ER characteristics and yielded ADD resistance in up to 40v% ethanol. The in-vitro data were subjected to PK simulations, which revealed similar codeine plasma levels when the medication is used concomitantly with alcoholic beverages. Taken together the in-vitro and in-silico results demonstrate that the incorporation of appropriate pore blockers presents a promising strategy to provide ADD resistance of multi-particulate systems.

NANEX: Process design and optimization.

Previously, we introduced a one-step nano-extrusion (NANEX) process for transferring aqueous nano-suspensions into solid formulations directly in the liquid phase. Nano-suspensions were fed into molten polymers via a side-feeding device and excess water was eliminated via devolatilization. However, the drug content in nano-suspensions is restricted to 30 % (w/w), and obtaining sufficiently high drug loadings in the final formulation requires the processing of high water amounts and thus a fundamental process understanding. To this end, we investigated four polymers with different physicochemical characteristics (Kollidon(®) VA64, Eudragit(®) E PO, HPMCAS and PEG 20000) in terms of their maximum water uptake/removal capacity. Process parameters as throughput and screw speed were adapted and their effect on the mean residence time and filling degree was studied. Additionally, one-dimensional discretization modeling was performed to examine the complex interactions between the screw geometry and the process parameters during water addition/removal. It was established that polymers with a certain water miscibility/solubility can be manufactured via NANEX. Long residence times of the molten polymer in the extruder and low filling degrees in the degassing zone favored the addition/removal of significant amounts of water. The residual moisture content in the final extrudates was comparable to that of extrudates manufactured without water.

Development of an Abuse- and Alcohol-Resistant Formulation Based on Hot-Melt Extrusion and Film Coating.

This study focused on the development of flexible (i.e., deformable) multiple-unit pellets that feature (i) a prolonged drug release, (ii) drug abuse deterrence, and (iii) a minimal risk of alcohol-induced dose dumping (ADD). Deformable pellets were prepared via an advanced continuous one-step hot-melt extrusion (HME) technique, with the drug (i.e., antipyrine and codeine phosphate) fed as an aqueous solution into the molten matrix material (i.e., cornstarch, gum arabic, and xanthan). Formulations that had suitable mechanical characteristics (i.e., high compression strength) were coated with a flexible Aquacoat(®) ARC film to ensure prolonged release and to avoid ADD. The pellets were characterized in terms of their mechanical properties and in vitro drug release behavior in alcoholic media. All formulations were abuse deterrent: they had a high compression strength and grinding the pellets into powder was impossible. Since the pellets comprising gum arabic and xanthan as a matrix did not remain intact during dissolution testing, they had a very fast drug release rate. Cornstarch-based pellets that swelled but remained intact in the dissolution media had a slower drug release. Coated cornstarch-based pellets had a prolonged release over 8 h and resistance to dose dumping in 20 and 40% ethanol. Our results indicate that cornstarch-based pellets manufactured via the advanced HME process followed by coating are a promising formulation that makes tampering difficult due to a high compression strength combined with robustness in alcoholic media.

Crystallographic textures and morphologies of solution cast Ibuprofen composite films at solid surfaces.

The preparation of thin composite layers has promising advantages in a variety of applications like transdermal, buccal, or sublingual patches. Within this model study the impact of the matrix material on the film forming properties of ibuprofen-matrix composite films is investigated. As matrix materials polystyrene, methyl cellulose, or hydroxyl-ethyl cellulose were used. The film properties were either varied by the preparation route, i.e., spin coating or drop casting, or via changes in the relative ratio of the ibuprofen and the matrix material. The resulting films were investigated via X-ray diffraction and atomic force microscope experiments. The results show that preferred (100) textures can be induced via spin coating with respect to the glass surface, while the drop casting results in a powder-like behavior. The morphologies of the films are strongly impacted by the ibuprofen amount rather than the preparation method. A comparison of the various matrix materials in terms of their impact on the dissolution properties show a two times faster zero order release from methyl cellulose matrix compared to a polystyrene matrix. The slowest rate was observed within the hydroxyl ethyl cellulose as the active pharmaceutical ingredients (APIs) release is limited by diffusion through a swollen matrix. The investigation reveals that the ibuprofen crystallization and film formation is only little effected by the selected matrix material than that compared to the dissolution. A similar experimental approach using other matrix materials may therefore allow to find an optimized composite layer useful for a defined application.

Dissolution testing of hardly soluble materials by surface sensitive techniques: clotrimazole from an insoluble matrix.

PURPOSE: The low aqueous solubility of many drugs impedes detailed investigation as the detection limit of standard testing routines is limited. This is further complicated within application relevant thin films typical used in patches or stripes for buccal or topical routes. METHODS: In this work a model system is developed based on spin - casting technique allowing defined clotrimazole and clotrimazole - polystyrene composite films preparation at a solid surface. Various highly sensitive techniques including quarz crystal microbalance (QCM), X-ray reflevtivity (XRR) and X-ray photon spectroscopy (XPS) are used to investigate the drug release over time into an aqueous media. RESULTS: The results reveal a steady drug release for both samples over the course of the experiments but with the release from the composite being significantly slower. In addition the dissolution rate of the clotrimazole sample initially increases up to 30 min after which a decrease is noted. XRR shows that this is a result of surface roughening together with film thickness reduction. The results for the composite show that the release in the composite film is a result of drug diffusion within the matrix and collapsing PS film thickness whereby XPS shows that the amount of clotrimazole at the surface after 800 min immersion is still high. CONCLUSION: It can be stated that the applied techniques allow following low mass drug release in detail which may also be applied to other systems like pellets or surface loaded nano-carriers providing information for processing and application relevant parameters.

In-line implementation of an image-based particle size measurement tool to monitor hot-melt extruded pellets.

This work focuses on the implementation and application of an in-line particle measurement tool to monitor particle properties of hot-melt extruded pellets. A novel image analysis system (Eyecon) is used to analyze pellets with a size of approximately 1mm. The method is based on photometric stereo imaging, which is achieved by three different-colored light sources arranged circularly around the lens. Several implementations, whereby the product stream was led through the optical sampling volume, have been tested. The advantages and disadvantages of each implementation are discussed and evaluated. The most suitable implementation was applied to an extrusion run with constant throughput and different cutting frequencies resulting in different pellet sizes. A particle size distribution comparison between the image analysis system and an off-line reference particle analysis (QICPIC) showed good agreement although only a small fraction of the particles were analyzed in-line. Additionally, some illustrative examples for process development are given. With this approach the capability of hot-die face pelletizing to manufacture nearly-spherical pellets with a narrow size distribution is proven.

Microstructure of calcium stearate matrix pellets: a function of the drying process.

Drying is a common pharmaceutical process, whose potential to modify the final drug and/or dosage form properties is often underestimated. In the present study, pellets consisting of the matrix former calcium stearate (CaSt) incorporating the active pharmaceutical ingredient ibuprofen were prepared via wet extrusion and spheronization. Subsequent drying was performed by either desiccation, fluid-bed drying, or lyophilization, and the final pellets were compared with respect to their microstructure. To minimize the effect of solute ibuprofen molecules on the shrinking behavior of the CaSt, low ibuprofen loadings were used, as ibuprofen is soluble in the granulation liquid. Pellet porosity and specific surface area increased during desiccation, fluid-bed drying, and lyophilization. The inlet-air temperature during fluid-bed drying affected the specific surface area, which increased at lower inlet-air temperatures rather than the pellet porosity. The in vitro dissolution profiles were found to be a nonlinear function of the specific surface area. Overall, the microstructure, including porosity, pore size, and specific surface area, of CaSt pellets was a strong function of the drying conditions.

Ibuprofen-loaded calcium stearate pellets: drying-induced variations in dosage form properties.

Pellets intended for oral dosing are frequently produced via extrusion/spheronization followed by drying. Typically, the last active process step, i.e., drying, is assumed to have little effect on the final dosage form properties (e.g., dissolution characteristics). Thus, there exist only a few studies of this subject. In the present study, calcium stearate/ibuprofen pellets were used as model system to investigate the impact of the drying conditions. Lipophilic calcium stearate matrix pellets containing 20% ibuprofen were prepared via wet extrusion/spheronization. Subsequently, desiccation, fluid-bed drying, and lyophilization were applied for granulation liquid removal. The impact of these drying techniques on the final pellet properties was evaluated. The in vitro dissolution behavior was dramatically altered by the drying techniques that were considered. The investigated pellets showed drug release rates that varied as much as 100%. As no polymorphic transitions occurred during drying, we focused on two possible explanations: (a) a change in the drug distribution within the pellets and (b) a change in pellet micro-structure (porosity, pore size). The ibuprofen distribution proved to be homogeneous regardless of the drying conditions. Pellet porosity and pore sizes, however, were modified by the drying process. Our results clearly demonstrate that a single process step, such as drying, can play a crucial role in achieving desired pellet properties and release profiles.

Use of the direct compression aid Ludiflash(®) for the preparation of pellets via wet extrusion/spheronization.

OBJECTIVE: Conventional solid oral dosage forms are unsuitable for children due to problems associated with swallowing and unpleasant taste. Additionally, the limit of tablets lays in the patient adapted dosing. Therefore, the suitability of Ludiflash(®), a direct compression aid for orally disintegrating tablets, was investigated for the preparation of individually dosable pellets. MATERIALS AND METHODS: Micropellets consisting of Ludiflash(®) and small amounts of microcrystalline cellulose were prepared via the wet extrusion/spheronization technique. Paracetamol and ibuprofen were applied as model drugs. The obtained pellets were characterized with respect to drug release and disintegration characteristics, mechanical properties, as well as size and shape. RESULTS AND DISCUSSION: Drug loading was possible up to 30% for ibuprofen and even up to 50% for paracetamol. Higher ibuprofen loadings resulted in considerably slowed drug release and higher paracetamol contents yielded in non-spherical pellets. In vitro release studies revealed that more than 80% of the drug was released within 30 and 60 min for paracetamol and ibuprofen, respectively. Drug release rates were highly influenced by the pellet disintegration behavior. Investigations of the release mechanism using the Korsemeyer-Peppas approach suggested Super Case II drug transport for all paracetamol formulations and anomalous drug transport for most ibuprofen formulations. All pellets exhibited a low porosity and friability, as well as a sufficiently high tensile strength, which was significantly influenced by the type of model drug. CONCLUSION: Ludiflash(®) can be applied as main excipient for the preparation of individually dosable pellets combining fast drug release and a high mechanical stability.