Patrick Rombaut

Comparative study on xanthan gum and hydroxypropylmethyl cellulose as matrices for controlled-release drug delivery I. Compaction and in vitro drug release behaviour

A comparative investigation has been undertaken to assess the performance of xanthan gum (XG) and hydroxypropylmethyl cellulose (HPMC) as hydrophilic matrix-forming agents in respect of compaction characteristics and in vitro drug release behaviour. The overall compaction characteristics are found to be quite similar to each other and typical of polymer behaviour. But the flow characteristics are different, i.e., XG is more readily flowable than HPMC. The observed difference in drug release profiles between these two potential excipients are explored and explained by the difference in their hydrophilicity and subsequent hydration properties.

Influence of Preparation Methods on Solid State Supersaturation of Amorphous Solid Dispersions: A Case Study with Itraconazole and Eudragit E100

PurposeThe present study aims to determine the drug / polymer miscibility level as a function of the preparation method for an amorphous solid dispersion model system containing itraconazole and eudragit E100. This value was compared to the theoretical crystalline drug solubility in the amorphous polymer and the miscibility of the amorphous drug in the amorphous polymer.MethodsThe amorphous solid dispersions were prepared via spray drying and film casting in order to evaluate the influence of the solvent drying rate. The experimental miscibility level was estimated using XRPD, MDSC, FT-IR, HPLC and TGA. The solubility and miscibility were estimated using the Flory-Huggins mixing theory and experimental drug in monomer solubility data.ResultsThe experimental miscibility level was found to be 27.5% w/w for spray-dried and 15% for film-casted solid dispersions. FT-IR measurements confirmed the absence of saturable interactions like hydrogen bonds, and analysis of the mixed glass transition temperatures suggested low adhesion forces in the amorphous mixture. The solubility analysis rendered a positive FH interaction parameter, a crystalline solubility of approximately 0.012% w/w and an amorphous drug-polymer miscibility of approximately 7.07% w/w.ConclusionThe solid dispersions are significantly supersaturated with respect to both crystalline solubility and amorphous miscibility demonstrating the influence of manufacturing methodology.

PLGA nanoparticles and nanosuspensions with amphotericin B: Potent in vitro and in vivo alternatives to Fungizone and AmBisome.

This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) and nanosuspensions with the polyene antibiotic amphotericin B (AmB). The nanoformulations were prepared using nanoprecipitation and were characterised with respect to size, zeta potential, morphology, drug crystallinity and content. Standard in vitro sensitivity tests were performed on MRC-5 cells, red blood cells, Leishmania infantum promastigotes and intracellular amastigotes and the fungal species Candida albicans, Aspergillus fumigatus and Trichophyton rubrum. The in vivo efficacy was assessed and compared to that of Fungizone and AmBisome in the acute A. fumigatus mouse model at a dose of 2.5 and 5.0mg/kg AmB equivalents. The developed AmB nanoformulations were equivalently or more effective against the different Leishmania stages and axenic fungi in comparison with the free drug. The in vitro biological activity, and especially hemolytic activity, clearly depended on the preparation parameters of the different nanoformulations. Further, we demonstrated that the superior in vitro antifungal activity could be extrapolated to the in vivo situation. At equivalent dose, the optimal AmB-loaded PLGA NP was about two times and the AmB nanosuspension about four times more efficacious in reducing the total burden than AmBisome. The developed AmB nanomedicines could represent potent and cost-effective alternatives to Fungizone and AmBisome.

Inulin hydrogels. II. In vitro degradation study

Inulin hydrogels have been developed as potential new carriers for colonic drug targeting. Since site-specific drug release of this delivery system is based on its bacterial degradation in the colon, the enzymatic digestibility of the prepared inulin hydrogels was assessed by performing an in vitro study using an inulinase preparation derived from Aspergillus niger. The amount of fructose liberated from the inulin hydrogels by the action of inulinase was quantified using the anthrone method. The equilibrium swelling ratio as well as the mechanical strength of the hydrogels were studied before and after incubation in inulinase solutions. The data obtained by these different methods indicate that enzymatic digestion of the inulin hydrogels appeared to be enhanced by a prolonged degradation time, a higher inulinase concentration and a lower degree of substitution and feed concentration of the hydrogel polymer. The inulin hydrogels exhibited an increase in equilibrium swelling after degradation compared to the swelling before degradation, suggesting that inulinase enzymes are able to diffuse into the inulin hydrogel networks causing bulk degradation.

Spray drying from complex solvent systems broadens the applicability of Kollicoat IR as a carrier in the formulation of solid dispersions

The presented study aims to explore the feasibility of preparing solid dispersions of the poorly soluble drug, itraconazole, with Kollicoat IR via spray drying, in order to broaden the application window of the polymer. In order to circumvent the need for a common solvent, Kollicoat IR was dissolved in a 50/50 (v/v) water/ethanol mixture and itraconazole was dissolved in a 50/50 (v/v) dichloromethane/ethanol mixture. In a first approach these two solutions were simultaneously spray dried via a spray nozzle with two inlets. In a second approach the two solutions were mixed prior to spray drying and the metastable solution was spray dried via a spray nozzle with a single inlet. This approach was also varied by adding HCl to the water phase of the Kollicoat IR solution. The resulting solid dispersions were characterized with MDSC, XRPD and their dissolution was followed in SGF. The results of the three data sets show that as the mixing between itraconazole and Kollicoat IR improves, the dissolution improves as well. Using the first approach, no mixing was observed between polymer and drug. The second approach on the other hand led to a reasonable degree of mixing as the solid dispersions were XRPD amorphous and no glassy mesofase of itraconazole was observed.

The Release Mechanism of an Oral Controlled-Release Delivery System for Indomethacin

This study was carried out to fully characterize the release kinetics of an oral controlled-release tablet formulation of indomethacin with xanthan gum. Matrix swelling, matrix erosion, and drug diffusion studies were performed to elucidate the operative release mechanisms of a tablet compressed from a ternary mixture of indomethacin-xanthan gum-lactose. Drug release tests were performed according to the USP paddle method in phosphate buffer pH 7.4, concurrently with the dissolution of the gum. Mean dissolution time (MDT) of the drug was calculated from the release profile and it was used as a parameter to evaluate the influence of (a) polymer content in the dosage form, (b) ionic strength of the medium, and (c) the rotation speed of the paddle on the release characteristics of the drug. There is a linear relationship between MDT and the inverse of polymer content. Within the range of ionic strength of the gastrointestinal tract, the salt concentration of the dissolution medium has a negative (inhibitory) effect on release rate of the drug and on matrix swelling. A positive (enhancing) influence of the salt concentration on drug diffusion in the hydrated matrices was noted. The polymer dissolution follows almost immediately the dissolution of the drug. A linear relationship between MDT and the inverse of paddle rotation speed has been observed. Swelling-controlled erosional process is the operative mechanism for indomethacin release from xanthan gum matrices.

Influence of polyethylene glycol chain length on compatibility and release characteristics of ternary solid dispersions of Itraconazole in polyethylene glycol/hydroxypropylmethylcellulose 2910 E5 blends

The present study aims to elucidate the influence of the polyethylene glycol chain length on the miscibility of PEG/HPMC 2910 E5 polymer blends, the influence of polymer compatibility on the degree of molecular dispersion of itraconazole, and in vitro dissolution. PEG 2000, 6000, 10,000 and 20,000 were included in the study. Solid dispersions were prepared by spray drying and characterized with MDSC, XRPD and in vitro dissolution testing. The polymer miscibility increased with decreasing chain length due to a decrease in the Gibbs free energy of mixing. Recrystallization of itraconazole occurred as soon as a critical temperature of ca. 75 degrees C was reached for the glass transition that represents the ternary amorphous phase. Due to the lower miscibility degree between the longer PEG types and HPMC 2910 E5, the ternary amorphous phase was further separated, leading to a more rapid decrease of the ternary amorphous phase glass transition as a function of PEG and itraconazole weight percentage and hence, itraconazole recrystallization. In terms of release, an advantage of the shorter chain length PEG types (2000, 6000) over the longer chain length PEG types (10,000, 20,000) was observed for the polymer blends with 5% of PEG with respect to the binary itraconazole/HPMC 2910 E5 solid dispersion. Among the formulations with a 15/85 (w/w) PEG/HPMC 2910 E5 ratio on the other hand, there was no difference in the release profile.

Shape and surface smoothness of pellets made in a rotary processor

Abstract The shape and surface smoothness of pellets made in a rotary processor by the wet granulation technique has been studied. Optical microscopy combined with image analysis was used to determine three shape parameters (circularity, roundness and elongation) and the fractal dimension, which is a characteristic for the surface smoothness of the pellets. This study reveals that pellets made in a rotary processor by the wet granulation technique are more variable in terms of their sphericity than in terms of their elongation. In order to obtain very spherical pellets, spheronization should go on for a long time with sufficient intensity. Furthermore, the spheronization enhancing properties of microcrystalline cellulose—thanks to its plastic properties when wetted—are confirmed. The fractal dimensions of the surface are close to 2, indicating that the pellets are characterized by a rather smooth surface. Nevertheless, small but significant differences in surface smoothness can be detected using this fractal approach. From the experiments performed in this study, it can be concluded that using the wet granulation technique in the rotary processor under the appropriate conditions, it is possible to produce excellent pellets in terms of sphericity and surface smoothness.

Effect of Compression on Non-isothermal Crystallization Behaviour of Amorphous Indomethacin

ABSTRACTPurposeTo evaluate the effect of tablet compression on the physical stability of amorphous indomethacin.MethodsThe amorphous indomethacin generated by melt cooling, rapid (5°C/min) or slow (0.2°C/min) cooling, was evaluated by PXRD, mDSC and FTIR analysis. Non-isothermal crystallisation behaviour was assessed using mDSC and any structural changes with compression were monitored by FTIR. Amorphous indomethacin was compressed in a DSC pan using a custom made die cavity-punch setup and further analysed in the primary container to minimize stress due to sample transfer and preparation.ResultsCompression of amorphous indomethacin induced and increased the extent of crystallisation upon heating. DSC results revealed that amorphous indomethacin generated by rapid cooling is more prone to compression induced crystallisation than the slowly cooled one. Onset temperature for crystallisation (Tc) of uncompressed slowly and rapidly cooled samples are 121.4 and 124°C and after compression Tc decreased to ca 109 and ca 113°C, respectively. Compression of non-aged samples led to higher extent of crystallisation predominantly into γ-form. Aging followed by compression led to crystallisation of mainly the α-form.ConclusionsCompression affects the physical stability of amorphous indomethacin. Structural changes originated from tablet compression should be duly investigated for the stable amorphous formulation development.

Internal and external structure of pellets made in a rotary processor

The internal and external structure of pellets made in a rotary processor by the wet granulation technique was studied using the following techniques: helium pycnometry to determine the true density, krypton adsorption to determine the specific surface area, mercury porosimetry, and scanning electron microscopy. The results of the true density measurements, specific surface area determinations and mercury porosimetry led to the hypothesis that the pellets were open porous sponge structures. Mercury mainly intruded in the macropore range (pores with a radius between 7 and 0.05 μm). The pores and cavities were partially closed as spheronization went on leading to air pockets in the pellets. Scanning electron microscopic pictures provided visual support for the hypothesis that the pellets had a porous surface and that the pellets contained cavities, which could be closed resulting in the formation of air pockets. To reduce the pore volume and smooth the surface, the rotor speed should be high and the spheronization time should be long. The plastic properties of wetted microcrystalline cellulose promoted the smoothing of the surface.