The effect of cores and coating dispersion composition on the mechanical and adhesion properties of hydroxypropyl methylcellulose films.

The influence of different additives on the mechanical properties of hydroxypropyl methylcellulose (HPMC) free films was studied using tensile testing. Free films were prepared using the cast method and sliced into bands, and their tensile strength and maximal elongation at break was measured. The results showed that the addition of PEG 400 and polysorbate 80 into the coating formulation had the most influence on the films' mechanical properties compared to the HPMC film used as a control. Tablet cores composed of microcrystalline cellulose and lactose with and without Mg stearate and compressed at three different compression forces were tested for wettability with coating formulations containing PEG 400 and polysorbate 80. For formulations with no Mg stearate added, the contact angle decreased with increasing core hardness and it also coincided with greater adhesion force of the coating. The addition of Mg stearate in the core led to reduced adhesion of the film coating with PEG 400, whereas the influence on the adhesion force of the film coating containing polysorbate 80 was negligible. The results also show that the adhesion force, regardless of the tablet core formulation, is highest at medium core hardness.

Consolidation trend design based on Young's modulus of clarithromycin single crystals.

The key aim of this study was to determine single mechanical properties of clarithromycin polymorphic forms in order to select some of them as more suitable for the tableting process. For this purpose, AFM single-point nanoindentation was used. The Young's moduli of clarithromycin polymorphs were substantially different, which was consistent with the structural variations in their packing motifs. The presence of the adjacent layers, which can easily slide over each other due to the low energy barrier (the lowest Young's modulus was 0.25 GPa) resulted in better bulk compressibility (the highest Heckel coefficient) of clarithromycin Form I. We also addressed the importance of tip geometry screening because the stress during the force mode often results in tip apex fracture. Even the initial manufacture of the diamond-coated tips can result in defects such as double-apex tips.

Understanding controlled drug release from mesoporous silicates: theory and experiment.

Based on the results of carefully designed experiments upgraded with appropriate theoretical modeling, we present clear evidence that the release curves from mesoporous materials are significantly affected by drug-matrix interactions. In experimental curves, these interactions are manifested as a non-convergence at long times and an inverse dependence of release kinetics on pore size. Neither of these phenomena is expected in non-interacting systems. Although both phenomena have, rather sporadically, been observed in previous research, they have not been explained in terms of a general and consistent theoretical model. The concept is demonstrated on a model drug indomethacin embedded into SBA-15 and MCM-41 porous silicates. The experimental release curves agree exceptionally well with theoretical predictions in the case of significant drug-wall attractions. The latter are described using a 2D Fokker-Planck equation. One could say that the interactions affect the relative cross-section of pores where the local flux has a non-vanishing axial component and in turn control the effective transfer of drug into bulk solution. Finally, we identify the critical parameters determining the pore size dependence of release kinetics and construct a dynamic phase diagram of the various resulting transport regimes.

Design of a drug delivery system with bimodal pH dependent release of a poorly soluble drug.

A delivery system which provides bimodal pH dependent release of poorly water soluble carvedilol in gastric and intestinal environment was designed. Preparation of solid dispersion with porous silica ensured a significantly higher dissolution rate of carvedilol in acidic and alkaline media in comparison to pure drug, while granulation of that solid dispersion with enteric polymer dispersion resulted in diminished immediate release in acidic media and fast release of the remaining drug in alkaline media. The ratio in quantities of first vs. second release was controlled with amount of enteric polymer dispersion used for granulation process. Desired 25 mg release of carvedilol at pH values 1.2 and 6.8 was achieved when 1.80 g of polymer per 1.0 g of solid dispersion (drug to silica ratio= 0.25 g : 2.0 g) was used.

Characterization of calcium alginate beads containing structurally similar drugs.

The aim of this study was to investigate the characteristics of alginate beads prepared by ionotropic gelation in which structurally similar drugs were incorporated. For this purpose theophylline and theobromine were selected as model drugs. The influence of incorporated drugs on bead characteristics such as size, shape, and morphology, as well as encapsulation efficiency, was examined. It was found that theobromine as well as theophylline content in beads significantly decreased with increasing hardening time due to drug diffusion into the hardening media. In theobromine beads the drug content was extremely improved by dropping the alginate and drug solution into an acidic calcium chloride solution, while theophylline content was to some extent improved by the hardening of beads in a calcium chloride solution saturated with the drug. The most evident difference between theophylline and theobromine beads was in their shape and morphology. Theobromine beads were round, while theophylline ones had an irregular shape with an extremely wrinkled surface. The distinction in shape was highly dependent on drug content. Additionally, it was demonstrated that beads' shape was dependent on preparation conditions as well. On the basis of x-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analyses and scanning electron microscope (SEM) photographs it was found that the most of the drug in bead was present in an amorphous state. Therefore, it is suggested that some drug-alginate interactions could be present in beads and might be responsible for the different shape of theophylline and theobromine beads. Thus it can be concluded that the preparation of beads by ionotropic gelation cannot be generalized even though structurally similar drugs are incorporated.

The dispersive component of the surface free energy of powders assessed using inverse gas chromatography and contact angle measurements.

The nonpolar parameter of solid surface free energy gamma(s)(d) has been determined for some pharmaceutical powders by means of contact angle measurement (Wilhelmy plate method) and inverse phase gas chromatography (IGC). For most samples, a good correlation between the results of the two methods was found. Additionally it was found that to get comparable results with the IGC method, contact angles obtained with totally nonpolar liquid should be used for calculating gamma(s)(d). Comparison of our results with those from the literature showed that the correlation depends on the method used for contact angle determination and the properties of the liquids used for contact angle measurements.

The utilization of surface free-energy parameters for the selection of a suitable binder in fluidized bed granulation.

Surface free energy was determined for model substances pentoxyfilline, acyclovir, lactose and binding agents (that were used in the granulation process) hydroxypropilmethyl cellulose (HPMC) and polyvinylpyrrolidone (PVP) were determined by contact angle measurements. The methods of Wu, Good-van Oss and Della Volpe were used for solid-surface free-energy calculation. Spreading coefficients (S) were calculated and correlated with granulate properties. Granulates consisted of model drug and binding agent, and were produced in fluid bed granulator Glatt powder coater granulator GPCG1 by means of spraying the colloidal solution of binder on the model substance. Granules contained either 5% or 10% binder. Inverse granules, however, were also produced by spraying the model drug (i.e. pentoxyfilline and lactose) on the binding agent (HPMC, PVP). Particle size distribution, friability, true density, bulk density and tapped density of the granulates were determined. Although many different parameters influence the granule properties, it has been found that the interactions between the drug and the binder play a very important role. Spreading coefficients were found to be in good correlation with the friability of granulates. Positive spreading coefficient values of the binder over the model substance correlate well with the low friability of the granules containing lower amount of binder, i.e. 5%. In the group of the same binder, the spreading coefficient values decrease from pentoxyfilline over lactose to acyclovir. Friability results show that, for the system under consideration, PVP offers certain advantages over the grade of HPMC employed. The increase of the binder amount from 5 to 10% resulted in more friable granulates. Lower work of cohesion of the binder (PVP and HPMC) than the work of adhesion between binder and the model substances is considered responsible for the higher friability of the granules. The inverse granulation process, where the suspension of the model substance was sprayed over the solid binder particles, proved more efficient with HPMC than with PVP. According to the spreading coefficient results, the binder should spread over the drug. However, the kinetics of wetting appears to play an important role in the granulation process. According to these results, the conclusion was made that water wets HPMC much faster than PVP.

Conformational analysis of 7-oxoacyl-L-alanyl-D-isoglutamines.

In a recent article (Planinsek, O., Srcic, S., 1999. Int. J. Pharm. 87, 199-207) some interesting physicochemical properties of a series N-(7-oxoacyl)-L-alanyl-D-isoglutamines with n=0-6 methylene groups between the terminal methyl and 7-oxo group were measured. In view of the practical importance of these N-acetylmuramyldipeptide(MDP) immunomodulator analogues and their interesting biological properties a detailed conformational analysis was undertaken for the series with n=3-6 methylene spacers between the 7-oxo and terminal methyl groups. The puzzle posed by the reversal of the measured water solubility and lipophylicity could be resolved by using the Monte Carlo approach to searching the conformational space of the molecules in this series. We have found that the increase in water solubility and drop in lipophylicity when the number of methylene groups is increased from 5 to 6 can be attributed to the change in predominant conformation in the conformational family as described by the Boltzmann distribution of conformations. Notwithstanding this, we point out the changes in biological response coupled to the nonlinearity of the physicochemical behaviour in the series.

Some physicochemical properties of 7-oxoacyl-L-alanyl-D-isoglutamines.

N-(7-Oxoacyl)-L-alanyl-D-isoglutamines are substances with similar effects on immune system as N-acetylmuramyldipeptide (MDP). They were synthesized to eliminate some side effects of MDP: pyrogenicity, leucopenia, hypertension and fast elimination from the body. The aim of our work was to determine some physicochemical properties of a series of N-(7-oxoacyl)-L-alanyl-D-isoglutamines, that have zero to six methylene groups between terminal methyl and 7-oxo group. The following properties were examined: water solubility, lipophilicity, thermal behaviour and true density. The results were compared and it was established that the lipophilic parameter determined by high-performance liquid chromatography is increasing by the increase of alkyl chain while the water solubility is decreasing at the same time. In both cases the substance with the longest chain (N-(7-tetrakanoyl)-L-alanyl-D-isoglutamine) is an exception. The lipophilic parameter of this substance is lower and water solubility higher than with the substances with three, four and five methylene groups between terminal methyl and 7-oxo group. These results can be explained by the twisted conformation of N-(7-tetrakanoyl)-L-alanyl-D-isoglutamine molecule in water solution. By means of thermal analysis it was discovered that the melting point is decreasing with the increase of alkyl chain. From the true density and melting enthalpy measurements it is evident that with the increase of alkyl chain the arrangement of molecules in solid state is increasing up to the molecule with four methylene groups between terminal methyl and 7-oxo group. Substances with longer chains have lower true density and melting enthalpy because of the different arrangements of the molecules.