Compaction properties of crystalline pharmaceutical ingredients according to the Walker model and nanomechanical attributes.

This study investigates the extent to which single-crystal mechanical properties of selected active ingredients (famotidine, nifedipine, olanzapine, piroxicam) influence their bulk compressibility and compactibility. Nanomechanical attributes of oriented single crystals were determined with instrumented nanoindentation, and bulk deformational properties were assessed with the Walker and Heckel models as well as the elastic relaxation index. Good correlations were established between bulk and single-crystal plasticity parameters: the Walker coefficient and indentation hardness. The Walker model showed more practical value for evaluating bulk deformational properties of the APIs investigated because their properties differed more distinctly compared to the Heckel model. In addition, it was possible to predict the elastic properties of the materials investigated at the bulk level because a correlation between the elastic relaxation index and compliance was established. The value of using indentation hardness for crystalline APIs was also confirmed because their compactibility at the bulk level was able to be predicted. Mechanically interlocked structures were characteristic of most polymorphic forms investigated, resulting in single crystals having isotropic mechanical properties. It was revealed that in such cases good correlations between single and bulk mechanical properties can be expected. The results imply that innate crystal deformational properties define their compressibility and compactibility properties to a great extent.

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.

Microparticle size control and glimepiride microencapsulation using spray congealing technology.

Drug-free microparticles were prepared using a spray congealing process with the intention of studying the influence of processing parameters. By varying the atomizing pressure and liquid feed rate, microparticles with median sizes (d((0.5))) from 58 to 278 microm were produced, with total process yields ranging from 81% to 96%. An increased liquid feed rate was found to increase microparticle size, and higher atomizing pressures were found to decrease microparticle size. Greater change in microparticle size was achieved by varying atomizing pressure, which can be considered a dominant process parameter regarding microparticle size. In addition, microparticles with glimepiride, a model poorly water-soluble drug, were prepared by spray congealing using three different hydrophilic meltable carriers: Gelucire 50/13, poloxamer 188, and PEG 6000. Spherical microparticles with relatively smooth surfaces were obtained, with no drug crystals evident on the surfaces of drug-loaded microparticles. XRPD showed no change in crystallinity of the drug due to the technological process of microparticle production. All glimepiride-loaded microparticles showed enhanced solubility compared to pure drug; however, Gelucire 50/13 as a carrier represents the most promising approach to the dissolution rate enhancement of glimepiride. The influence of storage (30 degrees C/65% RH for 30 days) on the morphology of glimepiride/Gelucire 50/13 microparticles was studied, and the formation of leaf-like structures was observed (a "blooming" effect).

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.

Investigation of the felodipine glassy state by atomic force microscopy.

The glassy state of felodipine was prepared by melting crystals of felodipine on a clean glass slide and cooling to room temperature. It has been confirmed that glassy felodipine is a metastable state, and undergoes transformation to the more stable crystalline form. Crystallization occurred slowly and spontaneously at room temperature, below the glassy state transition temperature (Tg). The contact mode of atomic force microscopy was used for topographical imaging of the glassy and crystalline states of felodipine. When the glassy felodipine region next to the recrystallized zone was exposed to controlled mechanical stress through the tip, rapid additional crystallization was observed. This crystallization process can be induced and imaged in real time by atomic force microscopy.

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.

The influence of magnesium stearate on the characteristics of mucoadhesive microspheres.

Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, x-ray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential scanning calorimetry. No differences were observed in the physical state of pipemidic acid and in microsphere shape and surface between different size fractions of microspheres, prepared with different amounts of magnesium stearate. Additionally, no correlation between the physical state of the drug in different microspheres and their biopharmaceutical properties was found.

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.

Micronization of drugs using supercritical carbon dioxide.

Particles from gas saturated solutions, a novel method for high pressure material processing, has been used for micronization of practically insoluble calcium-channel blockers nifedipine and felodipine and the hypolipidemic agent fenofibrate with the aim of increasing their dissolution rate and hence their bioavailability. Dependent on the pre-expansion conditions, a mean particle size of between 15 and 30 microm was achieved for micronized nifedipine and 42 microm for micronized felodipine. The particle size of processed fenofibrate, on the other hand, increased due to agglomeration. The highest dissolution rate was achieved by preparation of drug coprecipitates with PEG 4000.

Alternative solvent-free preparation methods for felodipine surface solid dispersions.

Surface solid dispersions were prepared via physical mixture and were either heated in a vacuum dryer or in a microwave oven for different periods of time. The physical state of felodipine in solid dispersions was studied using differential scanning calorimetry and x-ray powder diffractometry. USP paddle method was used for felodipine dissolution studies. The use of vacuum or microwave energy led to a significant improvement of felodipine dissolution which was caused partly by the amorphous state of felodipine and a large surface area of amorphous silicon dioxide.

Compatibility study between acetylcysteine and some commonly used tablet excipients.

Differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FT-IR), HPLC and TLC were used to investigate the interactions between the mucolytic drug acetylcysteine and a number of commonly used tablet and capsule excipients. Acetylcysteine was found to be compatible with microcrystalline cellulose (Avicel PH 101), sodium carboxymethylcellulose, amorphous silicon dioxide (Aerosil), PVP, cross-linked PVP (Polyplasdone XL), corn starch, saccharose and magnesium stearate. Acetylcysteine thermal stability (onset degradation temperature) was decreased in mixtures with corn starch, magnesium stearate, saccharose and lactose. Interactions of acetylcysteine with lactose, PEG 4000 and 6000, glycine, adipic acid and saccharin sodium were found using DSC and studied in detail with FT-IR, HPLC and TLC. The results suggest that acetylcysteine in mixtures with PEG 4000, glycine or saccharin sodium is degraded during storage at conditions of high temperature and humidity.

[The influence on some physicochemical parameters on drug release from PMMA salt hydrogels]. / Einfluss einiger physikochemischer Parameter auf die Wirkstofffreisetzung aus PMMA-Salz-Hydrogelen.

In vitro drug liberation results from PMMA (Eudispert)-salt hydrogels are explained from the aspect of polymer concentration, polymer molecular mass, viscosity as well of neutralisation grade and cation (Na+, K+, NH+4, ethanolamine, triethanolamine) of the polymer molecule and solubility properties of the drugs. Drug diffusion through hydrogel is regulated with the polymer network, in dependence of polymer nature and further with die mobility of water. The considered influences predominantly cover each other.

[Drug liberation from dermatica (author's transl)]. / Wirkstoff-Freisetzung aus Dermatica.

Investigated 0,1% ointments based on oleogels, hydrogels and O/W creams show differences by in-vitro evaluation of dexamethasone sodiumphosphate and dexamethasone release, which we have evaluated concerning the vehicle composition and its viscosity, the internal structure of systems and the drug properties. The results show dependence of drug availability on the vehicle gel structure order on the one, and on the drug activity on the other hand. The presence of a hydrocolloid (Eudispert-Na) in O/W creams improves the drug release.