Stanko Srčič

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.

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.

Polymorphism and pseudopolymorphism: Influencing the dissolution properties of the guanine derivative acyclovir

Abstract In this work we established that acyclovir exists in hydrated form and that the ratio between acyclovir and water molecules in the crystal structure is 3:2. The anhydrous crystalline form of acyclovir was also prepared. Both crystalline forms were examined by means of thermal analyses, X-ray powder diffraction, infrared spectroscopy, solubility and dissolution rate studies. The differences in almost all tested parameters between the acyclovir hydrated and anhydrous forms were observed. They were explained by different crystal forms of the substances examined. It was found, that besides hydrate, two anhydrous forms of acyclovir are present: the unstable one, obtained at a drying temperature below 150°C (which converts to the hydrate almost immediately in the atmosphere), and the stable one, obtained at drying temperatures above 150°C (which shows, on heating to 172°C, the solid-solid transition). It was thus postulated that acyclovir can exist as a pseudopolymorphic and polymorphic solvate.

Investigation of felodipine polymorphism and its glassy state

Abstract Felodipine (ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate) was investigated by means of DSC, FTIR and X-ray diffraction and three different polymorphic forms, designated as I–III, respectively, were found. During heating, no interconversion of any polymorphic form took place. After cooling the felodipine melt (in liquid N 2 or at ambient temperature) the glassy state was formed. The existence of glassy felodipine was confirmed by spin-lattice ( T 1 ) and spin-spin ( T 2 ) relaxation time measurements on a Bruker Pulse NMR spectrometer. During the heating of glassy felodipine recrystallization took place and two additional polymorphic forms, referred to as Im and IIIm, were observed.

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.

Some physicochemical properties of glassy felodipine

Abstract Felodipine, a normally crystalline and very slightly soluble Ca-antagonist was prepared in glassy form and some of its physicochemical properties were determined. The glassy state was confirmed by X-ray diffraction method, scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The influence of the cooling rate of the melt and the heating rate of the glass formed on the glass transition temperature was examined. The jump of the heat capacity, the area under the anomalous endothermic peak and the activation energy of the glass transition were calculated. The influence of the heating rate of the glassy felodipine on its crystallization was studied and the kinetic data of the crystallization were obtained. Dissolution tests were carried out and differences were established.

Determination of Solubility Parameters of Ibuprofen and Ibuprofen Lysinate

In recent years there has been a growing interest in formulating solid dispersions, which purposes mainly include solubility enhancement, sustained drug release and taste masking. The most notable problem by these dispersions is drug-carrier (in)solubility. Here we focus on solubility parameters as a tool for predicting the solubility of a drug in certain carriers. Solubility parameters were determined in two different ways: solely by using calculation methods, and by experimental approaches. Six different calculation methods were applied in order to calculate the solubility parameters of the drug ibuprofen and several excipients. However, we were not able to do so in the case of ibuprofen lysinate, as calculation models for salts are still not defined. Therefore, the extended Hansen’s approach and inverse gas chromatography (IGC) were used for evaluating of solubility parameters for ibuprofen lysinate. The obtained values of the total solubility parameter did not differ much between the two methods: by the extended Hansen’s approach it was δt = 31.15 MPa0.5 and with IGC it was δt = 35.17 MPa0.5. However, the values of partial solubility parameters, i.e., δd, δp and δh, did differ from each other, what might be due to the complex behaviour of a salt in the presence of various solvents.

Comparative study of the uniformity of coating thickness of pellets coated with a conventional Wurster chamber and a swirl generator-equipped Wurster chamber.

This study evaluated the performance of two bottom-spray coaters and the effect of pellet-size variability on coating uniformity. A conventional Wurster chamber was used for the first group of trials, and a Wurster chamber with a novel swirl-flow generator design was used for the second. The results confirmed that when using a conventional Wurster coating chamber, pellets with a smaller diameter receive significantly less coating material compared to those with larger diameters. The swirl generator-equipped Wurster chamber achieved close to uniform coating thickness regardless of pellet size. The ratio (MS) of the mass of dye deposited in the coating layer to pellet surface area indicates that coating was much more evenly distributed using the swirl-flow coater. Coating thickness was also analyzed using SEM micrographs and the results were in close agreement with the MS factor values. Inter-particle coating mass variation was also lower in case of swirl-flow coater. The results of this study show that a swirl-flow coater is suitable for coating particles of variable size. They also showed an improvement in coating process yield when using the swirl-flow coater.

Fluid-bed coater modifications and study of their influence on the coating process of pellets

Objective: In this study, different modifications of bottom spray fluid-bed coater with draft tube inserted were characterized and evaluated. Materials and methods: After coating the neutral pellets with polymeric solution comprising coloring agent pellet batches were characterized for coating variation, yield and degree of agglomeration. Results: Funnel-shaped distribution plate was found to improve process yield and decrease the degree of agglomeration at selected values of process parameters, whereas coating uniformity was worse in all cases when compared to conventional Wurster chamber. Results of the coating chamber with the swirl airflow generator indicate more uniform deposition of the coating material and in some cases an improved process yield and decreased formation of agglomerates when compared to conventional Wurster chamber. In series of experiments using Wurster chamber, having tangentially oriented air intake slots, which enabled introduction of air above the distribution plate, coating layer was more uniformly deposited on the pellet cores and formation of agglomerates was lower compared to the results obtained in a conventional Wurster coating chamber. Conclusion: Modifications of Wurster coating process by introducing swirling air motion within the draft tube or by introduction of air above the distribution plate have at selected values of process parameters resulted in reduced per-particle coating variation, degree of agglomeration and improved process yield.

In silico modeling of in situ fluidized bed melt granulation.

Fluidized bed melt granulation has recently been recognized as a promising technique with numerous advantages over conventional granulation techniques. The aim of this study was to evaluate the possibility of using response surface methodology and artificial neural networks for optimizing in situ fluidized bed melt granulation and to compare them with regard to modeling ability and predictability. The experiments were organized in line with the Box-Behnken design. The influence of binder content, binder particle size, and granulation time on granule properties was evaluated. In addition to the response surface analysis, a multilayer perceptron neural network was applied for data modeling. It was found that in situ fluidized bed melt granulation can be used for production of spherical granules with good flowability. Binder particle size had the most pronounced influence on granule size and shape, suggesting the importance of this parameter in achieving desired granule properties. It was found that binder content can be a critical factor for the width of granule size distribution and yield when immersion and layering is the dominant agglomeration mechanism. The results obtained indicate that both in silico techniques can be useful tools in defining the design space and optimization of in situ fluidized bed melt granulation.