Stane Srčič

Improvement of nifedipine dissolution characteristics using supercritical CO2

Abstract An application of supercritical fluids (SCFs) for processing of pharmaceuticals is presented. PGSS (Particles from Gas Saturated Solutions), a novel method for high pressure material processing, has been used to improve technological characteristics of the poorly water soluble calcium antagonist nifedipine. Nifedipine was micronized with PGSS and the influence of pre-expansion conditions on the particle size was studied. With PGSS, coprecipitates of nifedipine and PEG 4000 were prepared and evaluated. The solid dispersions had enhanced dissolution rates. The PGSS process shows some advantages over classical methods for solid dispersion preparation.

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 compressibility and compactibility of different types of lactose

Objective: The purpose of this study was to investigate and quantify flow properties, compressibility, and compactibility of various pharmaceutical lactose powders found on the market today (DCL-11, DCL-21, M‐200, Flowlac-100, and Tablettose 70, 80, and 100). Methods: Flow properties were estimated by measuring flow time, angle of repose, and the Hausner ratio. Particle rearrangement was studied using Kawakitas linear model. Compressibility was studied using two ‘out-of-die’ methods: (i) the Heckel model and (ii) a modified Walker model. Compactibility was quantified using two methods: (i) the tensile strength profile (Cp) and (ii) the compactibility factor (Pr). Statistical approach was used to analyze the results. Results: Flow properties of all materials were passable or better, except for M-200, which has very poor flowability. Compressibility results demonstrated that the most compressible lactose is spray-dried grade of lactose (Flowlac-100) and the least compressible is milled lactose (M-200). Compactibility studies showed that β‐lactose (DCL-21) forms tablets with superior tensile strength in comparison with α-lactose. Conclusion: Results of the compressibility study showed that the discriminative power of modified Walker model is greater in comparison with Heckel model. Compactibility methods yield similar and comparable results.

Deformation properties of pharmaceutical excipients determined using an in-die and out-die method

This study investigated deformation mechanisms of some commonly used pharmaceutical fillers, such as microcrystalline cellulose, lactose, dicalcium phosphate, isomalt and cornstarch, using a combination of the in-die and out-die method with the Heckel and Walker models. The tableting mixtures contained of 98.5% (w/w) filler, the rest consisted of dry binder and an antiadhesive agent. Our results showed that plasticity and elasticity may be considered independent deformation properties as highly plastic materials (microcrystalline cellulose, cornstarch) also exhibited high elasticity. Particular emphasis was placed on explaining the differences observed between the in-die and out-die method-comparison revealed that the differences are a consequence of the materials elastic properties. Larger error of in-die results can be expected for more elastic materials, and thus in-die Heckel should be used with some considerations. In contrast, the Walker model was found to be more robust and smaller differences were observed between the two methods. We consider the most correct results to have been obtained by the out-die approach, which excludes the elastic properties of the material evaluated. An excellent correlation between elastic determination at the single-particle level and multiple-particle scale was demonstrated, suggesting a great potential of nanoscale determination of a materials mechanical properties for better elucidation of deformation mechanisms.

Influence of inverse gas chromatography measurement conditions on surface energy parameters of lactose monohydrate.

Surface energy of any powder determined by inverse gas chromatography (IGC) should be independent of the measurement conditions or type of column used. In this study stainless steel and glass columns were filled with lactose powder. Dispersive and polar components of surface free energy were determined at different flow rates of carrier gas using lactose alone or diluted with calcinated diatomite (Chromosorb W). It was found that measurement conditions did not influence the value of the dispersive parameter of surface energy. On the contrary, K(a) and K(d) values were found to be dependent on dilution of lactose with Chromosorb W. The influence of other parameters on the results was found to be much smaller.

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.

Characterization of agglomerated carvedilol by hot-melt processes in a fluid bed and high shear granulator

The purpose of this study was to prepare and characterize granulated carvedilol by melt-in and spray-on melt granulation in a fluid bed and a high shear granulator. Granulates having comparable particle size distribution and good flow properties were obtained with proper adjustment of process parameters for each binder (poloxamer 188, polyethylene glycol 4000, and gliceryl monosterate), procedure (spray-on and melt-in) and equipment (fluid bed and high shear granulator). In-line probes for particle size measurements proved to be a useful tool for determining the end point of melt granulation. The product temperature during melt granulation was found to be the critical process parameter for achieving appropriate granulate particle size distribution. The results showed that melt granulation using hydrophilic binders is an effective method to improve the dissolution rate of carvedilol. The method of binder addition to the powders (melt-in or spray-on procedure) was found to strongly influence the dissolution rate of carvedilol. The highest dissolution rates were obtained when the spray-on procedure is used, independently from the type of granulator used. The results also suggest that the most probable explanation for the increase in the dissolution rate of granulated carvedilol is improvement of the wettability through intimate contact between hydrophilic binder and hydrophobic drug.

Surface Treatment of Indomethacin Agglomerates with Eudragit

Indomethacin is a widely used anti‐inflammatory drug with serious side‐effects. This drug was used as a model drug for the coating of agglomerates with a permeable film (Eudragit NE). The agglomeration of the crystals increased the flowability of the bulk crystals. The coating further improved the flowability, and also the uniformity of the mass of the filled capsules. The coating film also influenced the wetting of the samples. The coating decreased the surface free energy and therefore reduced the adhesion forces between both the dry and the wet particles. The modification of the flow properties and the even capsule filling can be explained by this phenomenon. Since coating film does not dissolve in the artificial gastric juice, the dissolution test was performed only in the artificial intestinal juice. The dissolution of indomethacin from the coated sample was changed significantly. Accordingly, coating of the crystals can be performed in order to protect the mucosa of the gastrointestinal tract or to promote the preparation of solid dosage form.

Nanosized particles of orlistat with enhanced in vitro dissolution rate and lipase inhibition

Orlistat is locally acting inhibitor of gastrointestinal lipases which has been developed for the treatment of obesity. The present study was designed with the intent to formulate orlistat in a different way compared to the current practice and investigate its inhibition of gastrointestinal lipases. Orlistat is considered as a technologically problematic and unmanageable substance because of waxy nature, low melting point and low chemical stability. The manuscript presents the critical issues regarding engineering of its nanosuspension with controlled particle size by melt emulsification and high pressure homogenization. In order to formulate dry product, lactose was dissolved in nanosuspension as filler and spray drying has been performed for obtaining the final powder product. Laser diffraction, scanning electron microscopy and atomic force microscopy have been used for orlistat nanosuspension characterization, dissolution studies and lipase inhibition studies were performed to characterize the in vitro efficacy of formulated orlistat. The advantage of selected technological procedures is nanosized orlistat with elevated in vitro dissolution rate in comparison to raw drug, physical mixture and marketed product. Furthermore, nanosuspension demonstrated significantly higher in vitro lipase inhibition in comparison to references. To conclude, the results show new technological solution and remarkable increase of pharmacological effect which could potentially lead to decreasing the dose and consequently dose dependent side effects.

Application of 14N NQR to the Study of Piroxicam Polymorphism

A study was conducted to test the capability of the (14)N nuclear quadrupole resonance (NQR) method to discriminate qualitatively and quantitatively among different forms of piroxicam. Samples of commercial piroxicam form I and its monohydrate were obtained on the local market. Additionally, samples of form I and II were prepared by recrystallization in 1,2-dichloroethane and ethanol, respectively. DSC and FT-IR were employed as reference methods. A (14)N NQR spectrometer was used to measure samples of different forms and mixtures of piroxicam at 2587 and 3439  kHz. DSC and FT-IR clearly confirmed differences between the different piroxicam forms. Measurements of (14)N NQR signals of different forms of piroxicam at 2587  kHz detected only spectral peaks of form I. The dependence of (14)N NQR signal intensity on the concentration of form I in mixtures with the monohydrate showed a clear linear relationship at both measured frequencies, though the scattering of data was greater at 3439  kHz due to the lower S/N ratio. The (14)N NQR method has the potential to become an additional and important spectroscopic tool in the study of solid-state forms, not only of pure active pharmaceutical ingredients or excipients, but also of their mixtures. This ability lends the method to a possible successful utilization at different levels of pharmaceutical manufacturing and product quality control.