Porous pellets as drug delivery system.

BACKGROUND: Multiparticulate drug delivery systems, such as pellets, are frequently used as they offer therapeutic advantages over single-unit dosage forms. AIM: Development of porous pellets followed by evaluation of potential drug loading techniques. METHOD: Porous microcrystalline pellets were manufactured and evaluated as drug delivery system. Pellets consisting of Avicel PH 101 and NaCl (70%, w/w) were prepared by extrusion/spheronization. The NaCl fraction was extracted with water and after drying porous pellets were obtained (33.2% porosity). Immersion of the porous pellets in a 15% and 30% (w/v) metoprolol tartrate solution, ibuprofen impregnation via supercritical fluids and paracetamol layering via fluidized bed coating were evaluated as drug loading techniques. RESULTS: Raman spectroscopy revealed that immersion of the pellets in a drug solution and supercritical fluid impregnation allowed the drug to penetrate into the porous structure of the pellets. The amount of drug incorporated depended on the solubility of the drug in the solvent (water or supercritical CO(2)). Drug release from the porous pellets was immediate and primarily controlled by pure diffusion. CONCLUSION: The technique described in this research work is suitable for the production of porous pellets. Drug loading via immersion the pellets in a drug solution and supercritical fluid impregnation resulted in a drug deposition in the entire pellet in contrast to fluid bed layering where drugs were only deposed on the pellet surface.

Preparation of pharmaceutical cocrystal formulations via melt mixing technique: A thermodynamic perspective.

The aim of the present study was to evaluate the thermodynamic properties of in-situ formation of cocrystal formulations by the melt-mixing method. Specifically, the thermodynamic mixing behaviour of carbamazepine-nicotinamide and ibuprofen-nicotinamide cocrystals prepared with the aid of Soluplus® (SOL) were evaluated using thermodynamic lattice-based solution theories. Thermodynamic miscibility of both cocrystals with SOL was predicted by calculating Gibb's free energy based on the Flory-Huggins (FH) interaction parameter (χ), while the activity coefficient of cocrystals estimated with the aid of solid-liquid equilibrium equation and FH lattice theory, showed good thermodynamic miscibility of the components at elevated temperatures used normally during melt-mixing based processes. Complete phase transition diagrams constructed with the aid of DSC measurements and FH solution theory, suggested the existence of two transition zones: (1) a stable cocrystal zone, located at the right-hand-side of the spinodal phase separation curve, where stable cocrystals are prepared and (2) an unstable cocrystal zone, located at the left-hand-side of the spinodal curve up to liquidus, where the matrixforming polymer sets a kinetic barrier to recrystallization and hence, a barrier to the formation of cocrystals. The validity of the suggested thermodynamic phase transition zones was experimentally verified by ATR-FTIR and hot-stage polarized light microscopy.

Artificial neural networks (ANNs) and partial least squares (PLS) regression in the quantitative analysis of cocrystal formulations by Raman and ATR-FTIR spectroscopy.

The present work describes the development of an efficient, fast and accurate method for the quantification of polymer-based cocrystal formulations. Specifically, the content of carbamazepine-nicotinamide (CBZ/NIC) and ibuprofen-nicotinamide (IBU/NIC) cocrystals in Soluplus®-based formulations was independently determined with the aid of either Raman or Attenuated Total Reflectance Fourier-Transform Infrared Spectroscopy (ATR-FTIR) spectroscopy. Spectra peaks from mixtures of IBU/NIC and CBZ/NIC cocrystals with Soluplus at a ratio ranging from 90/10 to 1/99 w/w (cocrystal to SOL) were evaluated and modelled with the aid of feed-forward, back-propagation artificial neural networks (ANNs) and partial least squares (PLS) regression analysis. A 25 full-factorial experimental design was employed in order to evaluate the effect of ANN's structure (number of hidden units) and training (number of iteration cycles) parameters along with the effect of Raman or FTIR spectra region and data preprocessing (direct orthogonal signal correction - DOSC, second derivative, or no preprocessing) on ANN's fitting performance. Results showed that when DOSC preprocessing was employed excellent ANN fitting in both Raman (root mean squared error of prediction (RMSEp) values of 0.43 and 0.34 for IBU/NIC-SOL and CBZ/NIC-SOL, respectively) and FTIR (RMSEp values of 0.04 and 0.03 for IBU/NIC-SOL and CBZ/NIC-SOL, respectively) spectra was obtained. Comparison of ANNs fitting results with PLS regression (RMSEp for IBU/NIC-SOL was 0.94 and 7.36, and for CBZ/NIC-SOL 7.29 and 15.63, using Raman and FTIR analysis, respectively) revealed ANN's fitting superiority, which can be attributed to their inherent non-linear predictive ability.

Production of aprepitant nanocrystals by wet media milling and subsequent solidification.

The present study investigates the effects of formulation and process parameters on the production of aprepitant nanosuspensions applying wet media milling and subsequent solidification. Six stabilizers were used: two brands of hydroxylpropylmethyl cellulose (HPMC E-15LV and Pharmacoat 603), hydroxypropyl cellulose (HPC-SSL), polyvinylpyrollidone (PVP), D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS 1000), Poloxamer P188 and sodium dodecyl sulfate (SDS), while two diluents (mannitol and sucrose) were incorporated prior to solidification by two methods (spray- and freeze-drying). The polymorphic purity of the raw material, the particle size of nanocrystals, and the physicochemical properties of the final dried powders were assessed. Focus was placed on the energetic aspects of the crystal structure of aprepitant in order to rationalize particle breakage during wet milling. It was found that a combination of cellulosic polymers with SDS are suitable stabilizers for the production of aprepitant nanocrystals (∼300nm or smaller) by wet media milling. Regarding the solidification of the nanosuspensions, spray-drying is advantageous compared to freeze-drying, as it leads to the production of almost spherical individual micron-sized agglomerates of nanocrystals and few secondary agglomerates of them which are expected to exhibit improved handling behavior. Spray-dried nanocrystal agglomerates containing Pharmacoat 603 and mannitol exhibit reduced hygroscopity compared to those prepared with sucrose and HPC-SSL, making them the excipients of choice.

Simultaneous quantification of carbamazepine crystal forms in ternary mixtures (I, III, and IV) by diffuse reflectance FTIR spectroscopy (DRIFTS) and multivariate calibration.

Diffuse reflectance FTIR spectroscopy (DRIFTS) coupled with modern multivariate calibration methods, namely artificial neural networks (ANNs) in two versions (ANN-raw and ANN-pca), support vector machines (SVMs), lazy learning (LL) and partial least squares (PLS) regression, is used in this study for the quantification of carbamazepine crystal forms in ternary powder mixtures (I, III, and IV). Two spectral regions (675-1180 and 3400-3600/cm) were selected and the data were partitioned into training and test subsets applying the Kennard-Stone design. It was found that all the selected algorithms perform better than the PLS regression (root mean squared error of prediction (RMSEP) from 3.0% to 8.2%). ANN-raw, trained on uncompressed spectral data, shows best predictive performance (RMSEP < 2.25%) but longest computation (up to 10 min). Principal component analysis (PCA) compression of the input spectral data accelerates significantly the computation (<16 s) at a relatively low cost in precision (RMSEP < 3.24%). The LL algorithm shows excellent performance in the 3400-3600/cm range (RMSEP < 1.6%), but in the 675-1180/cm range it shows strong dependence on data set structure (RMSEP between 1.6% and 8.9%). SVMs perform comparably well with ANNs (RMSEP < 3.1%), not showing the long computation time of ANNs (<1 s) and therefore may provide an attractive alternative to ANNs.

Spherical crystal agglomeration of ibuprofen by the solvent-change technique in presence of methacrylic polymers.

The effects of Eudragit(R) nature on the formation and spherical agglomeration of ibuprofen microcrystals have been examined when solvent change (ethanol-water) technique is applied. Four methacrylic polymers (Eudragit(R) S100, L100, RS, and RL), with different solubility and solubilizing ability, were used. The extrapolated points of maximum temperature deviation rate in crystallization liquid that reflect the maximum crystallization rate and the corresponding water addition were determined, as well as crystal yielding and incorporation of drug and polymer in the agglomerates. The physicomechanical properties of the agglomerates, such as size, sphericity, surface roughness and porosity, as well as flow and packing or compression behavior during tableting, were evaluated for different drug/polymer ratios. It was found that crystal yield is greatly reduced in the presence of water-insoluble polymers and that formation of the microcrystals and incorporation of drug and polymer are affected by the polymer nature. Crystal formation changes are attributed to alterations in the metastable zone, whereas the changes in drug and polymer incorporation and crystal yield are caused by changes in the polymers' solubility and micellization. The size of agglomerates depends on the polymer nature and its interactions with the ibuprofen microcrystals formed. Sphericity, surface roughness, and intraparticle porosity of agglomerates increase, in general, with the presence of polymer owing to changes in habit and growth rate of the microcrystals and to their coating before binding into spherical agglomerates. The particle density or intraparticle porosity and size changes determine flow or packing behavior and densification of agglomerates at low compression. The incorporation and brittleness of the polymer determine the deformation under higher compression pressure, expressed as yield pressure, Py.

Relations between crystallisation conditions and micromeritic properties of ibuprofen.

The effects of solvent, cooling rate and type of methacrylic polymer (Eudragit(R)) on the micromeritic properties (size, elongation ratio, roundness and fullness ratio), the temperature change in the crystallisation liquid, the crystal yield and the extent of agglomeration of ibuprofen crystals have been compared. Twenty batches of crystals were prepared and Latin square experimental design was applied with four levels for each factor. It was found that crystal yield (Y) is related to the extrapolated point of maximum rate of temperature-deviation (T(d)) with a logarithmic-type equation [Y=34.45lnT(d)-28.00] and to the area under the curve of temperature-deviation versus time (AUC) with a polynomial equation including cooling rate [Y=19.95AUC-1.57AUC/CR+63.00]. Crystal size is affected by the cooling rate and analysis of variance (ANOVA) showed that elongation ratio and fullness ratio of single crystals (P=0.05 and 0.05), as well as roundness and fullness ratio of agglomerates (P=0.05 and 0.1), are affected by the solvent. Post hoc statistical analysis of the solvent effects on the shape of crystals and agglomerates (Tukey's HSD multiple pairwise comparison test of means) indicated that their significance lies in the different polarity and may be attributed to interactions of solvent (acetone) with the growing crystal faces. Extent of crystal agglomeration was found to be inversely proportional to the ratio of elongation ratio/circle equivalent diameter of the single crystals.

Agglomeration state and migration of drugs in wet granulations during drying.

Migration of drugs was studied during drying of wet granules, agglomerated at pendular and funicular state (S(3) and S(4)). Granulating liquids of different viscosity (2.5 and 7.5 mPa s) and drugs and diluents of different solubility and wettability were employed and correlation was sought between distribution of the liquid, wet kneading parameters (torque and liquid consumption S%), solid-liquid interactions (work of adhesion and spreading coefficients) and the migration of drugs. It was found that drug migration, expressed as CV% of its content, was strongly dependent on the type of diluent. Also, the type of diluent exerted the strongest effect on torque and liquid consumption during wet kneading and a significant one on moisture content of the final granulations. Viscosity of the granulating liquid and molecular weight of the binder had no effect on liquid consumption but viscosity had a significant one on drug migration. Significant linear relationships were found between spreading coefficients and the liquid consumption (S%) at the mid-state of funicular agglomeration (S(3)+S(4))/2 or the torque at the capillary state S(5). Migration of drug was remarkably lower for drying in the microwave oven and increased from the pendular (S(3)) to the funicular (S(4)) agglomeration state when drying in conventional oven was applied. Linear relationships were found between migration (CV%) and the spreading coefficient of liquid on solid, lambda(LS), for the low and the high viscosity levels of the granulating liquid, with r=0.965, P=0.05 and r=0.901, P=0.10, respectively. Also, a general linear relationship (r=0.903 and P=0.002) accommodating all experimental data was found between migration (CV%) and the ratio lambda(LS)/viscosity. Drug migration increases with solubility and may become a problem in a range higher than 1 g in 148-400 ml of granulating liquid.

Solid state adsorption of antibiotics onto sorbitol.

The ability of two types of sorbitol, instant and crystalline, to hold antibiotics permanently after mixing has been assessed by an air sieving technique. Sorbitol instant was found to have a greater adsorption capacity and binding strength than crystalline sorbitol. The six antibiotics studied were found to fall roughly into two groups of different adsorption capacities: (1) pivampicillin, cephalexin monohydrate and erythromycin ethylsuccinate, and (2) ampicillin trihydrate, amoxycillin trihydrate and cloxacillin sodium. The former have slightly higher levels of adsorption than the latter. A negative linear relationship was found between the amount of antibiotic adsorbed onto dry sorbitol and that originally added to sorbitol. When adsorption is expressed as the weight of drug adsorbed per unit weight of sorbitol, an 'apparent' Langmuir isotherm results. This suggests that there are a number of adsorption sites available for holding drug particles, these sites being different for the different antibiotics.

Resistance to densification, tensile strength and capsule-filling performance of some pharmaceutical diluents.

The purpose of this study was to compare some indicators of capsule-filling performance, as measured by tapped density under different conditions, and elucidate possible quantitative relationships between variation of capsule fill-weight (%CV) and gravitational and inter-particle forces (attractive or frictional) derived from measurements of particle size, true density, low compression and tensile strength. Five common pharmaceutical diluents (lactose, maize starch, talc, Emcocel and Avicel) were investigated and two capsule-filling methods (pouring powder and dosator nozzle) were employed. It was found that for the pouring-type method the appropriateness of Hausner's ratio (HR), Carr's compressibility index (CC%) and Kawakita's constant (alpha) as indicators of capsule fill-weight variation decreases in the order alpha > CC% > HR; the appropriateness of these indicators also decreases with increasing cylinder size and with impact velocity during tapping. For the dosator-type method the appropriateness of the indicators decreases in the order HR > CC% > alpha, the opposite of that for the pouring-type method; the appropriateness of the indicators increases with decreasing cylinder size and impact velocity. The relationship between %CV and the ratio of inter-particle attractive to gravitational forces calculated from measurements of particle size and true density (Fvdw/Wp) was more significant for the pouring-type capsule-filling method. For the dosator-type method a significant relationship (1% level) was found between %CV and the product of Fvdw/Wp and a function expressing the increase, with packing density (p(f)), in the ratio of frictional to attractive inter-particle forces derived from compression (P) and tensile-strength (T) testing, d(log(P/T))/d(p(f)). The value of tapped density in predictions of capsule-filling performance is affected by the testing conditions in a manner depending on the filling method applied. For the pouring-type method predictions can be based on the ratio of attractive (inter-particle) to gravitational forces, whereas for the dosator-type method the contribution of frictional and attractive forces should, because of packing density change, also be taken into account.

Crystallization conditions and formation of orthorhombic paracetamol from ethanolic solution.

Orthorhombic paracetamol exhibits far better tabletability than the monoclinic form and its bulk crystallization from solution attracts much interest. In this study, temperature changes in supersaturated ethanolic solution have been recorded after seeding with orthorhombic crystals under different cooling temperatures (Tc) and agitation rates (AR). Average cooling rate (CR), time for maximum temperature deviation (tmax) and area confined between curves of measured and reference temperature plots (AUC) were calculated and correlated with crystal yield (Y). The micromeritic (size and shape) and the compression properties, the density and the orthorhombic content of the crystalline product were evaluated and related to the main crystallization conditions applied (Tc and AR). Conditions for optimal crystal yield and orthorhombic content were elucidated. It was found that crystal yield (Y) increased with AR and decreased with Tc. The ratio tmax/CR provided good prediction of crystal yield (Y = 58.92-1.386 tmax/CR, r2 = 0.964 and P = 0.0001). Tc and AR linearly affected crystal size and the size distribution, probably due to alterations in supersaturation, but they did not affect the crystal shape significantly. Density and compression properties (yield pressure and elastic recovery) were determined by the content of the orthorhombic form, which increased linearly with AR (P = 0.009) and with Tc (P = 0.039) when agitation was between 300 and 500 rev min(-1), while tmax decreased. At 700 rev min(-1) orthorhombic content was maximized and became independent to Tc. Higher orthorhombic content and crystal yield was expected for lower Tc and for lower tmax, which corresponded to higher AR and might have also been affected by alteration of seeding and harvesting procedure.

Effect of dietary saffron (Crocus sativus L.) on the oxidative stability of egg yolk.

1. The effects of dietary inclusion of red stigmas of Greek saffron (Crocus sativus L.) on the oxidative stability of shell eggs and liquid yolks were investigated and compared with those of dietary a-tocopherol. 2. Ninety-six Lohmann laying hens, 38 weeks old, distributed into 4 groups with 4 replicates each, were given either a control diet, diets enriched with 10 (SAF10) or 20 (SAF20) mg/kg saffron, or a diet enriched with 200 mg/kg a-tocopheryl acetate (VE200). 3. Following 6 weeks of feeding, eggs were collected and the rate of lipid oxidation was determined in refrigerated stored shell eggs, as well as in yolks adjusted to a pH of 6.2 or 4.2 and stored in the presence of light. 4. The results showed that the extent of lipid oxidation in shell eggs, as measured by malondialdehyde (MDA) formation, differed between dietary treatments, but did not change with storage time. In stored shell eggs, MDA levels differed between dietary treatments at all time points. 5. Yolks from the control group adjusted to pH 6.2 gave MDA values higher than those of the SAF10 group, which in turn were higher than those of the SAF20 group, a finding suggesting that saffron exerted a dose-dependent antioxidative activity. The VE200 group gave lower MDA values than the other groups at all time points. The oxidation profile of yolks at pH 4.2 showed a similar pattern but the rate of oxidation was greater.

Micromeritic and packing properties of diclofenac pellets and effects of some formulation variables.

The effects of two common diluents (microcrystalline cellulose and calcium phosphate dihydrate), two binding agents (gelatin and methacrylic polymer), and spheronization on the micromeritic (size, shape, density), flow, and packing properties of sodium diclofenac pellets were examined. The shape was assessed as the aspect ratio and was correlated to the flow rate and to the deviation of the tapped porosity from the value of 26%, which corresponds to the ideal rhombohedral packing of spheres. It was found that porosity deviation decreased greatly with spheronization, but it increased with hinder addition. Porosity deviation was proportional to the aspect ratio, while flow rate decreased logarithmically with porosity deviation. Porosity deviation may be a useful index for monitoring the quality of pellets, similar to the aspect ratio, as a successful, simple, and indirect indication of sphericity and of surface roughness as well.