Ioannis Nikolakakis

Preparation of carbamazepine–Soluplus® solid dispersions by hot-melt extrusion, and prediction of drug–polymer miscibility by thermodynamic model fitting

Hot-melt extrusion (HME) is a dust- and solvent-free continuous process enabling the preparation of a variety of solid dosage forms containing solid dispersions of poorly soluble drugs into thermoplastic polymers. Miscibility of drug and polymer is a prerequisite for stable solid dispersion formation. The present study investigates the feasibility of forming solid dispersions of carbamazepine (CBZ) into polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer (Soluplus) by hot-melt extrusion. Physicochemical properties of the raw materials, extrudates, co-melted products, and corresponding physical mixtures were characterized by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), attenuated total reflectance infrared (ATR-FTIR) spectroscopy and hot stage microscopy (HSM), while miscibility of CBZ and Soluplus was estimated on the basis of the Flory-Huggins theory, Hansen solubility parameters, and solid-liquid equilibrium equation. It was found that hot-melt extrusion of carbamazepine and Soluplus is feasible on a single-screw hot-melt extruder without the addition of plasticizers. DSC analysis and FTIR spectroscopy revealed that a molecular dispersion is formed when the content of CBZ does not exceed ∼5% w/w while higher CBZ content results in a microcrystalline dispersion of CBZ form III crystals, with the molecularly dispersed percentage increasing with extrusion temperature, at the risk of inducing transformation to the undesirable form I of CBZ. Thermodynamic modeling elucidated potential limitations and temperature dependence of solubility/dispersibility of carbamazepine in Soluplus hot-melt extrudates. The results obtained by thermodynamic models are in agreement with the findings of the HME processing, encouraging therefore their further application in the HME process development.

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 (Tukeys 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.

The Influence of Surfactant HLB and Oil/Surfactant Ratio on the Formation and Properties of Self-emulsifying Pellets and Microemulsion Reconstitution

Self-emulsifying oil/surfactant mixtures can be incorporated into pellets that have the advantages of the oral administration of both microemulsions and a multiple-unit dosage form. The purpose of this work was to study the effects of surfactant hydrophilic–lipophilic balance (HLB) and oil/surfactant ratio on the formation and properties of self-emulsifying microcrystalline cellulose (MCC) pellets and microemulsion reconstitution. Triglycerides (C8–C10) was the oil and Cremophor ELP and RH grades and Solutol the surfactants. Pellets were prepared by extrusion/spheronization using microemulsions with fixed oil/surfactant content but with different water proportions to optimize size and shape parameters. Microemulsion reconstitution from pellets suspended in water was evaluated by turbidimetry and light scattering size analysis, and H-bonding interactions of surfactant with MCC from FT-IR spectra. It was found that water requirements for pelletization increased linearly with increasing HLB. Crushing load decreased and deformability increased with increasing oil/surfactant ratio. Incorporation of higher HLB surfactants enhanced H-bonding and resulted in faster and more extensive disintegration of MCC as fibrils. Reconstitution was greater at high oil/surfactant ratios and the droplet size of the reconstituted microemulsions was similar to that in the wetting microemulsions. The less hydrophilic ELP with a double bond in the fatty acid showed weaker H-bonding and greater microemulsion reconstitution. Purified ELP gave greater reconstitution than the unpurified grade. Thus, the work demonstrates that the choice of type and quantity of the surfactant used in the formulation of microemulsions containing pellets has an important influence on their production and performance.

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 α-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 α-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.

Combined effects of wetting, drying, and microcrystalline cellulose type on the mechanical strength and disintegration of pellets.

Effects of wetting and drying conditions on micromeritic, mechanical and disintegration properties of microcrystalline cellulose (MCC) pellets were evaluated. Extrusion/spheronization and three drying methods (fluidized bed, microwaves, and freeze drying) were applied using two wetting liquids (water or water-isopropanol 60:40 w/w) and three MCC types: (standard, silicified, and modified). Additionally, the effects of drying method were compared on highly porous pellets prepared by the incorporation and extraction of pore former (NaCl). It was found that the drying method has the greatest effect on the pellet size and porosity followed by the wetting liquid. The modification of MCC resulted in reduced water retention ability, implying hornification, increased porosity, reduced resistance to deformation and tensile strength of pellets. The disintegration time also decreased markedly due to the modification but only in the low porosity range <37%. Silicification increased greatly the disintegration time of the low porosity pellets (<14%). Combination of water-isopropanol, freeze drying and modified MCC gave the greatest increase in pellet size and porosity. The increase in pellet porosity caused exponential reduction in the resistance to deformation, tensile strength and disintegration time, as expected. Compared to fluidized bed, the freeze drying resulted in 20-30% higher porosity for pellets prepared without pore former and 6% for those with pore former, indicating the possibility of preparing highly porous pellets by employing freeze drying.

Preparation of Porous Microcrystalline Cellulose Pellets by Freeze-Drying: Effects of Wetting Liquid and Initial Freezing Conditions

The effects of wetting liquid and initial freezing conditions on the pore volume and pore size distribution of freeze-dried microcrystalline cellulose (MCC) pellets were studied with mercury porosimetry. Freeze-drying was applied after extrusion/spheronization using two wetting liquids (water and water-isopropanol) and three initial freezing conditions (-30, 80, and -197 degrees C). Also, the effects of initial freezing were compared to those on pellets prepared with extraction of NaCl from Avicel(R)/NaCl pellets. Pellet porosity was found to increase with decreasing initial freezing temperature and the increase is greater for pellets made with water as wetting liquid. The mean pore diameter is greater for the extracted pellets, followed by nonextracted MCC pellets made with water and water-isopropanol. Also, the pore diameter is greater for freezing at -80 degrees C comparatively to that at -30 degrees C, while it is smaller for freezing at -197 degrees C. Narrower and more symmetrical pore size distributions were obtained with water-isopropanol at -197 degrees C. The higher porosity obtained with water alone and the smallest mean pore diameter and narrower distribution obtained with water-isopropanol may be due to the effects of H-bonding between isopropanol and water molecules on the nucleation and growth of ice crystals during the initial freezing.

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 natural zeolite (clinoptilolite) on the performance and litter quality of broiler chickens

Ioannis NIKOLAKAKIS, Vassilios DOTAS, Anastasios KARGOPOULOS, Lampros HATZIZISIS, Dimitrios DOTAS*, Zafiris AMPAS Department of Animal Production, Technological Educational Institute of Western Macedonia, Florina, Greece Department of Animal Production, Faculty of Agriculture, Aristotle University of Thessaloniki, Thessaloniki, Greece Department of Animal Production, Technological Educational Institute of Epirus, Arta, Greece Department of Agricultural Development, Democritus University of Thrace, N. Orestiada, Evros, Greece

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.

Effect of plasticiser type on the hot melt extrusion of venlafaxine hydrochloride

During hot melt extrusion (HME), phase changes and interactions due to thermo‐mechanical stresses affect the drug incorporation into polymeric matrices. Two HME compositions of venlafaxine HCl with Eudragit RSPO (Evonic, Darmstadt, Germany) as the matrix polymer and either citric acid monohydrate (CAMH) or Lutrol F127 (BASF, Ludwigshafen, Germany) as plasticisers were compared.