Biomedical subjects

S Malamataris

Publications and source records attributed to S Malamataris.

At least 19 recordsLinked to original sources

PubMed2006

Dynamic moisture sorption and desorption of standard and silicified microcrystalline cellulose.

Moisture sorption and desorption isotherms of standard and silicified microcrystalline cellulose (MCC and SMCC) were determined using an automatic multi-sample gravimetric analyzer, and compared by fitting different kinetic models, including the excess surface work model (ESW), the BET and GAB model, Young and Nelson model and recently developed parallel exponential kinetics (PEK) model. It was found that silicification affects the moisture sorption and desorption properties of SMCC mainly at high relative humidity (above 50% and 70%, respectively). In general, the differences in the moisture sorption and desorption properties of MCC and SMCC can be elucidated by the different kinetic models. Particularly the PEK model shows that hysteresis is related primarily to a fast sorption process, which corresponds to bound water, and secondarily to a slow process, which corresponds to sorption of free water and that SMCC acquires more water than MCC at RH higher than 50% by the slow (secondary) sorption process. A possible mechanism for this process is presumably the hydrolysis of SiO2 particles and formation of silanol groups that act as a water reservoir, preventing the accumulation of more water in the polymer matrix and thus may be protecting the structure of SMCC from undergoing irreversible structural changes that would impair its performance as an excipient.

Adsorption↗

PubMed2006

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.

Algorithms↗

PubMed2005

Flow rate of some pharmaceutical diluents through die-orifices relevant to mini-tableting.

The effects of cylindrical orifice length and diameter on the flow rate of three commonly used pharmaceutical direct compression diluents (lactose, dibasic calcium phosphate dihydrate and pregelatinised starch) were investigated, besides the powder particle characteristics (particle size, aspect ratio, roundness and convexity) and the packing properties (true, bulk and tapped density). Flow rate was determined for three different sieve fractions through a series of miniature tableting dies of different orifice diameter (0.4, 0.3 and 0.2 cm) and thickness (1.5, 1.0 and 0.5 cm). It was found that flow rate decreased with the increase of the orifice length for the small diameter (0.2 cm) but for the large diameter (0.4 cm) was increased with the orifice length (die thickness). Flow rate changes with the orifice length are attributed to the flow regime (transitional arch formation) and possible alterations in the position of the free flowing zone caused by pressure gradients arising from the flow of self-entrained air, both above the entrance in the die orifice and across it. Modelling by the conventional Jones-Pilpel non-linear equation and by two machine learning algorithms (lazy learning, LL, and feed-forward back-propagation, FBP) was applied and predictive performance of the fitted models was compared. It was found that both FBP and LL algorithms have significantly higher predictive performance than the Jones-Pilpel non-linear equation, because they account both dimensions of the cylindrical die opening (diameter and length). The automatic relevance determination for FBP revealed that orifice length is the third most influential variable after the orifice diameter and particle size, followed by the bulk density, the difference between bulk and tapped densities and the particle convexity.

Algorithms↗

PubMed2005

Drug release from tableted wet granulations comprising cellulosic (HPMC or HPC) and hydrophobic component.

The effects of component nature, proportion and processing on the release rate and mechanism were investigated for tablets comprising drug, cellulosic polymer and hydrophobic components. Four drugs differing in solubility (diclofenac sodium, ibuprofen, naproxen and indomethacin), two cellulosic polymers (HPC and HPMC) and hydrophobic Emvelop were used in two levels of mass fraction and weight ratio of drug:carrier and of cellulosic-hydrophobic component. Compression was applied after granulation or physical mixing. Drug release was evaluated in pH 6.5 phosphate buffer BP and elucidation of the release mechanism was attempted by fitting kinetic models. Statistical significance of the effects of formulation variables on the release rate and mechanism expressed by the coefficient, k, and exponent, n, of the power law kinetic model, respectively, was evaluated by ANOVA. It was found that for the release mechanism most significant is the effect of drug solubility followed by cellulosic polymer type, mixing procedure and drug mass fraction. Significant interaction between drug solubility and type of cellulosic polymer indicated that alteration in the swelling of HPMC and HPC is caused by the drug solubility. Weight ratio of cellulosic-hydrophobic component does not affect the release mechanism, but only the release rate. Similarly, for the release rate most significant was found the effect of drug solubility, followed by cellulosic polymer type, weight ratio of cellulosic-hydrophobic component, mixing method and drug mass fraction. Also significant were the interactions of drug solubility with the type and proportion of the cellulosic polymer and the processing applied. Depending on the drug solubility and type of polymer present, wet granulation can increase or decrease the release rate.

Cellulose↗

PubMed2003

Effects of initial concentration and seeding procedure on crystallisation of orthorhombic paracetamol from ethanolic solution.

The effects of some crystallisation conditions on the formation of orthorhombic paracetamol from ethanolic solution are examined when seeding technique is applied under fixed agitation (700 rpm) and harvesting time (30 min). Three equally spaced levels were used for initial concentration, C(I) (30 +/- 4% w/v), for seeding temperature, T(S) (7 +/- 7 degrees C) and for cooling temperature, T(C) (-10 +/- 10 degrees C). The influences on parameters of temperature change in the crystallisation solution were quantitatively determined as were influences on crystal yield (Y%), crystal size and shape, and orthorhombic content of the final crystalline product. Conditions for improvement of Y% under reproducible formation of orthorhombic form were elucidated. It was found that Y% increases remarkably by increasing C(I) but there is a corresponding decrease in the content of orthorhombic form. Increased content of monoclinic form is explained by nucleation under conditions of high C(I) (34% w/v), low seeding temperature (below 7 degrees C) and long seeding time (more than 14.7 min) in addition to transformation of grown orthorhombic seeds. However, reproducible formation of pure orthorhombic form is possible at medium C(I) (30% w/v) and optimal crystal yield (60.9% w/w) corresponds to -20 degrees C T(C) and 0 degrees C seeding temperature. Crystal size is affected by all the crystallisation conditions due to the alteration in the degree of supersaturation, and consequently, in the nucleation and growth processes. Aspect ratio is affected due to the presence of less elongated monoclinic crystals. The fullness ratio increases with the cooling temperature but decreases with the initial concentration, probably because of secondary nucleation on the crystal surfaces or erosion due to initiation of transformation.

Acetaminophen↗

PubMed2003

Artificial neural networks (ANNs) and modeling of powder flow.

Effects of micromeritic properties (bulk, tapped and particle density, particle size and shape) on the flow rate through circular orifices are investigated, for three pharmaceutical excipients (Lactose, Emcompress and Starch) separated in four sieve fractions, and are modeled with the help of artificial neural networks (ANNs). Eight variables were selected as inputs and correlated by applying the Spearman product-moment correlation matrix and the visual component planes of trained Self-Organizing Maps (SOMs). Back-propagation feed-forward ANN with six hidden units in a single hidden layer was selected for modeling experimental data and its predictions were compared with those of the flow equation proposed by. It was found that SOMs are efficient for the identification of co-linearity in the input variables and the ANN is superior to the flow equation since it does not require separate regression for each excipient and its predictive ability is higher. Besides the orifice diameter, most influential and important variable was the difference between tapped and bulk density. From the pruned ANN an approximate non-linear model was extracted, which describes powder flow rate in terms of the four network's input variables of the greatest predictive importance or saliency (difference between tapped and bulk density (x(2)), orifice diameter (x(3)), circle equivalent particle diameter (x(4)) and particle density [equation in text].

Excipients↗

PubMed2002

FT-IR and Raman spectroscopic methods for identification and quantitation of orthorhombic and monoclinic paracetamol in powder mixes.

FT-IR and Raman spectroscopic methods are suggested for identification of orthorhombic (form II) and monoclinic (form I) paracetamol and for their quantitative determination in mixes. The intensity ratio of the 836 cm(-1) FT-IR band (attributed to the presence of both forms) to the 806 cm(-1) monoclinic band plotted against the inverse monoclinic molar fraction (X) yields a straight line: I(836)/I(806)=0.515/X+0.700, r=0.9965 for eight calibration points on the regression line. Similarly, the area under the 454 cm(-1) band in FT-Raman spectra (which is attributed to both forms) over the area under the 465 cm(-1) band of monoclinic form is inversely related to its molar fraction (X): A(454)/A(465)=0.482/X-0.324, r=0.9954 for eight calibration points. Precision (RSD%) was <5% for both methods. Linear regression analysis between content and intensity of characteristic XRD reflections for four different samples gave r=0.9964 at 4.62 A and r=0.9894 at 3.70 A, for form II. For the content of form I, r=0.9596 at 3.37 A. The limit of detection for monoclinic form was estimated to be 0.012 mole fraction for both methods.

Acetaminophen↗

PubMed2002

Effects of harvesting and cooling on crystallization and transformation of orthorhombic paracetamol in ethanolic solution.

Orthorhombic paracetamol (form II) can be obtained from ethanolic solution when seeding technique is applied although it converts to monoclinic (form I) upon contact with the solvent. In the present work different cooling temperature T(C) (-20, -10 and 0 degrees C) was applied under fixed agitation (700 rpm) and the crystalline product was harvested after different crystallization time t(H) (20, 30 and 40 min). Crystal yield (Y%), micromeritic properties and orthorhombic content of the crystalline product were evaluated and related to T(C) and t(H). Conditions for optimal crystal yield and orthorhombic content were elucidated and kinetic parameters of solvent mediated transformation (induction times, t(it), and activation energy, E(a)) were determined. It was found that crystal yield (Y%) increases with t(H) and decreases with T(C). The mean crystal size and size distribution is affected linearly by T(C), probably due to alterations in the nucleation and growth processes. The effects on the crystal shape can be elucidated only after size classification. As the crystals grow, they become more elongated, with rougher surface due to secondary nucleation and alteration in growth rate of different crystal faces. Induction times for solvent mediated transformation (t(it)), were remarkably longer than those corresponding to appearance of monoclinic form, when large scale collection and drying of crystalline product was applied, probably due to residual solvent evaporation. The activation energy of solvent mediated transformation (E(a)=62.9 kJ/mol) is between those for nucleation in the solid state and in a solvent, indicating the operation of a mixed mechanism.

Acetaminophen↗

PubMed2002

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.

Acetaminophen↗

PubMed2001

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.

Analysis of Variance↗

PubMed2001

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.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

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.

Area Under Curve↗

PubMed2000

Preparation and characterisation of a new insoluble polymorphic form of glibenclamide.

A crystalline form of glibenclamide, with higher melting point (218 degrees C) and lower solubility in simulated gastric and intestinal fluids, was arisen during an attempt to elucidate transitional phases by melting, cooling and reheating. The new form was obtained from the glassy state, by applying sublimation at 130-160 degrees C and was characterised by differential scanning calorimetry (DSC), infrared (IR) spectroscopy, scanning electron microscopy (SEM), hot-stage microscopy (HSM), X-ray powder diffraction (XRD) and solubility studies. Formation of the new crystal form is considered as reason of reduction in dissolution and bioavailability of tablets.

Calorimetry, Differential Scanning↗

PubMed2000

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.

Acrylic Resins↗

PubMed1999

Crystallization of paracetamol from ethanol-water solutions in the presence of polymers.

We have examined the effect of polymer nature and concentration on yield and micromeritic, melting and compression properties of paracetamol crystals obtained from ethanol-water solutions using the solvent-change technique. Agar, gelatin, polyethylene-glycol (PEG) and polyvinylpyrrolidone (PVP) were the polymers used. These four polymers have different solubility in ethanol and water. It was found that the yield of crystallization may increase by up to 8% with agar, gelatin and PEG, polymers that are insoluble in ethanol, while the soluble PVP reduces yield by 14%. The size of crystals increased due to the addition of polymers and changed almost in parallel with the crystal yield for agar and gelatin. Gelatin resulted in the biggest crystals, agar in the most equidimensional (aspect ratio 1.45 and roundness 1.47) and PVP in the most elongated (aspect ratio 1.89 and roundness 2.13). PEG resulted in the most agglomerated crystals. Yield pressure, Py, decreased in the following order: agar > PEG > gelatin > PVP, which is the same order for the enthalpy of fusion. Gelatin and PEG significantly decreased the elastic recovery of tablets (0.05 level), probably due to plastic deformation of crystals and fragmentation of agglomerates, respectively. Crystallization of paracetamol in the presence of polymers by the solvent-change (ethanol-water) technique may permit increase of crystal yield, alteration of crystal shape and improvement of compression behaviour during tableting.

Acetaminophen↗

PubMed1998

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.

Capsules↗

PubMed1995

Extractionless high-performance liquid chromatographic method for the simultaneous determination of piroxicam and 5'-hydroxypiroxicam in human plasma and urine.

A simple and rapid (extractionless) high-performance liquid chromatographic method with UV detection, at 330 nm, was developed for the simultaneous determination of piroxicam and its major metabolite, 5'-hydroxypiroxicam, in human plasma and urine. Acidified plasma and alkali-treated urine samples are used and naproxen is added as internal standard. The separation is performed at 40 degrees C on a C18 Spherisorb column with acetonitrile--0.1 M sodium acetate (33:67, v/v, pH 3.3) as mobile phase. The retention time is 2.2 min for 5'-hydroxypiroxicam, 2.6 min for piroxicam and 3.2 min for naproxen. The detection limit is 0.05 micrograms/ml using a 100-microliters loop.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1993

Extractionless high-performance liquid chromatographic method for the determination of diclofenac in human plasma and urine.

An assay using reversed-phase high-performance liquid chromatography with ultraviolet detection, at 278 nm, was developed to measure diclofenac in human plasma and urine at concentrations suitable for biopharmaceutical studies. Indomethacin was used as internal standard and separation was performed at 40 degrees C on a C18 Spherisorb column with acetonitrile-0.1 M sodium acetate (35:65, v/v) (pH 6.3) as mobile phase. The sample preparation is simple and rapid (extractionless), and the total run time is less than 5 min. The retention time is 2.8 min for diclofenac and 3.6 min for indomethacin. The detection limit is 0.2 microgram/ml using a 20-microliters loop.

Chromatography, High Pressure Liquid↗