Stavros Malamataris

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.

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.

Simultaneous quantitative analysis of mebendazole polymorphs A-C in powder mixtures by DRIFTS spectroscopy and ANN modeling.

In the present study, a simple method, based on diffuse reflectance FTIR spectroscopy (DRIFTS) and artificial neural network (ANN) modeling is developed for the simultaneous quantitative analysis of mebendazole polymorphs A-C in powder mixtures. Spectral differences between the polymorphs are elucidated by computationally assisted band assignments on the basis of quantum chemical calculations, and subsequently, the spectra are preprocessed by calculation of 1st and 2nd derivatives. Then ANN models are fitted after PCA compression of the input space. Finally the predictive performance of the ANNs is compared with that of PLS regression. It was found that simultaneous quantitative analysis of forms A-C in powder mixtures is possible by fitting an ANN model to the 2nd derivative spectra even after PCA compression of the data (RMSEP of 1.75% for form A, 1.85% for B, and 1.65% for C), while PLS regression, applied for comparison purposes, results in acceptable predictions only within the 700-1750cm(-1) spectral range and after direct orthogonal signal correction (DOSC), with RMSEP values of 2.69%, 2.68%, and 3.40% for forms A, B, and C, respectively. Application of the ANN to commercial samples of raw material and formulation (suspension) proved its suitability for the prediction of polymorphic content.

Sustained-release of buspirone HCl by co spray-drying with aqueous polymeric dispersions

Sustained-release of buspirone HCl (BUH) was attempted by spray drying after dissolving in two commercially available aqueous polymeric dispersions (Eudragit RS 30 D or Kollicoat SR 30 D) at five different drug:polymer ratios (1:1, 1:2, 1:3, 1:6 and 1:9). The produced spray-dried agglomerates were evaluated in terms of their particle size and morphology, production yield, encapsulation efficiency and in-vitro release of BUH. Possible drug-polymer interactions were checked by Differential Scanning Calorimetry (DSC) and FT-IR spectroscopy. Scanning electron microscopy (SEM) was employed for the qualitative characterization of particle size and morphology. Encapsulation efficiency was generally high (around 100%) and independent of the polymeric dispersion type, while production yield was generally low (7.2-31.0%) and significantly lower for the case of Kollicoat SR 30 D (KSR) than for Eudragit RS 30 D (ERS). Scanning electron micrographs showed remarkable changes in size and shape of agglomerates due to the type of aqueous polymeric dispersion and drug:polymer ratio. In-vitro release of BUH from compacted co spray-dried agglomerates was remarkably slower and incomplete for the case of Kollicoat at drug:polymer ratio below 1, presumably due to increased plastic deformation of the developed coating instead of fragmentation in the case of Eudragit coating during compaction.

Apparent compressive elastic modulus and strength isotropy of compacts formed from binary powder mixes

Abstract An apparent compressive Youngs modulus of elasticity of cylindrical tablets, produced from binary powder mixtures compressed at two tableting rates, was compared with the tensile strength isotropy expressed as the ratio of axial to radial tensile strength. The binary powder mixtures comprised materials which differ in yield pressure and in the extent of elastic deformation, plastic flow and fragmentation during their consolidation. A log-linear correlation was found between the apparent Youngs modulus of elasticity of the tablets and the tensile strength isotropy, indicating that they were similarly related to the composition of the tablets. However, some differences in the effect of compression rate were evident. Thus, apparent Youngs modulus varied with compression rate, depending on the principal consolidation mechanism of the component materials. In contrast, the tensile strength isotropy was virtually unaffected by an increase in the compression rate except for mixtures of paracetamol with Avicel which showed a slight decrease in isotropy. The tensile strength isotropy — a measure of the interparticle bonding isotropy - of the tablets could be improved by increasing the apparent Youngs modulus, through the incorporation of a component, the particles of which undergo fragmentation or possess a high yield pressure.

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.

Pharmaceutical nanocrystals: production by wet milling and applications

Nanocrystals are regarded as an important nanoformulation approach exhibiting advantages of increased dissolution and saturation solubility with chemical stability and low toxicity. Nanocrystals are produced in the form of nanosuspensions using top-down (e.g., wet milling or high pressure homogenization) and bottom-up methods (e.g., antisolvent precipitation). Wet milling is a scalable method applicable to drugs with different physicochemical and mechanical properties. Nanocrystalline-based formulations, either as liquid nanosuspensions or after downstream processing to solid dosage forms, have been developed as drug delivery systems for various routes of administration (i.e., oral, parenteral, pulmonary, ocular, and dermal). In this review, we summarize and discuss the features, preparation methods, and therapeutic applications of pharmaceutical nanocrystals, highlighting their universality as a formulation approach for poorly soluble drugs.

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.