A new approach to the granulation of beta-cyclodextrin inclusion complexes

Cyclodextrins (CDs) are annular oligosaccharides containing 6-12 glucose unities joined together by alpha-1,4 bonds. They have a conical-truncated shape with a lipophilic cavity in which different molecules can be included resulting in a stable inclusion complex. The cyclodextrins have been widely applied in pharmaceutical technology with the objective of increasing the solubility, stability and bioavailability of drugs in different pharmaceutical dosage forms, such as tablets. In order to obtain beta-CD tablets, liquid dispersions of drug/beta-CD are usually submitted to different drying processes, like spray-drying, freeze-drying or slow evaporation, being this dry material added to a number of excipients. However, such drying processes can generate particulate materials showing problems of flow and compressibility, needing their conversion into granulates by means of wetting with granulation liquid followed by additional drying. In this work, the main objective was to evaluate the preparation of tablets without the need of this additional drying step. For this purpose an aqueous dispersion containing acetaminophen/beta-CD complex and cornstarch was dried using a spouted bed and the obtained granules were compressed in tablets. Acetaminophen was used as model drug due to its low water solubility and the inexpensive and widely available cornstarch was chosen as excipient. Acetaminophen powder was added into a beta-cyclodextrin solution prepared in distilled water at 70 degrees C. Stirring was kept until this dispersion cooled to room temperature. Then cornstarch was added and the resulting dispersion was dried in spouted bed equipment. This material was compressed into tablets using an Erweka Korsh EKO tablet machine. This innovative approach allowed the tablets preparation process to be carried out with fewer steps and represents a technological reliable strategy to produce beta-cyclodextrin inclusion complexes tablets. (C) 2010 Elsevier By. All rights reserved.

Stabilization of Endophytic Fungus Cercospora kikuchii Lipase by Spray Drying in the Presence of Maltodextrin and beta-Cyclodextrin

In this study the effects of spray-drying conditions on the retention of enzyme activity of lipase produced by the endophytic fungus Cercospora kikuchii have been investigated. Drying runs were carried out in a bench-top spray dryer with a concurrent flow regime. The influence of the variables inlet temperature of drying gas, Tgi (86.4 to 153.6 degrees C); mass flow rate of the enzymatic extract fed to the dryer, Ws (2.63 to 9.36g/min); and concentration of the drying adjuvant added to the extract, ADJ (1.95 to 12.05%), on the spray-drying performance and on product quality was evaluated through experimental planning and regression analysis. The use of maltodextrin, as a stabilizing agent, slightly improved the retention of enzyme activity compared to -cyclodextrin. Statistical optimization of the experimental results allowed the determination of the processing conditions that maximized the retention of the enzymatic activity (RAE), namely, concentration of drying adjuvants of 12.05%, inlet temperature of the drying gas of 153.6 degrees C, and flow rate of the enzymatic extract fed to the dryer of 9.36g/min for the both drying adjuvants investigated.

Stability Testing of Spray- and Spouted Bed-Dried Extracts of Passiflora alata

The aim of this research was to perform a stability testing of spray- and spouted bed-dried extracts of Passiflora alata Dryander (Passion flower) under stress storage conditions. Spouted bed- and spray-dried extracts were characterized by determination of the average particle diameter (dP), apparent moisture content (XP), total flavonoid content (TF), and vitexin content. Smaller and more irregular particles were generated by the spouted bed system due to a higher attrition rate (surface erosion) inside the dryer. The SB dryer resulted in an end product with higher concentration of flavonoids (approximate to 10%) and lower moisture content (1.6%, dry basis) than the spray dryer, even with both dryers working at similar inlet drying air temperature and ratio between the extract feed flow rate to drying air flow rate (Ws/Wg). Samples of the spouted bed- and spray-dried extracts were stored at two different temperatures (34 and 45 degrees C) and two different relative humidities (52 and 63% RH for 34 degrees C; 52 and 60% RH for 45 degrees C) in order to perform the stability testing. The dried extracts were stored for 28 days and were analyzed every 4 days. The flavonoid vitexin served as the marker compound, which was assayed during the storage period. Results revealed shelf lives ranging from 9 to 184 days, depending on the drying process and storage conditions.

ANALYSIS OF PRESSURE FLUCTUATIONS DURING WATER EVAPORATION IN SPOUTED BED

The aim of this work was to study the behaviour of conventional spouted beds during water evaporation and to analyze the pressure fluctuations at the maximum water evaporative capacity for different bed heights and air flow rates. The results showed that spout pressure drop could not indicate the proximity of maximum evaporative capacity; however this condition is denoted by a minimum in fountain height. The standard deviation and amplitude of the pressure fluctuations also showed a minimum point at the maximum water evaporation capacity. The frequency domain analysis of pressure fluctuations revealed that the dry bed has a dominant frequency varying from 6 to 8.2 Hz and that the peak of dominant frequency tends to disappear with the increase in water feed rate.

IDENTIFICATION OF THE STATE OF A WET SPOUTED BED THROUGH TIME-FREQUENCY ANALYSIS OF PRESSURE FLUCTUATION TIME SERIES

The feasibility of detecting instability in wet spouted beds via pressure fluctuation (PF) time-series analyses was investigated. Experiments were carried out in a cylindrical Plexiglas column of diameter 150 mm with a conical base of internal angle 60 degrees, an inlet orifice diameter of 25 mm and glass beads of diameter 2.4 mm. Transducers at several axial positions measured PF time series with incremental addition of aqueous sucrose solutions of different concentrations. Liquid addition affected the spouted bed dynamics, causing irregular spouting, increased voidage in the annulus, increased fountain height, irregular annulus height, channelling, agglomeration, and adhesion of particles to the column walls. Autocorrelations indicated the appearance of periodicities in the PF signals with increasing sucrose addition. Dominant peaks in power-spectral density developed at low frequencies with changing system dynamics. The results indicate that PF signals furnish relevant information on system dynamics, useful for monitoring and control of spouted bed operations such as particle coating and drying of paste-like materials.

INVESTIGATION OF ACOUSTIC SIGNALS AS A TOOL FOR CHARACTERIZING SPOUTED BED DYNAMICS

The feasibility of characterizing the dynamics of a spouted bed based on acoustic emission (AE) signals is evaluated. Acoustic emission signals were measured in a semi-cylindrical Plexiglas column of diameter 150 mm and height 1000 mm with a conical base of internal angle 60 degrees and 25 mm inlet orifice diameter. Data were obtained for U/U(ms), from 0.3 to 2.0, static bed height from 250 to 500 mm, and glass beads of diameter 1.2 and 2.4 mm. AE signals reflected the effects of particle size and U/U(ms), but in general were insensitive to bed depth, even when there were drastic changes in spouting flow patterns. The results indicate that the AE signals were insensitive to the spouted bed hydrodynamics for the conditions studied. Overall, it appears that the AE analysis is unlikely to be a suitable technique for discriminating spouted bed flow regimes, at least for the range of frequencies and operating conditions investigated.

Lipase Production by Endophytic Fungus Cercospora kikuchii: Stability of Enzymatic Activity after Spray Drying in the Presence of Carbohydrates

The present work deals with improving the production and stabilization of lipases from Cercospora kikuchii. Maximum enzyme production (9.384 U/ml) was obtained after 6 days in a medium supplemented with 2% soybean oil. The lipases were spray dried with different adjuvants, and their stability was studied. The residual enzyme activity after drying with 10% (w/v) of lactose, b- cyclodextrin, maltodextrin, mannitol, gum arabic, and trehalose ranged from 63 to 100%. The enzyme activity was lost in the absence of adjuvants. Most of the adjuvants used kept up at least 50% of the enzymatic activity at 5 degrees C and 40% at 25 degrees C after 8 months. The lipase dried with 10% of beta-cyclodextrin retained 72% of activity at 5 degrees C. Lipases were separated by butyl-sepharose column into 4 pools, and pool 4 was partially purified (33.1%; 269.5 U/mg protein). This pool was also spray dried in maltodextrin DE10, and it maintained 100% of activity.

Thesis summary: Standardized dried extracts of Brazilian medicinal plants: Assessment of technical and economic feasibility of spouted bed drying

This study is an integral part of a research project which seeks the establishment of protocols for the production of standardized herbal dried extracts emphasizing the spouted bed drying. This thesis was conducted at faculty of Pharmaceutical Science of Ribeiro Preto/University of So Paulo, Brazil, under supervision of Prof. Dr. Wanderley Pereira Oliveira*, defended on September 28, 2007.

A wavelet-based adaptive technique for adsorption problems involving steep gradients

A general, fast wavelet-based adaptive collocation method is formulated for heat and mass transfer problems involving a steep moving profile of the dependent variable. The technique of grid adaptation is based on sparse point representation (SPR). The method is applied and tested for the case of a gas–solid non-catalytic reaction in a porous solid at high Thiele modulus. Accurate and convergent steep profiles are obtained for Thiele modulus as large as 100 for the case of slab and found to match the analytical solution.

Computationally efficient solution techniques for adsorption problems involving steep gradients in bidisperse particles

A piecewise uniform fitted mesh method turns out to be sufficient for the solution of a surprisingly wide variety of singularly perturbed problems involving steep gradients. The technique is applied to a model of adsorption in bidisperse solids for which two fitted mesh techniques, a fitted-mesh finite difference method (FMFDM) and fitted mesh collocation method (FMCM) are presented. A combination (FMCMD) of FMCM and the DASSL integration package is found to be most effective in solving the problems. Numerical solutions (FMFDM and FMCMD) were found to match the analytical solution when the adsorption isotherm is linear, even under conditions involving steep gradients for which global collocation fails. In particular, FMCMD is highly efficient for macropore diffusion control or micropore diffusion control. These techniques are simple and there is no limit on the range of the parameters. The techniques can be applied to a variety of adsorption and desorption problems in bidisperse solids with non-linear isotherm and for arbitrary particle geometry.

A modified discrete random pore model allowing for different initial surface reactivity

We investigate here a modification of the discrete random pore model [Bhatia SK, Vartak BJ, Carbon 1996;34:1383], by including an additional rate constant which takes into account the different reactivity of the initial pore surface having attached functional groups and hydrogens, relative to the subsequently exposed surface. It is observed that the relative initial reactivity has a significant effect on the conversion and structural evolution, underscoring the importance of initial surface chemistry. The model is tested against experimental data on chemically controlled char oxidation and steam gasification at various temperatures. It is seen that the variations of the reaction rate and surface area with conversion are better represented by the present approach than earlier random pore models. The results clearly indicate the improvement of model predictions in the low conversion region, where the effect of the initially attached functional groups and hydrogens is more significant, particularly for char oxidation. It is also seen that, for the data examined, the initial surface chemistry is less important for steam gasification as compared to the oxidation reaction. Further development of the approach must also incorporate the dynamics of surface complexation, which is not considered here.

Adsorption in mesopores: A molecular-continuum model with application to MCM-41

The classical model of surface layering followed by capillary condensation during adsorption in mesopores, is modified here by consideration of the adsorbate solid interaction potential. The new theory accurately predicts the capillary coexistence curve as well as pore criticality, matching that predicted by density functional theory. The model also satisfactorily predicts the isotherm for nitrogen adsorption at 77.4 K on MCM-41 material of various pore sizes, synthesized and characterized in our laboratory, including the multilayer region, using only data on the variation of condensation pressures with pore diameter. The results indicate a minimum mesopore diameter for the surface layering model to hold as 14.1 Å, below which size micropore filling must occur, and a minimum pore diameter for mechanical stability of the hemispherical meniscus during desorption as 34.2 Å. For pores in-between these two sizes reversible condensation is predicted to occur, in accord with the experimental data for nitrogen adsorption on MCM-41 at 77.4 K.

Determination of coalescence kernels for high-shear granulation using DEM simulations

Discrete element method (DEM) modeling is used in parallel with a model for coalescence of deformable surface wet granules. This produces a method capable of predicting both collision rates and coalescence efficiencies for use in derivation of an overall coalescence kernel. These coalescence kernels can then be used in computationally efficient meso-scale models such as population balance equation (PBE) models. A soft-sphere DEM model using periodic boundary conditions and a unique boxing scheme was utilized to simulate particle flow inside a high-shear mixer. Analysis of the simulation results provided collision frequency, aggregation frequency, kinetic energy, coalescence efficiency and compaction rates for the granulation process. This information can be used to bridge the gap in multi-scale modeling of granulation processes between the micro-scale DEM/coalescence modeling approach and a meso-scale PBE modeling approach.

A novel nucleation apparatus for regime separated granulation

A novel nucleation apparatus is presented for the production of narrow sized nuclei from various powder and binder liquid combinations. Mono-sized binder liquid droplets are produced by a specially designed mono-disperse droplet generator. The droplet generator is positioned above a conveyor belt, transporting a powder bed through the spray zone of the droplet generator. By nucleating powder on a conveyer belt, the nucleation mechanism is completely separated from all other granulation mechanisms due to the lack of relative motion between primary particles and/or formed nuclei. Nucleation tests were performed using chalcopyrite and limestone powders with water as the binder liquid. At all operating conditions, the formed nuclei were found to originate from multiplicities of drops that merged on the powder bed surface. Investigation of the dynamics of nuclei formation showed that powder-binder liquid combinations with fast penetration dynamics result in less variation in the number of droplets from which nuclei originate. Smaller and more narrowly distributed nuclei were also achieved by increasing powder speed through the spray zone.

Dimensionless spray flux in wet granulation: Monte-Carlo simulations and experimental validation

Dimensionless spray flux Ψa is a dimensionless group that characterises the three most important variables in liquid dispersion: flowrate, drop size and powder flux through the spray zone. In this paper, the Poisson distribution was used to generate analytical solutions for the proportion of nuclei formed from single drops (fsingle) and the fraction of the powder surface covered by drops (fcovered) as a function of Ψa. Monte-Carlo simulations were performed to simulate the spray zone and investigate how Ψa, fsingle and fcovered are related. The Monte-Carlo data was an excellent match with analytical solutions of fcovered and fsingle as a function of Ψa. At low Ψa, the proportion of the surface covered by drops (fcovered) was equal to Ψa. As Ψa increases, drop overlap becomes more dominant and the powder surface coverage levels off. The proportion of nuclei formed from single drops (fsingle) falls exponentially with increasing Ψa. In the ranges covered, these results were independent of drop size, number of drops, drop size distribution (mono-sized, bimodal and trimodal distributions), and the uniformity of the spray. Experimental data of nuclei size distributions as a function of spray flux were fitted to the analytical solution for fsingle by defining a cutsize for single drop nuclei. The fitted cutsizes followed the spray drop sizes suggesting that the method is robust and that the cutsize does indicate the transition size between single drop and agglomerate nuclei. This demonstrates that the nuclei distribution is determined by the dimensionless spray flux and the fraction of drop controlled nuclei can be calculated analytically in advance.