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ABSTRACT: Top-spray fluidized bed granulation with axial fluidization airflow from the bottom of the granulator is well-established in the pharmaceutical industry. The application of swirling airflow for fluidized bed granulation was more recently introduced. This study examined the effects of various process parameters on the granules produced by side-spray fluidized bed with swirling airflow using the central composite and Box-Behnken design of experiment. Influence of the amount of binder solution, spray rate, and distance between spray nozzle and powder bed were initially studied to establish operationally viable values for these parameters. This was followed by an in-depth investigation on the effects of inlet airflow rate, atomizing air pressure and distance between spray nozzle and powder bed on granule properties. It was found that the amount of binder solution had a positive correlation with granule size and percentage of lumps but a negative correlation with size distribution and Hausner ratio of the granules. Binder solution spray rate was also found to affect the granules size. High drug content uniformity was observed in all the batches of granules produced. Both inlet airflow rate and atomizing air pressure were found to correlate negatively with granule size and percentage of lumps but correlate positively with the size distribution of the granule produced. Percentage of fines was found to be significantly affected by inlet airflow rate. Distance between spray nozzle and powder bed generally affected the percentage of lumps.
AAPS PharmSciTech 12/2012; · 1.43 Impact Factor
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ABSTRACT: This study assessed the utility of near-infrared (NIR) spectroscopy for the real-time monitoring of content uniformity and critical quality attributes (tensile strength, Young's modulus, and relative density) of ribbed roller compacted flakes made by axially corrugated or ribbed rolls. A custom-built setup was used to capture off-line NIR spectra from the flakes containing micronized chlorpheniramine maleate, microcrystalline cellulose, lactose, and magnesium stearate. The partial least square regression method was employed to build calibration models from these off-line NIR spectra using experimental design and validated using test set validation. During calibration model development, various factors, such as spectral acquisition mode, probe positioning, spectral preprocessing method, and beam size, were investigated to improve the prediction ability of the models. The statistical results obtained for calibration models and their validation revealed that dynamic spectral acquisition and proper probe positioning were very crucial to minimize the incorporation of variability in NIR spectra resulting from the flake's undulation. Calibration and validation statistics also suggested the importance of selecting appropriate spectral preprocessing method and beam size. In this study, best calibration models resulted from standard normal variate followed by first derivative preprocessed dynamic spectra captured using beam size ~1.2 mm. Best calibration models constructed from off-line NIR spectra were used in real-time analysis of flake attributes. Finally, adequacy of best calibration models was established from real-time prediction results. Overall, with the proposed setup, it was possible to monitor the roller compaction process in real time for various properties associated with the ribbed flakes in a rapid, efficient, and nondestructive manner.
AAPS PharmSciTech 12/2012; · 1.43 Impact Factor
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ABSTRACT: The photophysical properties of chlorin e6 (Ce6) in twelve different protic, aprotic and non-polar solvents were investigated using ultraviolet-visible and fluorescence spectroscopic methods. Solvatochromic effects were determined by the changes in quantum yield, Stokes shift, fluorescence half-life and excited state dipole moments of Ce6 in the different solvents. The absorption shifts observed in different solvents were further analyzed using the Kamlet-Abboud-Taft model and the nature of solute-solvent interactions between Ce6 and different protic and aprotic solvents was elucidated. The quantum yields were found highest in protic solvents (except water), followed by aprotic and non-polar solvents. Solvent polarity parameters showed a linear increasing trend with Stokes shift and fluorescence half-life, which indicated the presence of Ce6-solvent interaction. Using the Kamlet-Abboud-Taft model, a direct correlation between the solvent polarity parameters and absorption shift was observed, which substantiated the existence of Ce6-solvent interaction by hydrogen bond formation. The excited state dipole moments in specific protic and aprotic solvents were found to be higher than the ground state dipole moments, implying a more polar nature of Ce6 during excited state transition.
Journal of Fluorescence 11/2012; · 2.11 Impact Factor
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ABSTRACT: Pellet coating is traditionally carried out using the Wurster coater. This study investigated the feasibility of pellet coating in a newly developed coater built with a unique airflow system, the Supercell™ coater (GEA Pharma Systems, UK). A full factorial design study was carried out to evaluate the influences of the spray rate of the coating dispersion, batch size of the pellet load, pellet size fraction and plenum pressure of the fluidizing air on the color coating of pellets in the Supercell™ coater. Results showed that pellets could be successfully coated using the Supercell™ coater. Higher plenum pressures and lower spray rates were found to minimize pellet agglomeration during coating. Although coating efficiencies were comparable amongst the different pellet size fractions, larger batch sizes of pellets were coated with higher efficiencies. Process optimization was carried out for each pellet size fraction and a large batch size (120 g) in combination with a high plenum pressure (1,500 mm WC) were deemed optimal. Optimal spray rates differed according to pellet size fraction and a lower spray rate was required for smaller pellets. Pellet flow patterns observed during coating were dependent on the pressure drop across the fluidized load. A 'swirling' pellet flow pattern was generally observed at coating conditions which led to optimal outcomes.
AAPS PharmSciTech 09/2012; · 1.43 Impact Factor
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ABSTRACT: This study aimed to explore the use of the chicken chorioallantoic membrane (CAM) with laser doppler perfusion imaging (LDPI) as a platform to assess absorption of vasoactive drugs.
The optimal age of the CAM to be employed in the test and the indicator of vasoactivity were first established. Test substances that included common solvents and vasoactive drugs were tested on the CAM surface to determine their irritancy and blood perfusion effects.
Insignificant changes in blood perfusion were observed with deionized water, 0.9% w/v soldium chloride and 5% w/v glucose monohydrate, as well as theophylline and glucagon. Complex changes in blood perfusion were detected with ethanol, N-methyl-2-pyrrolidone, glycerin and propranolol. Both caffeine and glyceryl trinitrate resulted in a drop in blood perfusion.
It was concluded that the LDPI offers a rapid and non-invasive method to measure blood perfusion in the CAM. The latter provides a potentially useful platform in formulation studies to evaluate the effects of additives on drug absorption using caffeine or glyceryl trinitrate as model drugs.
The Journal of pharmacy and pharmacology. 04/2012; 64(4):517-29.
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ABSTRACT: The aim of this study was to utilize high-speed video imaging for understanding the disintegrability of compacts and disintegrant action upon wetting. High-speed video imaging was used to visualize the disintegration of compacts and effect of wetting on free disintegrant particles. Acquired images were processed using MATLAB, and changes in the compact area and instantaneous motion of compacted particles on contact with water were analyzed. The capillary action of compacts was also determined for various disintegrants. Finally, the breakdown behavior of compacts prepared with selected disintegrants was analyzed at different compression forces to evaluate recovery of compaction strain. Water-insoluble inert diluent, dicalcium phosphate, was used as a comparator. The results from this visualization study provided an in-depth understanding of the disintegrant behavior of free and compacted disintegrant particles upon wetting. The mechanisms of swelling, capillary action, disruption of particle-particle bonds and strain recovery were successfully monitored by video imaging. The disintegration of compacts containing crospovidone appeared to be less influenced by swelling or wicking action. The influence of compression force on the disintegration of selected disintegrants confirmed that strain recovery is the dominant mechanism for the disintegrant action of crospovidone.
Journal of Pharmaceutical Sciences 03/2012; 101(6):2155-64. · 3.06 Impact Factor
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ABSTRACT: The chick chorioallantoic membrane (CAM) was explored as a biological membrane for use in the study of drug permeation with a Franz diffusion cell.
The CAM was removed from fertilized chicken eggs of embryo age 9-18 days. The permeation profiles of nicotine through the fresh CAM were first obtained with a Franz diffusion cell. The permeation profiles of nicotine through frozen CAM, snake skin, pig skin, pig retina and pig buccal mucosa were also determined and compared with those of the fresh CAM.
The permeability coefficient of the CAM varied with its age. The CAM at embryo age 13 was the most robust, showing the lowest standard error in permeability. It was thus chosen for comparative studies with snake skin, pig skin, retina and buccal mucosa. The CAM was found to be most similar to the buccal mucosa in terms of permeation profile and permeability coefficient values. Frozen CAM was also found to have a higher permeability coefficient than fresh CAM. The enhanced permeability was attributed to freezing, which affected the integrity of the CAM structure.
From the findings, CAM shows potential as an alternative to the pig buccal mucosa as an in-vitro buccal model. The robustness of the CAM for drug permeation studies is affected by its age.
The Journal of pharmacy and pharmacology. 10/2011; 63(10):1283-9.
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ABSTRACT: The possibility of continuous processing in pharmaceutical tablet manufacturing is hampered by the viscoelastic recovery of tablets post-compaction. Compacted tablets are typically aged before coating to allow complete viscoelastic recovery so as to avoid subsequent coating defects. There has been little attempt to overcome tablet recovery in order to enable continuous processing and improve manufacturing efficiency. However, with the introduction of improved or newly developed types of tablet-coating equipment, there is renewed interest in the coating of tablets in-line. In-line tablet coating is defined as the coating of tablets immediately after compaction. It is a one-step highly integrated system that circumvents the delay in processing time typically given to allow viscoelastic recovery of tablets. This review aims to summarize the requirements of an in-line tablet-coating system. The possibility of carrying out in-line tablet coating in the near future will also be discussed.
Pharmaceutical Development and Technology 06/2011; · 1.36 Impact Factor
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ABSTRACT: The aim of this study was to identify and optimize the critical process parameters of the newly developed Supercell quasi-continuous coater for optimal tablet coat quality. Design of experiments, aided by multivariate analysis techniques, was used to quantify the effects of various coating process conditions and their interactions on the quality of film-coated tablets. The process parameters varied included batch size, inlet temperature, atomizing pressure, plenum pressure, spray rate and coating level. An initial screening stage was carried out using a 2(6-1(IV)) fractional factorial design. Following these preliminary experiments, optimization study was carried out using the Box-Behnken design. Main response variables measured included drug-loading efficiency, coat thickness variation, and the extent of tablet damage. Apparent optimum conditions were determined by using response surface plots. The process parameters exerted various effects on the different response variables. Hence, trade-offs between individual optima were necessary to obtain the best compromised set of conditions. The adequacy of the optimized process conditions in meeting the combined goals for all responses was indicated by the composite desirability value. By using response surface methodology and optimization, coating conditions which produced coated tablets of high drug-loading efficiency, low incidences of tablet damage and low coat thickness variation were defined. Optimal conditions were found to vary over a large spectrum when different responses were considered. Changes in processing parameters across the design space did not result in drastic changes to coat quality, thereby demonstrating robustness in the Supercell coating process.
AAPS PharmSciTech 12/2010; 12(1):119-31. · 1.43 Impact Factor
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ABSTRACT: A photophysical study describing the effects of the polymer polyvinylpyrrolidone (PVP), on the binding interaction between chlorin e6 (Ce6) with bovine serum albumin (BSA) and human plasma proteins such as very low-density lipoprotein (VLDL), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) was performed using a steady-state fluorescence technique. Combined Ce6-PVP was found to have very stable photostability at three different temperatures (4°C, 21°C and 37°C) when dissolved in an aqueous solution containing 5% and 10% fetal calf serum. The partition coefficient of combined Ce6-PVP was relatively more hydrophilic than that of Ce6 alone. There was a marked increase in the emission profile of Ce6-PVP and the correlated bathochromic shift on the addition of proteins. These results also suggest that Ce6-PVP might have slightly greater association energy with VLDL in comparison to Ce6 alone. The co-localization of Ce6 and Ce6-PVP in cells was also assessed using confocal microscopy. The association of Ce6 with PVP resulted in an enhanced cellular uptake of Ce6 within the cytoplasmic compartment of cells. The present study supported the hypothesis that PVP improves the permeability of Ce6 through the biological membranes of cells.
European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 10/2010; 76(2):245-52. · 3.15 Impact Factor
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ABSTRACT: The objectives of this study were to assess the utility of near infrared (NIR) spectroscopy for simultaneous in-line quantification of the contents of drug and excipients in tablets and to monitor the tabletting process in real time. Direct compression tablet formulations comprising micronized chlorpheniramine maleate, lactose, microcrystalline cellulose and magnesium stearate were used. A custom built NIR setup was used for in-line spectral acquisition (980-1900nm with 1nm resolution) during the tabletting process. Calibration models using dynamic spectral acquisition were prepared and validated using design of experiment approach. During tabletting, stratified sampling of tablets was also carried out to compare the NIR prediction results and subsequent UV analysis results for drug content. The results obtained with calibration and validation statistics confirmed the accuracy of models used to predict contents of tablet components. Stratified sampling results for drug content did not exhibit any significant statistical variation. However, in-line quantification enabled the content analysis of individual tablets in the production batch and detection of content uniformity problems towards the end of the tabletting process. Furthermore, it provided the assurance of in-process content uniformity monitoring of the individual excipients during the tabletting process.
International journal of pharmaceutics 08/2010; 396(1-2):63-74. · 2.96 Impact Factor
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ABSTRACT: The primary purpose of this study is to develop a visiometric process analyzer for online monitoring of particle mass flow rate in the bottom spray fluid bed coating process. The secondary purpose is to investigate the influences of partition gap and air accelerator insert size on particle mass flow rate using the developed visiometric process analyzer. Particle movement in the region between the product chamber and partition column was captured using a high speed camera. Mean particle velocity and number of particles in the images were determined by particle image velocimetry and morphological image processing method respectively. Mass flow rate was calculated using particle velocity, number of particles in the images, particle density and size information. Particle velocity and number findings were validated using image tracking and manual particle counting techniques respectively. Validation experiments showed that the proposed method was accurate. Partition gap was found to influence particle mass flow rate by limiting the rate of solids flux into the partition column; the air accelerator insert was found to influence particle mass flow rate by a Venturi effect. Partition gap and air accelerator insert diameter needed to be adjusted accordingly in relation to the other variability sources and diameter of coating cores respectively. The potential, challenges and possible solutions of the proposed visiometric process analyzer were further discussed.
International journal of pharmaceutics 08/2010; 395(1-2):215-21. · 2.96 Impact Factor
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ABSTRACT: This study aims to classify annular bed flow patterns in the bottom spray fluid bed coating process, study their influence on coat uniformity and investigate the feasibility of developing real-time annular bed flow pattern detection as a PAT tool.
High-speed imaging and particle image velocimetry were used to visualize annular bed flow. Color coating and subsequent tristimulus colorimetry were employed to determine influence of annular bed flow pattern on coat uniformity. Feasibility of monitoring annular bed flow pattern through an observation window was tested using miniaturized particle velocity field and time series particle velocity orientation information.
Three types of annular bed flow patterns were identified. Plug flow gave the best coat uniformity followed by global and localized fluidization. Plug flow may be advantageous for high spray-rate conditions, large-scale coating and prevention of particle segregation. Plug flow could be differentiated from the other flow patterns through a simulated observation window.
Annular bed flow patterns were classified and found to influence particle coat uniformity noticeably. Availability of annular bed flow information for large-scale coaters would enable adjustments for process optimization. This study highlights the potential of monitoring annular bed flow pattern as a PAT tool.
Pharmaceutical Research 03/2010; 27(5):756-66. · 4.09 Impact Factor
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ABSTRACT: Particle recirculation within the partition column is a major source of process variability in the bottom spray fluid-bed coating process. However, its locality and complex nature make it hidden from the operator. The aim of this study was to take snapshots of the process by employing a visiometric process analyzer based on high-speed imaging and ensemble correlation particle image velocimetry (PIV) to quantify particle recirculation. High-speed images of particles within the partition column of a bottom spray fluid-bed coater were captured and studied by morphological image processing and ensemble correlation PIV. Particle displacement probability density function (PDF) obtained from ensemble correlation PIV was consistent with validation experiments using an image tracking method. Particle displacement PDF was further resolved into particle velocity magnitude and particle velocity orientation histograms, which gave information about particle recirculation probability, thus quantifying the main source of process variability. Deeper insights into particle coating process were obtained and better control of coat uniformity can thus be achieved with use of the proposed visiometric process analyzer. The concept of visiometric process analyzers was proposed and their potential applications in pharmaceutical processes were further discussed.
Journal of Pharmaceutical Sciences 07/2009; 99(1):346-56. · 3.06 Impact Factor
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ABSTRACT: We have determined the influences of polyvinylpyrrolidone (PVP) on the topical delivery of chlorin e6 (Ce6) in malignant bladder cells. The chick chorioallantoic membrane (CAM) was used to model the tumor spheroids that resemble small residual bladder tumors prior to vascularization. Macroscopic fluorescence imaging showed that Ce6-PVP-induced fluorescence had a higher sensitivity and specificity for delineating tumor from the adjacent normal CAM compared to Ce6 alone. Nonlinear regression analyses have shown that Ce6-PVP has a longer half-life in the tumor compared to Ce6. The uptake ratio of Ce6-PVP was found to have a 2-fold increase across the CAM when compared to that of Ce6, indicating that PVP was able to facilitate diffusion of Ce6 across the membrane. Confocal laser scanning microscopy further confirmed that Ce6-PVP has better penetration in the CAM as well as in the tumor cells compared to Ce6. The present work contributes to our understanding of the Ce6-PVP drug-polymer system by demonstrating for the first time that the presence of PVP facilitates the transport of Ce6 across the chorioallantoic membrane.
Journal of Biophotonics 11/2008; 1(5):395-407. · 4.34 Impact Factor
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ABSTRACT: Alginate/starch blends were used as wall material to encapsulate fish oil by spray-drying. The effects of alginate type and content on microsphere morphology, yield and microencapsulation efficiency were investigated. The ability of microspheres to confer protection to the microencapsulated fish oil on storage under stress was also determined. The results showed that the addition of alginate to the wall component resulted in rounder microspheres with higher oil encapsulation efficiencies. Microencapsulated oil was found to be more stable to degradation compared to unencapsulated oil.
Journal of Microencapsulation 09/2008; 26(3):263-71. · 1.55 Impact Factor
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ABSTRACT: The aim of this study was to investigate the antimicrobial activities of calcium ions and other cross-linking agents of alginate dressings, as well as their compatibility with commonly used topical antimicrobials.
The antimicrobial activities of cross-linking agents and antimicrobials (five antibiotics and four antiseptics) were evaluated by the broth dilution method. The interactions between individual cross-linking agents and antimicrobials were evaluated using the chequerboard test against common skin pathogens, Staphylococcus aureus and Pseudomonas aeruginosa.
From the MIC determined, antibiotics were the most active, followed by the antiseptics and cross-linking agents. Calcium ions, which are commonly used to cross-link alginate, exhibited very weak antimicrobial activity and higher fractional inhibitory concentration than the other cross-linking agents. The use of calcium and gentamicin resulted in antagonism against S. aureus. In contrast, aluminium, zinc and copper ions exhibited higher antimicrobial activities but insignificant interactions with the antimicrobials.
Commonly used topical antimicrobials that are active against the skin pathogens S. aureus and P. aeruginosa could be potentially incompatible with calcium alginate dressings. Copper, zinc and aluminium ions are more suitable cross-linking agents for alginate as they do not show antagonism with the antimicrobials and could impart antimicrobial property to the resultant dressing.
Journal of Antimicrobial Chemotherapy 08/2008; 62(1):105-8. · 5.07 Impact Factor
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ABSTRACT: We have determined the influences of polyvinylpyrrolidone (PVP) on the topical delivery of chlorin e6 (Ce6) in malignant bladder cells. The chick chorioallantoic membrane (CAM) was used to model the tumor spheroids that resemble small residual bladder tumors prior to vascularization. Macroscopic fluorescence imaging showed that Ce6-PVP-induced fluorescence had a higher sensitivity and specificity for delineating tumor from the adjacent normal CAM compared to Ce6 alone. Nonlinear regression analyses have shown that Ce6-PVP has a longer half-life in the tumor compared to Ce6. The uptake ratio of Ce6-PVP was found to have a 2-fold increase across the CAM when compared to that of Ce6, indicating that PVP was able to facilitate diffusion of Ce6 across the membrane. Confocal laser scanning microscopy further confirmed that Ce6-PVP has better penetration in the CAM as well as in the tumor cells compared to Ce6. The present work contributes to our understanding of the Ce6-PVP drug–polymer system by demonstrating for the first time that the presence of PVP facilitates the transport of Ce6 across the chorioallantoic membrane. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)
Journal of Biophotonics 07/2008; 1(5):395 - 407. · 4.34 Impact Factor
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ABSTRACT: Lamination of alginate matrix tablet at acidic pH can compromise its function as a sustained release carrier. This phenomenon is associated with the conversion of sodium alginate to alginic acid. An innovative approach for controlling the release of a highly water-soluble drug from such matrices is presented in this paper. Inclusion of pH-modifiers was employed to raise the micro-environmental pH within matrices undergoing dissolution at gastric pH. The changes in micro-environmental pH of hydrating alginate matrices were visualized with the aid of a pH-indicator and subsequently quantified using image analysis. Transient elevation in micro-environmental pH impeded alginate protonation and minimized or prevented matrix lamination, contributing to preservation of drug diffusion barrier. Significant reduction in the rate of drug release at pH 1.2 was achieved in the presence of such additives. The action of pH-modifiers was synergistically enhanced in the presence of a carbon dioxide barrier formed by effervescing sodium bicarbonate, reducing drug release in the acidic medium from 60 to 20%. Further insight into the influence of lamination on drug release from alginate compacts was given.
European Journal of Pharmaceutical Sciences 05/2008; 33(4-5):361-70. · 3.21 Impact Factor
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ABSTRACT: The effectiveness of an interactive mixture as a rapid drug delivery system is compared with that of a solid dispersion. The influences of drug load, particle size, and crystallinity of these test systems are investigated. The interactive mixtures and solid dispersions were prepared from polyethylene glycol (PEG) 3350 and hydrophobic nifedipine drug by means of physical mixing and melting methods, respectively. The formed products were subjected to drug particle size and crystallinity analyses, and dissolution tests. In comparison with the interactive mixtures, the solid dispersions with low drug load were more effective as a rapid drug delivery system, as the size of a given batch of drug particles was markedly reduced by the molten PEG 3350. The rate and extent of drug dissolution were mainly promoted by decreasing effective drug particle size. However, these were lower in the solid dispersions than in the interactive mixtures when a high load of fine drug particles was used as the starting material. This was attributed to drug coarsening during the preparation of the solid dispersion. Unlike solid dispersions, the interactive mixtures could accommodate a high load of fine drug particles without compromising its capacity to enhance the rate and extent of drug dissolution. The interactive mixture is appropriate for use to deliver a fine hydrophobic drug in a formulation requiring a high drug load.
Drug Development and Industrial Pharmacy 03/2008; 34(2):206-14. · 1.49 Impact Factor
