Nkere K. Ebube

Sustained Release of Acetaminophen from Heterogeneous Matrix Tablets: Influence of Polymer Ratio, Polymer Loading, and Co-active on Drug Release

The aim of this research was to investigate the effect of pseudoephedrine (PE), polymer ratio, and polymer loading on the release of acetaminophen (APAP) from hydroxypropyl methyl cellulose (HPMC)/polyvinylpyrrolidone (PVP) matrices. Granules formulated with APAP or both APAP and PE, and various blends of HPMC and PVP were compressed into tablets at varying compression forces ranging from 2000 to 6000 Ib. In vitro drug release from the matrix tablets was determined and the results correlated with those of tablet water uptake and erosion studies. Drug release from the formulations containing both APAP and PE was slower than those containing only APAP (P < 0.05, F = 3.10). Drug release from tablets formulated with APAP only showed an initial burst at pH 1.16 or 7.45, and at high total polymer loading (> or = 9.6%). Formulations containing both APAP and PE showed slower drug release at pH 1.16 than at pH 7.45. At pH 1.16, a decline in the percentage of APAP released occurred after 18 hours. This was due to the hydrolysis of APAP to p-aminophenol. The drug dissolution data showed good fit to the Korsmeyer and Peppas model, and the values of the release exponents ranged from 0.20 to 0.62, indicating a complex drug release pattern. Tablet erosion studies indicated that the amount of APAP released was linearly related to the percentage of tablet weight loss. The kinetics of tablet water uptake was consistent with a diffusion and stress relaxation controlled mechanism. Overall, the results of this study indicated that PE, as a co-active in the formulation, modified the matrix, and hence retarded APAP release.

Preformulation studies and characterization of the physicochemical properties of amorphous polymers using artificial neural networks

The utility of artificial neural networks (ANNs) as a preformulation tool to determine the physicochemical properties of amorphous polymers such as the hydration characteristics, glass transition temperatures and rheological properties was investigated. The neural network simulator, CAD/Chem, based on the delta back-propagation paradigm was used for this study. The ANNs software was trained with sets of experimental data consisting of different polymer blends with known water-uptake profiles, glass transition temperatures and viscosity values. A set of similar data, not initially exposed to the ANNs was used to validate the ability of the ANNs to recognize patterns. The results of this investigation indicate that the ANNs accurately predicted the water-uptake, glass transition temperatures and viscosities of different amorphous polymers and their physical blends with a low % error (0-8%) of prediction. The ANNs also showed good correlation between the water-uptake and changes in the glass transition temperatures of the polymers. This study demonstrated the potential of the ANNs as a preformulation tool to evaluate the characteristics of amorphous polymers. This is particularly relevant when designing sustained release formulations that require the use of a fast hydrating polymer matrix.

Comparative dissolution studies for mefenamic acid-polyethylene glycol solid dispersion systems and tablets.

The purpose of this study was to enhance the dissolution of mefenamic acid (MFA) through the formation of solid dispersion systems, and to compare the dissolution of the unformulated dispersions with those of formulated dispersions in tablets. Solid dispersions of MFA were prepared in polyethylene glycol 3350 (PEG) as a binary system, and PEG and Tween 20 (TW) as a ternary system by the melt method. The dispersions were characterized by dissolution, scanning electron microscopy, and powder x-ray diffraction studies. A decrease in MFA composition in the binary dispersion systems from 50 to 5% w/w resulted in a 50% increase in the dissolution rate during the period of study, and this was threefold higher than that of pure MFA. Incorporation of TW in the preparation of ternary dispersion systems resulted in a further increase in MFA dissolution. A sevenfold increase in MFA dissolution was observed when the ternary system composition was MFA/PEG/TW 4.7:93:2.3 (% w/w). Scanning electron microscopy and x-ray diffraction pictures showed an increase in size and decrease in crystallinity of the dispersions, respectively. Compression of the dispersions into tablets did not have any effect on the dissolution of the drug from the dispersions. Compression of pure MFA and Avicel PH 101, which was used as a diluent and disintegrant, resulted in a threefold increase in dissolution. However, the dissolution of the uncompressed mixture was identical to that of pure MFA. Thus, further processing of the solid dispersions into tablets did not decrease the rate of dissolution of the drug in the dispersions. This may be very important in the formulation of solid dispersions as tablets, which could lead to a reduction in the dose of practically water-insoluble drugs.

Effect of drug, formulation and process variables on granulation and compaction characteristics of heterogeneous matrices. Part 1: HPMC and HPC systems

Abstract The purpose of this study was to investigate the effects of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) ratios, total polymer loading and the use of pseudoephedrine as a co-active on the physical properties of acetaminophen granulation as well as that of the compressed tablets. The incorporation of pseudoephedrine to the acetaminophen–polymer formulations resulted in a decreased amount of water required for the wet granulation process. Moreover, the particle size of the granules decreased and the tablet hardness increased. Increasing the HPMC-to-HPC ratio increased both the particle size of granules and the tablet hardness. No clear trend in the particle size of granules and the tablet hardness was seen when the total polymer loading was varied at a given HPMC-to-HPC ratio. The tablet disintegration time was not influenced by the presence of pseudoephedrine; however, it decreased for the formulations containing a lower total polymer content. All the matrix systems investigated showed good compressibility. The effect of pseudoephedrine on the physical properties of wet granulated or compressed acetaminophen tablets was attributed to interference in the hydration characteristics of the matrix polymers.

Controlled Release Tacrine Delivery System for the Treatment of Alzheimer's Disease

Alzheimers disease is a neurodegenerative condition that affects approximately 5 million people and is the fourth leading cause of death in America. Tacrine is one of the three drugs approved by the FDA for the treatment of Alzheimers disease. However, the drug has a short biologic half-life of 2-3 hr and gastrointestinal, cholinergic, and hepatic adverse reactions that are associated with high doses of the drug. The aim of our study was to formulate a controlled release delivery system of tacrine that could be used to minimize the side effects associated with the drug. Microparticles of tacrine were formulated using poly(D,L-lactide-co-glycolide) (PLG). PLG and tacrine were dissolved in mixed organic solvents and added to a polyvinyl alcohol solution that was stirred at a constant rate. The organic solvent was evaporated overnight and the formed microparticles were collected by filtration, dried, and sieve-sized. The effects of such formulation variables, as molecular weight of polymer, stir speed during preparation, and drug loading on encapsulation efficiency (EEF), and in vitro release profiles of tacrine were investigated. An increase in the molecular weight of polymer from 8,000 to 59,000 and 155,000 resulted in approximately 10-fold increase in EEF, but the rate of release decreased with increasing molecular weight. Stir speed during preparation had an effect on the EEF but not on the rate of release. Drug loading did not have a significant effect on the EEF but had an effect on the rate of tacrine release. The results suggest that tacrine could be delivered at controlled levels for weeks for the treatment of Alzheimers disease.Alzheimers disease is a neurodegenerative condition that affects ~5 million people and is the fourth leading cause of death in America. Tacrine is one of the three drugs approved by the FDA for the treatment of Alzheimers disease. However, the drug has a short biologic half-life of 2?3 hr and gastrointestinal, cholinergic, and hepatic adverse reactions that are associated with high doses of the drug. The aim of our study was to formulate a controlled release delivery system of tacrine that could be used to minimize the side effects associated with the drug. Microparticles of tacrine were formulated using poly(D,L-lactide-co-glycolide) (PLG). PLG and tacrine were dissolved in mixed organic solvents and added to a polyvinyl alcohol solution that was stirred at a constant rate. The organic solvent was evaporated overnight and the formed microparticles were collected by filtration, dried, and sieve-sized. The effects of such formulation variables, as molecular weight of polymer, stir speed during preparation, and drug loading on encapsulation efficiency (EEF), and in vitro release profiles of tacrine were investigated. An increase in the molecular weight of polymer from 8,000 to 59,000 and 155,000 resulted in ~10-fold increase in EEF, but the rate of release decreased with increasing molecular weight. Stir speed during preparation had an effect on the EEF but not on the rate of release. Drug loading did not have a significant effect on the EEF but had an effect on the rate of tacrine release. The results suggest that tacrine could be delivered at controlled levels for weeks for the treatment of Alzheimers disease.

Relating Formulation Variables to in Vitro Dissolution Using an Artificial Neural Network

The purpose of this paper was to investigate the effect of several experimental variables on the ability of a neural network to predict in vitro dissolution rate as a function of product formulation changes. Neural network software was trained with sets of hypothetical and experimental data consisting of 4-15 formulations with known in vitro drug dissolution profiles and the ability of the trained model to recognize patterns was validated against similar formations not used to train the neural network. The effect of selected variables, e.g., number of hidden-layer nodes and iterations, as well as the use of replicate or mean data on the accuracy of the predictions was investigated. The importance of optimizing the number of hidden-layer nodes and iterations was demonstrated. The prediction error increased for validation data sets that were outside the range of the training data set. Accurate predictions were obtained with as few as four formulations in the training set, provided the formulations were carefully chosen, and the number of formulation variables were small. Also, limiting the validation set to one formulation was not sufficient to validate the neural network model. Increasing the size of the training set, or replication of the input and output data, also provided more accurate predictions. The neural network accurately predicted in vitro drug release provided the neural network variables were optimized, and the training and validation data sets were appropriately selected.

Effect of Drug, Formulation, and Process Variables on Granulation and Compaction Characteristics of Heterogeneous Matrices: Part II. HPMC and PVP Systems

AbstractA heterogeneous matrix comprising hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) at various ratios was granulated using acetaminophen and pseudoephedrine as model drugs. The effect of drug, polymer ratio, total polymer loading, and volume of the granulating fluid on granule growth, granule size distribution, compaction, and tablet properties of the matrix was studied. Formulations containing both acetaminophen and pseudoephedrine required less water to granulate than those containing only acetaminophen. Moreover, the particle sizes of granules prepared with acetaminophen and pseudoephedrine were smaller than those containing only acetaminophen. Tablet hardness increased and friability decreased considerably in all formulations containing pseudoephedrine. In general, the tablet hardness and tablet disintegration time varied with changes in total polymer loading, fraction of HPMC in the matrix, and composition of the model drug(s). All the matrix systems studied showed good flow...

Preformulation studies and characterization of proposed chondroprotective agents: glucosamine HCl and chondroitin sulfate.

Purpose: Glucosamine HCl and chondroitin sulfate are proposed chondroprotective agents commonly used as dietary supplements. This study examined the physicochemical and mechanical properties of chondroitin sulfate, glucosamine HCl powder, and glucosamine HCl granulation obtained from various sources. Methods: The particle size distributions of the materials were determined using sieve analysis and time-of-flight techniques. Polarized light microscopy was used to examine particle morphology. Powder x-ray diffraction studies, moisture sorption isotherms, deformation behavior, powder flow, and compaction characteristics were also investigated. The polarized light microscopy and x-ray diffraction patterns showed that chondroitin sulfate is amorphous while glucosamine HCl is crystalline. Particle sizes of chondroitin sulfate and glucosamine HCl varied widely, depending on their source or manufacturing technique (e.g., granulation). The studied samples of shark-derived chondroitin sulfate had a small median particle size (4 μm) compared to that derived from bovine cartilage (17 μm). Different moisture sorption profiles were obtained for the glucosamine HCl granulations studied. Glucosamine HCl granulation from Supplier I showed no observable moisture sorption, while the granulation from Supplier II showed an approximately 5% weight gain. Conversely, chondroitin sulfate was extremely hygroscopic and deliquescent. The Carrs indices for glucosamine HCl samples ranged from 12.5 to 31.5; for chondroitin sulfate the values were 25.2 and 53.6. The compression analysis showed that all chondroitin sulfate samples exhibited plastic deformation behavior, with the shark-derived chondroitin sulfate forming superior compacts when compared to the bovine. The dominant mechanism of compression of glucosamine HCl powder was brittle fracture, whereas wet granulated glucosamine HCl exhibited plastic deformation with enhanced mechanical strength. Conclusions: The physicochemical and mechanical characteristics between the various dietary supplements studied varied greatly. Data obtained from this study provide an understanding of the physicomechanical behavior of chondroitin sulfate and glucosamine HCl. Application of this knowledge would facilitate development of stable solid dosage forms containing these materials.