Effect of Solubility on Polymer Swelling and Drug Release from Modified Release Polyethylene Oxide (PEO) Matrix Tablets (T3158)
H. Li, X. Gu, Faculty of Pharmacy; University of Manitoba

Purpose:  To investigate the effect of drug solubility on polymer swelling behaviours and drug dissolution profiles from modified release PEO matrix tablets using a texture analyzer.

Methods:  A series of modified release PEO matrix tablets were prepared by using Polyox® WSR301 at varying ratios (10-50%) and direct tableting compression. Pseudoephedrine (PED, solubility 565.3 +/- 0.3 mg/ml) or acetaminophen (AMP, solubility 18.9 +/- 0.3 mg/ml) was incorporated into the tablets as the model compounds. In vitro dissolution of the tablets was conducted using the USP Apparatus 2. The thickness of gel formation during drug dissolution was recorded using a texture analyzer. Relationship among gel layer thickness, PEO ratio, drug solubility and dissolution was correlated and interpreted.

Results:  Drug dissolution and gel formation were directly proportional to drug solubility and PEO ratio in the matrix tablets. PED released much faster from the formulations than AMP due to its higher aqueous solubility; the time required for 50% of drug release (DT50%) ranged 0.9-1.7 hours for the PED tablets and 6.5 -9.0 hours for the AMP tablets respectively. Diffusion exponent values differentiated significantly between the two preparations, 0.46-0.58 for PED and 0.70 -0.86 for AMP, indicating a diffusion-controlled release mechanism from the PED tablets but an erosion-controlled release mechanism from the AMP tablets. Gel layer thickness of the PED tablets was much larger than that of the AMP tablets; there was a linear correlation between gel layer thickness and PEO proportion used in the tablets.

Conclusions:  Drug solubility and matrix polymer ratio directly affected water penetration into the tablet matrix and polymer gelling formation, subsequently resulting in modified release profiles of PED and AMP. The study demonstrated a unique application of texture analyzer in characterization of tablet formulation and drug dissolution.
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Oral Transmucosal Delivery of Tetrahydrocannabinol and Pro-drugs via Hot-melt Polymeric Matrices: In-vivo Studies in Rabbits (M1176)
M. Munjal1, P. B. Lindgren2, H. C. Fyke2, M. A. ElSohly3, M. A. Repka3
1Department of Pharmaceutics, 2The National Center for Natural Products Research, 3Department of Pharmaceutics, The National Center for Natural Products Research, The University of Mississippi,University, MS 38677

Purpose: To investigate the in-vivo absorption potential of ∆9-Tetrahydrocannabinol (THC) through the buccal route using the rabbit as a model animal.

Methods.: THC and its pro-drugs – hemisuccinate (HS) and hemiglutarate (HG) – were incorporated into polyethylene oxide polymeric matrices using a hot-melt method. Noveon® (bioadhesive) and other excipients were also added to aid in the formation of a stable, bioadhesive delivery system. For the animal studies, these matrices were cut into appropriately sized circular discs containing approximately 5 mg equivalent of THC. The rabbits were sedated with ketamine:xylazine intramuscular injection prior to intubation, and subsequently anesthetized with oxygen and isoflurane gas. Blood samples were collected from the rabbit’s lateral ear artery for up to 5 hrs. The collected blood samples were centrifuged to separate the plasma which was further extracted, derivatized and analyzed for THC and THC-COOH content using GC-MS.

Results: A serum concentration-time curve was constructed upon intravenous injection of an ethanolic solution of THC displaying a rapid decline in drug levels. Upon application of the parent or pro-drug-incorporated polymeric formulation to the rabbit’s buccal pouch area, THC blood levels exhibited high variability. For example, a sharp increase in the THC plasma level was obtained with the THC-HG-loaded matrix in one of the animals, with maximum concentration of 68.7 ng/ml observed at 30 min. Similar formulations of discs containing THC or THC-HS produced plasma concentrations of 11.2 and 4.7 ng/ml, respectively, after 30 min.

Conclusion: Continuous anesthesia of the animals was obtained using the general anesthetic, isoflurane. High plasma vs. time concentrations were obtained for THC following administration of the parent/pro-drug loaded polymeric matrices via the buccal route. However, these plasma-time profiles were determined to be erratic. Studies are ongoing to attain controlledrelease of THC and pro-drugs.
This work was partially funded by NIH grants #1R41 GM067304-01 and # P20RR17701.
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Synergistic or Antagonistic Effect of Binary Combination of Hydrophilic Polymers in Controlled Release (M1216)
L. Li, S. Sethia, S. Gupta, T. Chowdhury, S. Ahmed; Formulation R&D, Barr Laboratories, Inc.

Purpose:  To evaluate the combination effect of binary hydrophilic polymers on drug controlled release by using various methods.

Methods:  The viscoelastic properties of the individual polymer and binary combinations were compared using a TA Rheometer. Viscosity –shear rate profiles of the polymer solutions were measured at various pH conditions. A modified Moisture Sorption Analyzer was used to explore the rate of moisture uptake of the individual and combined polymers at 99% RH. A Texture-Analyzer was used to measure the gel strength of polymer tablets after hydration. Dissolution study was carried out in USP apparatus II for drugs with various degree of solubility.

Results:  Among the polymers evaluated such as HPC, HEC, HPMC, Sodium CMC, Carbopol and their combinations, synergistic combination effect was observed for HPC and Sodium CMC. The viscosity of the HPC/Sodium CMC combination increased approximately 100% relative to individual polymers. However, interestingly, antagonistic effect was observed for HPC and Carbopol. The viscosity dropped about 90% compared to the individual polymers. Combination of HPMC/Carbopol, and HPC/HEC showed no interaction. The gel strength study indicated good correlation with the viscosity changes. However, the moisture uptake method did not correlate with other Methods:  The combination matrixes such as HPC/Sodium CMC and HPC/Carbopol showed synergistic or antagonistic controlled release effect on the dissolution of a highly water-soluble drug.

Conclusion:  In controlled release formulation, combination of two hydrophilic polymers can result in unexpected synergistic or antagonistic effect on polymer gel strength, and further influence the drug release from the polymer matrix. Viscosity measurement and texture analysis are useful methods on studying of the combination effect.
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Analysis of Matrix Geometry and Front Movements for Hydroxypropyl Methyl Cellulose (HPMC), Hydroxypropyl Cellulose (HPC), and Polyethylene Oxide (PEO)(M1220)
S. Missaghi, R. Fassihi; School of Pharmacy, Temple University

Purpose: To compare the swelling and erosion characteristics and drug release properties of extended-release matrix tablets having different size and shape, employing HPMC, HPC, and PEO.

Methods: Three different matrix formulations were prepared using HPMC (MethocelK100M), HPC (KlucelHXF), and PEO (PolyoxWSR303) at 40%w/w, blended with microcrystalline cellulose (40%w/w), tetracycline (19.5%w/w) as a drug marker, and magnesium stearate (0.5%w/w). Tablets were manufactured using direct compression method with two different geometries (500 and 800mg; round and oval). The swelling and erosion characteristics and the release properties of each tablet were investigated in deionized water, using USP 28-appartus II modified with a mesh device, operated at 75 rpm. Tablets were removed at pre-determined time intervals and subjected to textural analysis and cross-sectioning. The extent of water uptake and tablet erosion was evaluated using gravimetrical analysis.

Results: Depending on their composition and geometry, all tablets demonstrated different degrees of swelling and erosion. Initially, PEO-matrices showed the greatest extent of water uptake and axial swelling followed by HPMC and HPC. As for erosion properties, HPC-matrices demonstrated the lowest extent of erosion followed by HPMC and PEO. The cross-sections of tablets at 3 hours exhibited distinct fronts with differentiable gel layer thickness. The inter-relationship between the matrix composition/geometry and its release properties in relation to internal structural changes, as determined with textural analysis, was also investigated.

Conclusions: Dynamics of swelling, erosion, and front movements in matrices having round or oval shape demonstrated disproportional changes in shape, erosion, and swelling in each case. Regardless of original shape, the overall change in aspect ratios during swelling were in the order of HPMC>PEO>HPC, while the extent of drug release from matrices was in the order of PEO>HPMC>HPC. The significance of these effects in relation to change in overall textural properties of each matrix and their erosion characteristics is discussed.
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Design and development of controlled release matrices: modeling release kinetics by texture analysis and response surface methodology (RSM) (M1224)
Y. El-Malah, S. Nazzal
Department of Basic Pharmaceutical Sciences, The University of Louisiana at Monroe, Monroe, LA 71209

Purpose:   The objectives of this study were (1) investigate the effect of carbopol and polyox (Low MW) on release kinetics of theophylline from controlled release matrix tablets, (2) statistically evaluate the effect of polymer blends on dissolution rate by RSM, and (3) develop an optimized tablet with a 12-hour, zero-order release kinetics.

Methods:   The effect of polymer blend on diffusion and swelling kinetics was evaluated using a TA-XTPlus Texture Analyzer. A timerepeat compression model using a modified In-Vitro dissolution assembly was developed and applied for this study. A 3-factor, 3-level D-Optimal design was used to explore the linear and quadratic response surfaces and construct a second order polynomial model. Factors investigated were: low MW Polyox (X1), carbopol (X2), and lactose(X3). Responses were: time to 50% release (Y1), and cumulative percent of drug released after 2, 4, 6, 8, and 12hrs (Y2-Y6). Tablets of variable compositions were compressed at 5000 lb using concave 10mm punches. Dissolution was evaluated in USP Type II apparatus.

Results:  Carbopol concentration showed significant effect (p < 0.05) on the response (Y1). This effect was demonstrated by contour and ternary surface plots. Polyox had marginal effect on dissolution. Polyox effect was apparent on modulating release pattern, which was expressed as the release exponent (n). This effect was further verified from the yield strength values derived from the Texture ¡§force-displacement curves¡¨. RSM predicted optimum levels of X1, X2, and X3 under the constrained dissolution variables: 2hr: 17%, 4hr: 33.3%, 6hr: 50%, 8hr: 66.7%, and 12hr: 100%. A new formulation was prepared according to the predicted levels. Observed responses were 2hr: 21.3%, 4hr: 37.9%, 6hr: 56.7%, 8hr: 76.6%, and 12hr: 99.9%.

Conclusion:  Low MW Polyox plays a critical role in modulating drug release and diffusion from hydrophilic matrices in which carbopol is the primary diffusion controlling polymer.
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In Vitro Performance Characterization of Expandable Tablets using the Texture Analyzer (M1233 )
P. Shao1, J. Wan1, L. Lu2; 1Solids Development- Ann Arbor, Pfizer Global Research and Development, 2Chemical Engineering,University of Michigan

Purpose:  To develop a method to characterize the physical performance (swelling rate and rigidity) of expandable tablets using Texture Analyzer.

Methods:  An experimental expandable tablet formulation was used as a platform to develop a method on the texture analyzer to characterize the swelling rate and rigidity of expandable tablets. The experimental set-up for swelling rate measurement consisted of a mesh stand and agitator placed inside a jacketed beaker maintained at 37ºC. Dry tablets were placed on the mesh stand and the probe was positioned at the center of the tablet. The test was initiated upon the addition of water at 37ºC. For swelling rate determination, a software sequence was written so that the probe will maintain a constant tracking force as the tablet swells by traveling up to accommodate the force buildup. Distance traveled by the probe versus time data was recorded to estimate swelling rate. To characterize rigidity, the probe was programmed to compress down on the tablet at a constant speed until it penetrated the entire height of the tablet. Force versus distance data was recorded to estimate tablet rigidity.

Results:  Swelling profiles were generated for the expanding tablet for different tracking force values. A tracking force of 2g was determined to be optimum for swelling rate determination. Force versus distance data was recorded during rigidity measurement using control tablets at 2 and 4 hour swelling times. Area under the force-distance curve and maximum force experienced by the probe were calculated and compared for different probes at 2 and 4 hour swelling times. A trigger force of 0.5g using the cylinder probe was determined to be optimum for rigidity measurement.

Conclusion: A method was developed to characterize the swelling rate and rigidity of expandable tablets. The method was subsequently applied to different expandable tablet formulations.
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Pre-plasticized vs. simultaneously plasticized ethylcellulose powder for dry polymer powder coating (M1239)
I. Terebesi, R. Bodmeier; College of Pharmacy, Freie Universität Berlin

Purpose:  To compare the suitability of pre-plasticized ethylcellulose powder and micronized ethylcellulose (simultaneous spraying of a plasticizer during coating) in the dry powder coating of pellets for extended drug release applications.

Methods:  Pre-plasticized ethylcellulose powder was prepared by spray-drying Surelease, a commercially available aqueous ethylcellulose dispersion containing medium chain triglycerides (MCT) as plasticizer. The powder (particle size: 3.1±0.6 µm) was used for dry powder coating in a fluidised bed coater. The coated pellets (model drug: chlorpheniramine maleate) were cured and the  drug release (USP paddle apparatus, 37°C, 100rpm, pH 6.8 phosphate buffer) was compared to the release of pellets, which were coated with ethylcellulose powder under the simultaneous spraying of the plasticizer. The plasticizer efficiency was determined with the mechanical properties of ethylcellulose films (texture analyzer).

Results:  The effectiveness of MCT as a plasticizer is comparable to the one of dibutylsebacate and acetylated monoglycerides. A higher plasticizing efficiency was found for plasticizers from the citrate family with acetyltributylcitrate≤ acetyltriethylcitrate≤ triethylcitrate≤ tributylcitrate. Uncured pellets coated with spray-dried Surelease powder had an extended drug release with approximately 85% drug released within 8h. With curing, the limiting release profile was achieved at 60°C/24h or 80°C/30min (with approx. 69% drug release after 8h). Although medium chain triglycerides do not belong to the best plasticizers for ethylcellulose, the drug release was comparable to coatings from pure ethylcellulose with simultaneous plasticizer additions with optimized plasticizer type. At 80°C/2h, all formulations gave the limiting release profile.

Conclusion: Spray-dried Surelease as a pre-plasticized ethylcellulose powder required only mild curing conditions to achieve extended drug release from dry polymer powder coated pellets. The drug release was comparable to the release from pellets coated with pure micronized ethylcellulose powder with simultaneous spraying of the plasticizer.
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Application of Texture Analyzer for Evaluating the Performance of Enteric Coated Tablets (T2201)
A. Higuera, J. Zhu, A. Grill, N. Basu
Preformulation PR&D, Forest Research Institute

Purpose:  To determine tablet size and coating thickness and relate them to enteric coating and drug release characterization of Compound A at Q (NLT 85% released) in dissolution testing as a control of product performance.

Methods:  Both core and tablets enteric coated at various levels (2, 4, 6 & 10% w/w gain) with Eudragit L-50 with core tablets were analyzed for diameter using a TA.XT texture analyzer at a surface detection force of 0.6 gm with a No. 8 stainless steel cylindrical probe. Dissolution testing was conducted using USP apparatus 2 in USP pH=1.2 buffer followed by a medium replacement of USP pH=6.8 buffer. The enteric coating performance was determined by the amount of drug leached in pH=1.2 medium at t=2 hr while drug release characterization was determined by the amount of drug released in pH=6.8 at t=4 hr.

Results:   The tablet sizes of various enteric coated tablets increased as the coating levels increased, except at the low coating level where no differences in diameter were observed between core and coated tablets. In addition, tablets coated at various levels did not meet enteric coating performance requirement by displaying dose dumping at pH=1.2 where tablets coated at much higher levels did not. On the other hand, tablets coated at higher levels demonstrated an incomplete drug release LT85%, which did not reach the desired Q.

Conclusion:  Texture analyzer has been successfully used to measure the coating thickness of the enteric coated tablets, which then will indirectly help predicting the drug release characteristics and the product performance.
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Effect of Gelatin Bloom Strength and Xylitol Addition on Texture Parameters of Chewable Softgel Films (T3153)
H. Nasri, L. Fonkwe, X. Guo, Research & development, Banner Pharmacaps Inc.

Purpose:  The objective of this study is to investigate the influence of gelatin bloom strengths and xylitol addition on moisture retention and texture parameters such as chewiness, hardness, and adhesivenss of the chewable softgel films.

Methods:  Softgel films were made by casting appropriate amounts of the chewable gel masses containing different gelatin grades (60-80, 100 and 150 bloom strengths) or with xylitol at levels between 0% to 10% (w/w) on a Teflon overlay. The Films were dried overnight at room temperature. The thickness of the films was determined by a multiple point measurements using a caliper. The dried films were stored in HDPE Bottles at 40 ^oC and 75% R.H. for 3 months. Samples were taken at pre-determined time points. The moisture content of the films was determined by a moisture analyzer (Computrac Max 1000, Arizona Instrument). The texture analysis was performed to evaluate chewiness, hardness, and adhesiveness of the chewable films using a texture analyzer (TA.XTPlus, Texture Technologies Corp.).

Results:  The thickness of the chewable softgel films was about 0.10 inch. Films with lower bloom strength grade of gelatin appeared more chewable. Moisture analysis showed that xylitol addition increased moisture retention of the films by up to 3% over the control sample (0% xylitol). Texture Analysis showed that increasing the xylitol level from 0.5% to 10% (w/w) resulted in slight improvement of chewiness but increased hardness. Initial stability indicated the possible crystallization of xylitol from the films during storage.

Conclusion: The results of this study revealed that the selection of appropriate bloom strength of gelatin could be essential for the chewability and the possibility of using Xylitol as a mean to enhance moisture retention and chewiness when formulating chewable softgel capsules.
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Effect of Solubility on Polymer Swelling and Drug Release from Modified Release Polyethylene Oxide (PEO) Matrix Tablets (T3158)
H. Li, X. Gu; Faculty of Pharmacy, University of Manitoba
Purpose: To investigate the effect of drug solubility on polymer swelling behaviours and drug dissolution profiles from modified release PEO matrix tablets using a texture analyzer.

Methods: A series of modified release PEO matrix tablets wereprepared by using Polyox® WSR301 at varying ratios (10−50%) and direct tableting compression. Pseudoephedrine (PED, solubility 565.3±0.3 mg/ml) or acetaminophen (AMP, solubility 18.9±0.3 mg/ml) was incorporated into the tablets as the model compounds. In vitro dissolution of the tablets was conducted using the USP Apparatus 2. The thickness of gel formation during drug dissolution was recorded using a texture analyzer. Relationship among gel layer thickness, PEO ratio, drug solubility and dissolution was correlated and interpreted.

Results: Drug dissolution and gel formation were directly proportional to drug solubility and PEO ratio in the matrix tablets. PED released much faster from the formulations than AMP due to its higher aqueous solubility; the time required for 50% of drug release (DT50%) ranged 0.9−1.7 hours for the PED tablets and 6.5−9.0 hours for the AMP tablets respectively. Diffusion exponent values differentiated significantly between the two preparations, 0.46−0.58 for PED and 0.70−0.86 for AMP, indicating a diffusion-controlled release mechanism from the PED tablets but an erosion-controlled release mechanism from the AMP tablets. Gel layer thickness of the PED tablets was much larger than that of the AMP tablets; there was a linear correlation between gel layer thickness and PEO proportion used in the tablets.

Conclusions: Drug solubility and matrix polymer ratio directly affected water penetration into the tablet matrix and polymer gelling formation, subsequently resulting in modified release profiles of PED and AMP. The study demonstrated a unique application of texture analyzer in characterization of tablet formulation and drug dissolution.
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Dynamic Swelling of Superporous Hydrogels under Compression (T3159)
W. Han, H. Omidian, J. Rocca, Lead Optimization, Kos Pharmaceuticals, Inc

Purpose:  The dynamic swelling of superporous hydrogel (SPH) platforms were investigated in simulated gastric fluid (SGF) under different compression forces and temperatures.

Method:  Elastic SPH platforms were synthesized, purified and dried. TA.XT.Plus Texture Analyzer was utilized in this study. A given SPH sample was placed in a weighing dish and subjected to a constant compression force. Then SGF was brought into contact with the SPH. The timer was set to start once the SPH began to swell under compression. Texture Analyzer recorded the relationship of SPH expansion and elapsed time. The study was conducted in a temperature-controlled chamber. With this study, the dimensional swelling ratio was defined as the ratio of the height of the swollen gel to the height of the dried gel.

Results:  The SPH platforms could rapidly swell under compression in SGF and reached their equilibrium swelling capacities within two minutes. Regardless of the swelling medium temperature, the dimensional swelling ratios of 1.6 and 1.4 were obtained when SPH was compressed under 5 grams and 50 grams, respectively. The SPH swelled slower under 50 grams of compression due to its initial dense microstructure. The dynamic swelling properties including equilibrium swelling capacity and swelling rate was similar for the SPHs evaluated at various medium temperatures of 5, 25, and 37 ^oC.

Conclusions:  The dynamic swelling of elastic SPH platform was found compression-dependent and not sensitive to temperature of the swelling medium. This property can potentially be exploited in designing gastroretentive superporous hydrogels and swellable drug delivery systems.
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Physical Characterization of Soft Gelatin Capsules: II. Capsule drying end point, and  mechanical parameters (T3161)
E. Hassan1, S. Gumudavilli2, K. Magee2, D. Goldman2
1Formulation Development and Scientific Affairs, 2Formulation Develeopment and Scientific Affairs, Pharmaceutics International Inc.

Purpose:  To characterize the drying end point of soft gelatin capsules (SGCs), relative to mechanical parameters such as capsule bursting strength, hardness, and elasticity

Methods:  SGCs were manufactured from a 150 bloom bovine gelatin, filled with a polyethylene-glycol-based fill. Capsules were dried under 20% relative humidity at 24°C for 9.5 days. During the drying process, capsule samples were withdrawn periodically and tested for shell and fill moisture content using Computrac moisture analyzer, and Karl Fisher titrator, respectively. Capsule hardness, elasticity, and bursting strength were concurrently measured using a TA.XTPlus Texture Analyzer (Texture Technologies, USA). Correlation between water loss and the mechanical parameters were also investigated.

Results:  While shell moisture content equilibrated to 6% ± 1% after 3days of drying, fill moisture content approached 7% ±1% only at the end of drying. On the other hand, capsule bursting strength reached 50kg (maximum equipment capacity) after 3 days of drying. In addition, capsules showed improved elasticity factor from 0.5 after 3 days of drying to 0.6 at the end of drying time. Among tested parameters, only capsule hardness correlated well with the fill water content and the drying time.

Conclusion:  During capsule drying, loss of water, and gaining of mechanical strength occur simultaneously. After initial drying, moisture at the capsule shell becomes constant, as water from the fill replaces the water evaporated from the shell. Capsule hardness testing can be used as an overall indicator for both capsule drying and the mechanical quality of soft gelatin capsules.
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Physical Characterization of Soft Gelatin Capsules: I. Non-destructive measurement of capsule hardness and elasticity. (T3162)
E. Hassan1, I. Singh2, E. Coutinho2, D. Goldman2
1Formulation Development and Scientific Affairs, 2Formulation Develeopment and Scientific Affairs, Pharmaceutics International Inc.

Purpose:  To develop a quantitative method for determining both hardness and elasticity of soft gelatin capsules.

Methods:  We defined soft gelatin capsule (SGC) hardness (Hx%) as the force required to reduce the capsule diameter by a specified percentage(x%). On the other hand, capsule elasticity was defined as the ratio between the force applied onto the capsule surface during a compression phase, and the resistance exerted by the capsule when that force is released. Thus the elasticity factor was measured as the ratio between the area under the force-displacement curve while applying the force (AUCa) and that exerted while removing the force (AUCr). Hardness and elasticity of Vegetable oil (oil)-filled or polyethylene glycol (PEG)-filled capsules were evaluated using a TA.XTPlus Texture Analyzer (Texture Technologies, Scarsdale, NY), fitted with a TA-4 1.5In.-diameter flat probe traveling 10%, 25% and 50% of capsule diameters.

Results:  Capsules’ hardness ranged from 2.8kg to 30.2kg, with hardness values increasing as the traveling distance increased from 10 to 50%. On the other hand, capsules’ elasticity was reduced from 0.79 for oil-filled capsules tested at a distance equals to10% of capsule diameter, to 0.11 for a polyethylene-glycol-filled capsules tested at distance equivalent to 50% of the capsule diameter. Using same gel mass, oil-filled capsules were consistently softer( less hard) and more elastic than PEG-filled capsules.

Conclusion:  The proposed test methodology provided a quantitative approach to measure a formerly subjective attribute of soft gelatin capsules. This test can be used as an important tool for development of soft gel capsule products.
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Hot-Melt Extruded Blends of Poly(DL-lactide-co-glycolide) 50:50 and Hydrophilic Polymers: Degradation and Mucoadhesion Characterization (T3172)
M. Kaur, D. Flanagan; Pharmaceutics, University of Iowa

Purpose:  To study the effects of hydrophilic polymers such as polyethylene oxide (PEO, MW-1x105), hydroxypropyl cellulose (HPC, MW-1x106 and HPC-LMW, MW-8x104) and hydroxyethyl cellulose (HEC, MW-1x106) on poly(DL-lactideco- glycolide) (PLGA, 50:50, MW-36x103) hydrolysis kinetics in hot-melt extruded polyblends and to characterize their mucoadhesive properties.

Methods:  Binary blends of PLGA with hydrophilic polymers of varying weight fractions (0-100% PLGA) were prepared by hot-melt extrusion. PLGA degradation in polyblend pellets was determined gravimetrically in phosphate buffered saline (PBS, pH 7.4, I= 0.15 or 0.5 at 370C), by measuring medium pH and by gel permeation chromatography (GPC). Polyblends were evaluated for their water absorption properties gravimetrically, as well. Morphologies of fractured polyblend pellet surfaces were observed using scanning electron microscopy (SEM). Mucoadhesion for polyblend films was determined using a TA.XTPLUS texture analyzer in 6% (w/v) mucus solutions.

Results:  Preliminary data suggested PLGA degradation retardation by HPC and PEO in low ionic strength buffer (0. 15). At 0.5 ionic strength, weight loss profiles of PLGA-HPC showed at most 5% loss of HPC even at 50% HPC up to about 10 days; HPC-LMW showed more than 10% loss at HPC compositions >20% whereas PEO and HEC completely leached out at greater than 10% composition. Increased water-uptake coincides with PLGA erosion. GPC analysis showed that high PEO and HPC-LMW compositions decreased PLGA degradation rate by five-fold whereas HPC and HEC decreased the rate by two-fold. SEM micrographs of PLGA-hydrophilic polymers show porosity at > 20% hydrophilic polymer after leaching. Work of mucoadhesion follows the order HPC > PEO ≡ HPC-LMW >HEC at 50% hydrophilic polymer.

Conclusions:  Degradation study results show that all hydrophilic polymers retard PLGA degradation in high ionic strength buffer. Hydroxypropyl cellulose imparts more mucoadhesiveness to PLGA compared to other hydrophilic polymers.
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Investigations into the use of hydrogels as mechanical skin simulants for jet injectors (W4207)
S. Corr1, G. Eccleston1, J. Hempenstall2, N. Hudson3
11Department of Pharmaceutical Sciences, 3Department of Pure and Applied Chemistry, University of Strathclyde, 2Product Development-1 Harlow, Pharmaceutical Development, GlaxoSmithKline

Purpose. To develop mechanistic understanding of jet injection (needle free) into skin by (i) investigating selected hydrogels as mechanical skin simulants and (ii) assessing the suitability of Young’s modulus (in unconfined compression) as a strength measure to correlate hydrogel properties with jet injection parameters in relation to skin in vivo.

Method. Cross-linked polyacrylamide gels (5-30 %w/w) were prepared by in-situ co-polymerisation and gelatin gels (16-52 %w/w) by dissolution of gelatin in water (65°C) and cooling (4°C) to set. Hydrogels prepared as cuboids at a range of dimensions (cross-sectional area, A0, and length, l0). Gel strength parameters in unconfined and confined compression (e.g. apparent Young’s modulus (E) and work of fracture (W)), were determined at room temperature (18°C) for a range of gel dimensions, probe diameter, and probe velocity, v. For visualization experiments, samples of gel samples were injected with dye (0.2 mL of 1.5 mM solution of sulforhodamine B dye) using a commercial jet injector, and penetration characteristics were correlated with gel strength parameters.

Results. Typical data for gelatin: probe diameter, 2 mm; l0, 30 mm; A0, 500 mm2; v, 10-4 ms-1; concentration, 52.3 %w/w:, E, 9.22 ± 0.99 MPa; W, 18.71 ± 5.29 mJ; normalised penetration depth, 0.41 ± 0.09. An increase in E and W and decrease in normalised penetration depth with increasing gel concentration was shown for both gels. The relationship between sample geometry, probe diameter, E and other strength measures (e.g. W) was different for each hydrogel. Both gel types displayed similar visual injection characteristics. Changing probe speed indicated that E did not display rate dependency within the range studied.

Conclusions. Both gels are equivalent as visualization aides. Young’s modulus, as determined by unconfined compression may be a suitable qualitative parameter for jet penetration studies, but may not be quantitatively applied to skin in vivo.
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Effects of Polyethylene Glycol on Characteristics of Gelatin Gel Masses and Films (W4212)
Q. Fang, L. Fonkwe and X. Guo; Research & Development, Banner Pharmacaps Inc., 4125 Premier Drive, High Point, NC 27265

Purpose:  The objectives of this study were to investigate the combined effects of polyethylene glycol (PEG) and Sorbitol Special (SS) on characteristics of gel masses (viscosity, gelling and melting temperatures), and films (glass transition and melting temperatures, mechanical strength and elasticity).

Experimental Methods:  A full factorial experimental design was employed for the study, including four levels of PEG 400 (0, 5, 10, and 15%) and three levels of Sorbitol Special (10, 15 and 20%). Gel masses were prepared and held @ 60 C for 24 hrs. Viscosity, gelling and melting points were determined using an AR 1000 Rheometer with a range of shear rate of 0 to 50/s (TA Instruments, Newcastle, DE). Films were cast and dried overnight. Resiliency tests were conducted on films to evaluate the mechanical strength and elasticity using a Texture Analyzer. Glass transition and melting temperatures of films were determined using a Differential Scanning Colorimeter (DSC) with a heating rate of 5 oC/min. All acquired raw data were analyzed using JMP statistical software (SAS Institute, Inc.).

Results and Discussion:  Viscosity of gel masses decreased by adding more PEG and Sorbitol Special due to the fact that both of them are plasticizers to gelatin. The gelling points increased as more Sorbitol Special was added. Gel melting points were less affected by the amount of PEG and SS added. The glass transition temperature of dried films increased as more SS added; PEG addition didn’t affect Tg significantly (p<0.09). The film melting temperatures decreased as more PEG and SS added (p<0.009). Films containing more PEG and SS were weaker, but more elastic (p< 0.002).

Conclusions:  PEG lowered the melting temperature of gelatin films. This may be the cause for failures of physical stability of PEG-filled softgel capsules under accelerated conditions. Many pharmaceutical softgel capsules are filled with polyethylene glycol (PEG) based liquids. Polyethylene glycol interacts with the gelatin-based shell, causing a variety of physical stability problems, including sticking, softening, and leaking. This study will help understand the interactions, and find ways to avoid the negative effects and take advantage of the positive effects of PEG.
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Effect of Drugs on Properties of Gel mass and Films  (W4215)
K. Madrigal, L. Fonkwe, Q. Fang, X. Guo; Research & development, Banner Pharmacaps Inc.

Purpose:  To investigate the effects of the drug and its loading on the rheological properties of soft gelatin gel masses containing different type of gelatins and the mechanical properties of the films.

Method:  Naproxen sodium and Dextromethorphan HBr were selected as the acidic and basic model drug, respectively. Acid processed (175 Bloom pig skin) or lime-processed (150 Bloom lime bone) gelatin was used. The drug powder was dispersed in a gel mass containing gelatin, glycerin and water. Each drug was evaluated in gel masses containing either gelatin. Drug loading was from 0 to 4% for the basic drug and 0 to 5.0% for the acidic drug. The gel masses were dried to form drug containing films at room temperature. Gel mass rheological properties (viscosity, gelling temperature, melting temperature, storage modulus and gel elasticity) were determined using an AR1000 rheometer. The mechanical properties were measured using a Texture Analyzer.

Results:  The acidic drug did not change the viscosity of pig skin gelatin gel mass but increased the viscosity of the lime processed gelatin gel mass at 5% drug loading. The acidic drug lowered gelling and melting temperatures, gel strength (storage modulus) and gel elasticity in both acid-processed and lime-processed gelatin gel masses. The basic drug seemed to reduce the viscosity of lime-processed gelatin gel mass. In the acid-processed gelatin mass, there was little change in viscosity with drug loading. The basic drug lowered gelling and melting temperatures as well as gel strength (storage modulus). Transparent films were formed for the basic drugs in both gelatins while the acidic drug formed opaque films. The type of drugs and its solubility in the film could modify mechanical properties of the films.

Conclusions:  Drug loading of both acidic and basic drugs caused minimal decrease in viscosity of acid-processed masses compared to lime-processed gelatin. For the acidic drug, some changes in rheological properties were observed. Drug loading affected the mechanical properties of films.
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Characterization of Gelatins from Various Natural Sources (W4218)
L. Fonkwe, K. Sukur, Q. Fang, X. Guo
Research & development, Banner Pharmacaps Inc.

Purpose:  To evaluate and characterize gelatins from various natural sources for applications in soft gelatin capsules.

Method. Limed bovine bone gelatin, limed bovine skin gelatin, limed porcine bone gelatin, acid porcine skin gelatin, fish gelatin and poultry gelatin were selected. Gelatin solutions were prepared in water at concentrations of 15, 30, 45 & 60% (w/w). Each solution was poured into a sample cup and aged for 24 hours at ambient temperature prior to measurements. The gel strength of each gel formed was measured using a TA-XT2 texture analyzer (Texture Technologies Corp.). Rheological properties (viscosity at 60C, gelling temperature, melting temperature storage modulus and elasticity) of each sample were analyzed using an AR1000 rheometer (TA Instrument).

Results:  The viscosities of the different gelatin solutions were similar at the same concentration. Poultry gelatin appeared to have the lowest viscosity at concentrations above 30% while fish and bone gelatin appeared to have slightly higher viscosities. Bovine, porcine and poultry gelatin had similar gelling and melting temperatures which were higher than the gelling and melting temperatures of fish gelatin. The differences of storage moduli (measure of gel strength at 10C) and elasticity of the gels were not significant at the same concentration. An exponential relationship was established between the gelatin concentration and parameters.

Conclusions:  Based on the parameters analyzed, the gelatin from the various sources analyzed could be utilized for soft gelatin capsule manufacturing. The most significant difference observed among the parameters was the lower gelling and melting temperatures of fish gelatin. It may require certain adjustments during soft gelatin capsule manufacturing and may affect some capsule properties.
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Further Investigations of Deliquescence Lowering in Binary Mixtures: Implications of Lowering RH0 in Binary Mixtures (W4242)
A. Salameh, L. Taylor; Industrial and Physical Pharmacy, Purdue University

Purpose. To study the chemical reactivity and mechanical properties of a mixture which exhibits the phenomenon of lowering of the deliquescence point. A further goal was to investigate the eutonic composition of a model API-excipient system.

Methods. Preliminary studies of chemical reactivity utilized sucrose-citric acid system. Water activity (aw) versus time profiles and RH0mix of sucrose-citric acid system were determined. Physical mixtures (50:50 %w/w) of citric acid:sucrose were stored above and below RH0mix to induce concretion. Mechanical testing using a TA analyzer was used to assess the degree of caking. The eutonic composition was prepared by crystallizing a solution saturated with respect to both the model API, diphenhydramine HCl, and sucrose. Raman microscopy was used to map the crystallized phase.

Results. Saturated solutions of sucrose and citric acid had decreasing aw profiles with time indicating that sucrose was being hydrolyzed in the presence of citric acid leading to decreased aw readings. In addition, the same mixture showed a large discrepancy between the RH0 and aw values. Citric acid-sucrose physical mixtures stored below the RH0mix remained free flowing, while mixtures cycled above and below RH0mix formed agglomerates that showed a yield point when crushed using the TA analyzer. Diphenhydramine HCl and sucrose saturated solution crystallized into circular formations. Raman microscopy mapping showed DPH and sucrose crystallized together as an intimate phase.

Conclusion. Preliminary studies indicate that chemical reactivity will be increased in sucrose-citric acid mixtures that are exposed to RH’s higher than RH0mix and significant caking/concretion will be induced by RH fluctuations that exceed RH0mix. From a saturated solution, deliquescent API and excipient tend to crystallize into intimate structures (possibly the eutonic).
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Synchronization of swelling, erosion, and release in a novel and robust formulation of glipizide (W5066)
S. Jamzad, R. Fassihi; School of Pharmacy, Temple University

Purpose:  To develop a robust direct compression monolithic controlled release (CR) matrix formulation for glipizide equivalent to push-pull osmotic pump system Glucotrol XL.

Methods:  Several monolithic matrix formulations were developed for glipizide by blending the drug substance (10mg/tablet) with various types and levels of release modifying ingredients (HPMC and lactose), magnesium stearate, and colloidal silicone dioxide followed by direct compression. Drug release, hydration, and erosion were evaluated in pH 6.8 phosphate buffer at 75rpm using USP 27 dissolution apparatus II modified by insertion of mesh. Textural analysis was performed using TA-XT2i Texture Analyzer and the force-displacement-time profiles at different time points were determined. Similarity factor (f2) and difference factor (f1) were calculated.

Results:  Developed formulations demonstrated linear release profile similar to Glucotrol XL push pull osmotic pump. In these formulations changing the amount and grade of the polymers and lactose within a range of ±20% w/w did not affect the release profiles significantly. The results of hydration and erosion study revealed the linear interdependence of swelling, diffusion, and erosion on drug release kinetics.

Conclusions:  A robust matrix CR formulation for glipizide was developed with linear release profile similar to Glucotrol XL. It was shown that release profile could be maintained within an acceptable range by controlling the degree of swelling/hydration of the matrix. Regardless of the composition of the formulation, linearity of release was fully dependent on synchronization of three parameters namely swelling, erosion and textural properties of the matrix. Changes in the formulation within ±20% w/w of release modifying agents did not change either the drug release kinetics or the synchronization characteristics. The robustness observed can lead to ease of scale-up, successful in-vivo performance, and improved compliance with SUPAC guidelines.
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The development and characterisation of a novel thermosetting, bioadhesive polymer as a platform for drug delivery (W5095)
T. Laverty, D. Jones, G. Andrews; School of Pharmacy, Queen’s University of Belfast

Purpose:  To develop and manufacture a novel thermo responsive bioadhesive gel as a novel drug delivery model.

Methods:  Pluronic (Poloxamer) 407 gels (15, 20, 25 and 30% w/w) were formed via the slow addition of polymer to deionised water at 8°C which were then left to refrigerate at 4°C for 24 hours to ensure complete dissolution and aid the removal of trapped air. Pluronic 20 and 25% w/w were chosen as candidates for further analysis through the introduction of 5 and 10% w/w Gantrez. Rheological analysis was carried out at 32°C and at 4°C using a TA systems AR2000 rheometer with a 4 or 6cm diameter parallel plate geometry or concentric cylinder and a 1mm plate gap, as previously reported (Jones et al. 2001). The mucoadhesive strength was determined by measuring the force required to detach the formulations from a mucin disc using a texture analyser as previously described (Jones et al. 1999). Throughout the study five replicates of each measurement was carried out.

Results:  All formulations were found to exhibit pseudoplastic flow with minimal thixotropy. Interestingly the introduction of gantrez to the 20% pluronic system caused a decrease in viscosity at 32°C the opposite effect was seen when rheological analysis was carried out at 4°C.

Conclusions:  Gantrez interacts with the pluronic structure in some way causing a complementary decrease in viscosity. The interaction between these polymers will require further study before any novel drug delivery system with these polymer mixes are developed.

References:
Jones, D.S., Irwin, C. R., Woolfson, A.D., et al. (1999) J. Pharm. Sci. 88: 592-598.
Jones, D.S., Brown, A.F., Woolfson, A.D. (2001). J. Pharm. Sci. 90(12): 1978-1990.
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In-vitro evaluation of mucoadhesive tablet formulations as potential tools to increase colonic residence time (W5116)
M. McGirr1, M. McAllister2, A. Basit1; 1Department of Pharmaceutics, The School of Pharmacy, 2Strategic Technologies, Pharmaceutical Development, GlaxoSmithKline

Purpose:  To measure the mucoadhesive properties of three tablet formulations containing various grades of Carbopol ®(CP) as a potential tool to increase colonic residence.

Method. TX-20 Texture Analyser was used to measure the Peak Detachment Force (PDF) for the test formulations. CPgrades 974PNF, 971NF and 980NF were evaluated as: i) Mucoadhesive Film coats (0.5-1% weight gain), ii) Direct compression matrix cores (5 and 10% w/w) iii) Wet granulated matrix cores (5 and 10% w/w).Tablet cores were 8mm diameter, 250mg weight. Test tablets were attached to a 20mm diameter Aluminium probe using adhesive and placed in the hydration media, pH 6.8 phosphate buffer, for 1, 2 and 4 minutes. The probe was lowered to create contact between the test material and a glass surface and was held for 1 minute with 2N force before retracting at a speed of 10.0mm/s.

Results:  It was demonstrated that the grade of CP effects mucoadhesive abilities in the order of CP 974PNF > 980NF > 971NF. Type ii formulations exhibit the greatest PDF (1.280N, 5% CP 974PNF, 4 minute hydration) which increase with hydration time. In contrast, type i formulations show significantly lower adhesion (0.118N CP 974PNF 4 minute hydration), this is reduced with hydration time. Comparison of type ii and iii formulations shows the granulation process affects the mucoadhesion of these systems, type iii formulations exhibit reduced adhesion by up to 0.2N after 4 minutes hydration. It was also observed that mucoadhesion increases with increased CP levels.

Conclusions:  We have shown that in all cases mucoadhesive tablet formulations can be made and tested in-vitro, all three systems exhibit mucoadhesive properties with type ii and iii formulations possessing the greatest potential as tools to increase colonic residence time.
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Application of Texture Analysis in Study of Hydrophilic Solvents Compatibility with Hard Gelatin Capsules (W5142)
X. Mei, F. Etzler, Z. Wang; Pharmaceutics, Boehringer Ingelheim Pharmaceuticals, Inc.

Purpose:  To develop and apply a new technology – Texture Analysis for evaluation of hard gelatin capsule compatibility with hydrophilic solvents.

Methods:  Isotherms of empty capsules were generated by incubating the capsules with saturated salt solutions at 25C for at least 20 days. Moisture content was determined by TGA (105C for 16 hours). Individual hydrophilic solvents (ethanol, propylene glycol, PEG 400) or their mixtures in Cremophor EL were manually filled into capsules and stored in a sealed aluminum pouch at 25 C/60% RH or 40C/75% RH for one week or 12 days. The capsules were then emptied and analyzed by Texture Analysis. The tests were conducted using a "Return to Start" test option with a "Force in Tension" mode. Different parameters (i.e. elastic modulus, tensile strength and elongation at break) were calculated with software Texture Exponent 32.

Results:  Capsules with different mechanical properties were quantitatively characterized by Texture Analysis. Both elastic modulus and tensile strength dropped when capsules became softer and weaker with increasing water content. Meanwhile the elongation at break increased dramatically for capsules containing more than 18% water. In contrast, decreasing of moisture content made capsules harder and tougher demonstrated by an increase of elastic modulus as well as tensile strength. When water content dropped below 8%, the capsules became so brittle that the tensile strength and elongation at break started decreasing. It was also demonstrated that ethanol or propylene glycol alone would soften and weaken the capsules. In contrast, capsules filled with pure PEG 400 became hard and tough. Furthermore, strong interactions between propylene glycol and ethanol or PEG 400 were identified.

Conclusions:  A new technology – Texture Analysis which was sensitive, convenient and rapid was developed. The technique was used to evaluate hydrophilic solvents compatibility with hard gelatin capsules.
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Effect of Gelatin Bloom Strength and Xylitol Addition on Texture Parameters of Chewable Softgel Films (W5152)
H. Nasri, L. Fonkwe and X. Guo, Research & Development, Banner Pharmacaps Inc., 4125 Premier Dr., High Point, NC 27265.

Purpose:  The objective of this study is to investigate the influence of gelatin bloom strengths and xylitol addition on moisture retention and texture parameters such as chewiness, hardness, and adhesivenss of the chewable softgel films.

Methods:  Softgel films were made by casting appropriate amounts of the chewable gel masses containing different gelatin grades (60-80, 100 and 150 bloom strengths) or with xylitol at levels between 0% to 10% (w/w) on a Teflon overlay. The Films were dried overnight at room temperature. The thickness of the films was determined by a multiple point measurements using a caliper. The dried films were stored in HDPE Bottles at 40 C and 75% R.H. for 3 months. Samples were taken at pre-determined time points. The moisture content of the films was determined by a moisture analyzer (Computrac Max 1000, Arizona Instrument). The texture analysis was performed to evaluate chewiness, hardness, and adhesiveness of the chewable films using a texture analyzer (TA.XT.Plus, Texture Technologies Corp.).

Results:  The thickness of the chewable softgel films was about 0.10 inch. Films with lower bloom strength grade of gelatin appeared more chewable. Moisture analysis showed that xylitol addition increased moisture retention of the films by up to 3% over the control sample (0% xylitol). Texture Analysis showed that increasing the xylitol level from 0.5% to 10% (w/w) resulted in slight improvement of chewiness but increased hardness. Initial stability indicated the possible crystallization of xylitol from the films during storage.

Conclusion:  The results of this study revealed that the selection of appropriate bloom strength of gelatin could be essential for the chewability and the possibility of using Xylitol as a mean to enhance moisture retention and chewiness when formulating chewable softgel capsules.
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Formulation of a delta-9-tetrahydrocannabinol pro-drug utilizing poly(ethylene oxide) matrices (W5174)
S. Thumma1, M. Repka2; 1Department of Pharmaceutics, 2Department of Pharmaceutics, The National Center for Natural Products Research, School of Pharmacy, The University of Mississippi

Purpose:  To study the effect of molecular weight of poly(ethylene oxide) (PEO) on the bioadhesive properties, release characteristics, and stability of hot-melt casted films containing a pro-drug of delta-9-Tetrahydrocannabinol (THC), THChemiglutarate( HC-HG).

Methods:   A hot-melt casting method was used to prepare PolyOx®PEO polymeric matrices incorporated with 5% THC-HG. Bioadhesive measurements were performed on both placebo polymeric films and those containing the drug (THC-HG) utilizing the TA.XT2i Texture analyzer equipped with a TA-57R probe. The data was analyzed using Texture ExpertTM software. Release studies were performed according to USP 28 apparatus-5, paddle-over-disk method. Film samples were analyzed by HPLC. Stability studies were performed on the films at four different temperature conditions (-18, 4, 25 and 40°C) to determine the % THC-HG remaining for up to 6 months.

Results:  Peak adhesive force and work of adhesion of each of the polymeric matrices was found to increase with an increase in molecular weight of PolyOx®PEO. The presence of THC-HG at a concentration of 5% did not significantly effect the peak adhesive force or work of adhesion of the matrices. Sustained-release of the drug was observed from films containing higher molecular weight PEO (80% drug released from PolyOx®PEO N-750 and PolyOx®PEO WSR1105 in 9hrs and 12 hrs, respectively) while a faster release was observed from the lower molecular weight PEO (100% drug release from PolyOx®PEO N-10 and PolyOx®PEO N-80 in 2 and 3 hrs, respectively). No significant degradation of THC-HG was observed in all of the polymer matrices after one week.

Conclusion:  The results of the present study suggest that lower molecular weight PEO can be optimized, both in terms of bioadhesion and release characteristics, for the mucosal delivery of THC-HG. The studies are relevant to development of a stable bioadhesive transmucosal matrix system for the therapeutic delivery of delta-9-THC.
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Development of Silicone Adhesive Patch containing Clindamycin Phosphate for the Treatment of Acne (R6082)
V. Raul, G. Schalau II, L. Nartker, G. Loubert, J. Cabala, K. Ulman; Life Sciences Healthcare, Dow Corning Corp.

Purpose:  The purpose of this study was to develop a topical patch containing 2, 5 and 10 % w/w of clindamycin phosphate (CP) that would initial display a burst effect followed by steady state drug release. Upon loading with CP, it was important to maintain control of the physicochemical properties, adhesion and cohesion in order to ensure therapeutic effectiveness and wear. It was also critical to confirm the antimicrobial activity of CP in the silicone adhesive matrix.

Methods:  In vitro drug release testing was performed using Franz static diffusion cells. Analysis was completed using a HPLC equipped with a photo-diode array detector at 210 nm. Calibration curve solutions yielded r-values >0.99. Rheological properties, complex viscosity (Eta*), elastic modulus (G’) and the viscous modulus (G”) were each evaluated using a dynamic oscillating rheometer. Adhesion and tack were evaluated using the TA-XTPlus Texture Analyzer (Texture Technologies). Drug particles and drug particle distribution were evaluated using optical microscopy and scanning electron microscopy. Antimicrobial activity was evaluated using zone of inhibition testing using the causative organism of acne, propionibacterium acnes (P. acnes).

Results:  CP drug release was shown to be dependent on the drug-loaded concentration. Acceptable drug release kinetics and content uniformity were demonstrated at all three drug loadings (CP). Drug release profiles confirmed an initial burst effect followed by a steady state release over time. Rheology and texture analyzer results showed evidence that the physicochemical properties of the drug loaded silicone adhesive matrix did not significantly change versus the control adhesive. Microscopy results indicated that drug morphology and size did not change with time. Microbiological testing confirmed the antimicrobial activity of a CP patch using P. acnes.

Conclusion:  Based on physical characterization and drug kinetics results performed during this study, silicone adhesive matrices loaded with 2, 5 and 10 % w/w CP were shown to potentially be effective for the treatment of acne.
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Development and Evaluation of Topical Drug Delivery Patches Formulated with a Silicone Elastomer Gel (R6085)
G. Schalau II, J. Cabala, G. Loubert, V. Raul, X. Thomas; Healthcare Science & Technology, Dow Corning Corporation

Purpose:  To determine the suitability of a novel silicone adhesive as the carrier matrix for a variety of pharmaceutical ingredients in topically-applied drug delivery patches. This new (patent pending) type of adhesive combines the pressure sensitive characteristics and long wearing time associated with viscoelastic silicone adhesives and the elastomeric properties and hurtfree removal of silicone tacky gels.

Methods:  The non-optimized formulations were prepared by blending the pharmaceutical active ingredients with the SSA. The formulations were cast and cured onto a polyester substrate. The physical properties of tack and adhesion were evaluated using a texture analyzer. The release kinetics of the formulations were evaluated using Franz static diffusion cells with complete replacement of receptor solution at specified intervals. Estimation of the amount of active in the receptor solution was performed via UV spectrophotometer or an HPLC equipped with a photodiode array detector.

Results:  Cohesive patches without significantly diminished tack or adhesion were prepared with clobetasol propionate, niacinamide, clindamycin phosphate and hydrocortisone. In vitro drug release studies revealed release rates that varied with the amount of active loaded into the patch. Controlled release profiles were attained with all actives at each loading concentration. The orders of the drug release profiles varied, depending on the active that was loaded into the matrix.

Conclusion:  The silicone gel provides acceptable release kinetics for several drugs as evidenced by the in vitro drug release studies. Homogeneity of drug dispersion within the matrix can be achieved. The distinctive features of this new adhesive type combine to create a drug delivery vehicle that is compressible and tacky with higher adhesion levels than traditional silicone tacky gels.
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Delivery of poly-ionic pharmacons to the colon using poly-electrolyte complexes. (R6130)
H. Shah, J. Johnson, C. Wilson
Pharmaceutical Sciences, University of Strathclyde

Purpose:  To study the release of a polyionic species (pentosan-polysulphate sodium) from a swelled poly-electrolyte complex (PEC) under simulated colonic conditions.

Methods:  A swollen PEC, composed of chitosan (NH3 +) and poly-acrylic acid (COO-), has been described by Wilson andcolleagues, 2003(Patent:WO-03/067952). Rather than the solvent approach used previously, the PEC was made by mixing the polymers physically in an equal mass ratio. Pentosan polysulphate sodium (PPSNa) was incorporated (50 % w/w) and a furfural method was developed to measure its release. Swelling of the PEC with and without PPSNa was determined by gravimetric analysis after hydration in simulated colonic pH at room temperature. Gel strength of the PEC was determined by texture analysis (TA-XT2i). Dissolution studies were performed using modified USP XXIII apparatus II (paddle) in simulated colonic pH (5.8 and 7.6, phosphate buffer) at 37 ± 1 ºC for 25 hours.

Results:  The PEC swelled up to 3722 ± 219 % w/w (n=3) at simulated colonic pH forming an insoluble gel network. The gel strength was 45.1 ± 7.7 g (n=3). The furfural method was sensitive for the quantitative determination of PPSNa between 0.02 mg/ml and 0.8 mg/ml (R2 0.99) with no interference from the polymers. Similar amounts of PPSNa were released at pH 5.8 (80.5 ± 3.5 %, n=3) and 7.6 (80.7 ± 6.2 %, n=3) after one hour. The incomplete release of PPSNa from PEC suggests some interaction with the oppositely charged polymer.

Conclusions:  The swollen PEC provides a delivery system containing water to aid local diffusion and distribution to the colon wall. PPSNa may aid syndecan-1 signaling in the inflamed gut in a manner similar to heparin, which would be of benefit in treating bowel diseases. Further release of PPS should occur after digestion of the chitosan by colonic bacteria, which is currently being investigated.

Conclusion: Under in vitro conditions, the microspheres demonstrated minimal hydration, swelling and erosion. Drug release occurred predominantly by Fickian diffusion. The microspheres provided drug concentrations above the MIC value for S.aureus. The surface pH of the microspheres was within acceptable limits for the oral cavity. DSC analysis confirmed an interaction between chitosan and tetracycline during microsphere preparation. The characterised microspheres can be proposed as a suitable delivery system for localised periodontal therapy
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Characterisation of Newly Developed Multipolymeric Mucoadhesive Controlled Release Matrices of Propranolol HCl
T. Govender1, A. Munasur1, D. Chetty2, V. Pillay3, C. Dangor1
1University of KwaZulu Natal, South Africa, 2GlaxoSmithKline, USA, 3Florida A&M University, USA

Purpose: To characterise a multipolymeric matrix formulation of a Propranolol HCl buccal delivery system developed for optimal mucoadhesivity and controlled drug release

Methods: Tablets matrices comprising of drug and polymers were compressed (Carver Press) as per an optimised formulation identified from an experimental design. Maximum detachment force (MDF) measurements (Digital Force Gauge); drug release (USP 24-Apparatus II); model fitting of drug release data (Win Nonlin Version 3.1); swelling and erosion studies; textural profiling (Texture Analyser XT2ì, Stable Micro Systems); thermal analyses (Mettler Toledo TC15, TA Controller); morphology (Philips SEM 500) and surface pH determinations were performed

Results: A MDF of 792 ±167.25 mN and a desired controlled release profile of 10.27 ± 1.18% in the 1st hour and 84.37 ±4.31% by the 8th hour was displayed for a formulation optimised via a Box-Behnken design. An n-value of 0.94 using the Power Law model was obtained.The Hopfenberg Model most appropriately described the drug release suggesting that surface erosion was instrumental in the observed drug release behaviour. This was in agreement with the erosion data which demonstrated the dominance of erosion, while swelling was negligible up until the 8th hour. Textural profiling showed an initial rapid hydration of the system, which could be beneficial for an enhanced mucoadhesivity. DSC thermograms illustrated interaction effects between drug and excipients during mixing, compaction and drug release. Surface morphology changes identified during mucoadhesivity measurements and post dissolution supported the observed mucoadhesive and controlled release behaviour. The surface pH ranged from 6.62 to 6.83 for the duration of the study

Conclusion: Characterisation of the multipolymeric matrix tablet provided a useful mechanistic insight with regards to the observed mucoadhesivity and controlled drug release behaviour. The results suggest that the polymeric blend identified shows potential for the optimal delivery of Propranolol HCl for buccal administration
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Solution-Cast Films As A Predictive Tool In Formulating Rupturable Coat Of Time-Delayed Capsules
L. Hodges, H. Stevens, A. Mullen
University of Strathclyde

Purpose: To investigate the mechanical properties of solution-cast, triacetin-plasticised ethylcellulose (EC) films in order to rationally formulate the EC outer coating of a time-controlled delivery system

Methods: Mixtures containing 2-6% (w/v) EC, Standard 10 grade, and either 20% (w/w of EC) or 1.8g triacetin in 50:50% (v/v) acetone and isopropyl alcohol (total volume 150ml) were stirred for at least six hours then poured onto a Teflon-coated plate (31cm X 31cm). The dried films were peeled off and cut with a sharp scalpel and an American Society for Testing and Materials dumbbell-shaped metal template. Sample thicknesses were measured at five points. The force generated in stretching the films was measured using a Texture Analyser (TA-XT2). The data, normalised with respect to mean thickness of each film, was analysed for statistical significance with ANOVA in Minitab v.13

Results: Overall, increasing polymer concentration increased tensile stress at break, work done to break film and elastic modulus of film. Tensile strain at break decreased with increasing polymer concentration in films with constant triacetin weight but no significant effect was observed in films with constant EC: triacetin weight ratio

Conclusions: This method allows the rational selection of a suitable rupturable outer coating for a novel delivery device with a programmed lag phase
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Puncture Test To Simulate Rupturing Of Ethylcellulose Coat Of A Time-Controlled Delivery System
L. Hodges, H. Stevens, A. Mullen
University of Strathclyde

Purpose: To simulate the rupturing of ethylcellulose (EC) coat of a swelling-controlled, capsule-based delivery system by puncture testing solution-cast films

Methods: Mixtures containing 3% (w/v) EC (Standard 10 grade) and 20-60% (w/w of EC) triacetin in 50:50% (v/v) acetone and propan-2-ol, total volume 150ml, were stirred for at least 6 hours then poured onto a Teflon-coated plate. The dried films were cut into 25mm diameter discs and immersed in a 37°C water bath. At 30-minute intervals, from 0 to 150 min, samples were removed, dried between two sheets of filter paper and stored in a 37°C hot cupboard prior to testing. The discs were secured between two cylindrical Perspex blocks with a 8mm diameter hole. A 6mm diameter stainless steel probe attached to a Texture Analyser TA-XT2 (2kg load cell) was driven through the film. The data obtained (10xnx15) was analysed for statistical significance at 5% level using ANOVA in Minitab v.13

Results: Increasing length of time in 37°C water significantly increased mean strain at film puncture (p=0.002), mean work done to rupture film (p=0.035) and mean modulus of film (p<0.0005) in films plasticised with 50% (w/w of EC) triacetin The increase in mean puncture strength was however not significant (p=0.063). Immersion in water did not significantly affect films with lower triacetin concentrations. Increasing triacetin concentration caused significant decreases in all parameters: mean puncture strength (p<0.0005), mean strain at film puncture (p<0.0005), mean work done to puncture film (p<0.0005) and mean modulus of film (p=0.002)

Conclusions: Changes in the puncture properties were only observed in the highly-plasticised films, hence over-plasticisation during construction of the final dosage form may have a detrimental effect on the ability of the swelling agent to rupture the coat. Quantifying the parameters in this manner allows rational development of our delivery system
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Hydrational and Force-Profiling Parameters of Different Glycosidic Co-Polymers
J. Jackson1, K. Long1, J. Sweet1, M. Danckwerts2, V. Pillay2
1Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, USA, 2University of the Witwatersrand, Department of Pharmacy and Pharmacology, Johannesburg, South Africa

Purpose: To elucidate and quantify the relationship between the hydrational dynamics and stress-strain properties of glycosidicallylinked M and G residues of alginates

Methods: The MG ratios for the 6 alginate polymers studied varied from 0.8 to 1.2. 1%w/v polymer solutions were crosslinked in 2%w/v solutions composed of either zinc sulfate, calcium chloride, and/or a binary mixture to produce small spherical gelispheres. These gelispheres were cured for 24 hours and dried at 21°C for 48 hours. Crosslinked gelispheres were accurately weighed and placed into glass vials containing 15mL deionized water. Each vial was placed in an orbital shaker bath set at 37°C and 50 rpm. At pre-determined intervals over 24 hours, a complete sample was removed, air-dried, and assessed for matrix erosion. Hydrated gelispheres were also analyzed at specific time intervals over a period of 96 hours employing a Textural Analyzer for stress-strain behavior associated with matrix tolerance, fracture resistance energy and resilience

Results: Calcium alginate matrices exhibited high matrix erosion ranging from 27%-57%. The binary mixture of zinc sulfate and calcium chloride produced the most significant variation in matrix erosion (7%-60%). Polymers crosslinked with zinc sulfate showed the lowest matrix erosion with values ranging from 8%-25%. The mean matrix tolerance values for matrices crosslinked either in calcium, zinc sulfate or the binary mixture was 47%, 49%, and 51% respectively. Accordingly the fracture resistance energy averaged at 0.01152, 0.01158 and 0.010907 Joules for matrices crosslinked in calcium chloride, zinc sulfate, and the binary mixture respectively. Matrix resilience did not vary significantly with all systems having a mean value of approximately 34%. In general the lower MG ratios produced lower hydration (erosion), higher matrix tolerance, fracture resistance energy and resilience

Conclusion:The stress-strain behavior and hydration characteristics of alginates are closely related and significantly change as their MG ratios vary
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Effect of Various Lubricants on the Properties of Fast-Melting Tablets
S. Jeong, K. Tan, S. Kimura, Y. Fu, K. Park
Purdue University

Purpose: To find good lubricants keeping quick disintegration and yet high mechanical strength of tablets, and apply them to make fast-melting tablets (FMTs)

Methods: Granules were prepared with or without various lubricants including talc, Mg stearate, Pruv®, Compritol 888ATO®, and polyethylene glycol 4000. The granules (300 mg) were compressed on a single punch Carver Laboratory Press (Carver Inc.) at various pressures using plane-face punches. To simulate tablet ejection, a new tool was designed and applied by Texture analyzer (Texture Technologies Corp.). 100 mg of each granule was put into the die and compressed with certain pressures, then measured the force to eject from the die. Tablet tensile strength and porosity were measured using a Texture analyzer and helium pycnometer, respectively. Tablet wetting time was measured from the time to completely wet a tablet, which was placed on the pre-wetted filter paper

Results: Tablet tensile strength increased linearly, however porosity decreased exponentially as the compression pressure increased. When 300 pounds pressure was applied, porosity was about 30%, tensile strength 3.4 kg/cm2 and wetting time less than 3 seconds without any lubricants. Particle size distribution of the granules affected the tablet properties, such as ejection energy, wetting time, and tensile strength. When lubricants were incorporated, the tablet ejection energy was in the order of Mg stearate< Pruv®<talc<Compritol 888ATO®. As the concentration of lubricants increased, the tablet crushing strength is decreased and the wetting time increased. Pruv®, Compritol 888ATO®, and PEG 4000 can be used alone or combinations as good lubricants for FMTs

Conclusions: Several hydrophilic lubricants and combinations of them were found to be suitable for making FMTs. They can reduce the friction between the granule and the die-wall while keeping the desirable tensile strength and quick disintegrating properties
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The use of x-carrageenan as a novel extrusion aid
P. Kleinebudde, M. Thommes
Heinrich-Heine-University Duesseldorf

Purpose The aim of this study was to assess the use of x-carrageenan as a novel extrusion aid by using different actives and fillers

Methods The pellets were produced by wet extrusion and spheronisation using a twin screw extruder (Mikro 27GL-28D, Leistritz, Germany), a spheroniser (RM 300, Schlueter, Germany) and a fluid bed dryer (GPCG-1.1, Glatt, Germany). The loss on drying was determined for calculating the water content based on dry mass of the extrudates. Pellet size and shape were described by mean Feret diameter and aspect ratio determined by image analysis. The mechanical characteristics of pellets were investigated by using a texture analyser (TA.XT2i, SMS, UK). Dissolution tests were performed by using a paddle apparatus according to USP 26

Results Different kinds of pellets were produced by using 20% microcrystalline cellulose (MCC) as standard extrusion aid or 20% x- carrageenan as new extrusion aid. Additionally, the formulations contained 40% or 80% actives (acetaminophen, hydrochlorothiazide, mesalacine, theophylline) and 40% or 0% fillers (dicalcium phosphate dihydrate, lactose monohydrate, maize starch, mannitol). Using equivalent formulations x-Carrageenan required higher water content for pelletisation compared to MCC. The evaluation of shape and size of the pellets demonstrated that both extrusion aids produced pellets with similar properties. x-Carrageenan pellets exhibited a lower tensile strength than MCC pellets. In all cases, x- Carrageenan pellets disintegrated and offered a fast dissolution of the actives in contrast to pellets produced with MCC, which showed matrix dissolution. The different actives and fillers formulated with x-carrageenan exhibited only a low influence on size, shape and tensile strength of the manufactured pellets

Conclusion x-Carrageenan is a suitable extrusion aid to produce pellets without MCC. In a wide range of formulations with x- carrageenan it was possible to achieve pellets with high quality and fast dissolution
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Investigations of the water granulation of different hydrophilic matrix polymers
A. Larsson, M. Vogt, J. Herder
Pharmaceutical Technolgy

Purpose The aim of this study is to characterize the water granulation and compaction process for different hydrophilic matrix polymers, measure the water-polymer and determine the mechanism behind formation and compaction behaviour of these granules

Methods A lab-sized high shear granulation mixer was used to water granulate hydrophilic matrix polymers. HPMC 60SH-4000, PEO, Xanthan, and HEC were used as polymers. The sieved particle size distribution, the bulk/tapped density and the compaction behaviour were analysed. The gel swelling was determined by a TA-HDi® Texture Analyser. A water sorption method was developed. SEM pictures were taken of some of sieved fractions

Results A constant increase in torque was observed during the initial phase of the granulation. This indicates that the powder in contact with the water creates a viscous gel layer and the cohesion process can occur immediately. The bulk and the tapped densities and the tensile strength decreased with increasing ratio of water:polymer. The particle size distribution became bimodal after granulation. Xanthan is the most hydrophilic polymer (highest degree of swelling, high water sorption rate) and forms the largest granules at low water:polymer ratios. In contrast, HPMC has the lowest degree of swelling and water sorption rate, and it forms smaller granules at the same addition ratio. These observations imply that more hydrophilic powders develop faster and thicker gel layers. This makes the cohesion between the polymer particles during the granulation possible at lower added amount of water

Conclusion By determining the polymer-water interaction parameters it is possible to predict and determine the build up mechanism during the granulation of hydrophilic matrix polymers
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Study on the Correlation of Drug Dissolution and Polymer Swelling from a Matrix Tablet Using Texture Analyzer
H. Li, X. Gu
Faculty of Pharmacy, University of Manitoba, Winnipeg, CANADA

Purpose: To study the relationship between drug dissolution and polymer swelling from a controlled release matrix tablet of pseudoephedrine using texture analyzer

Methods: A series of controlled release matrix tablets of pseudoephedrine were prepared by direct compression Method: using identical compression force. Controlled release of pseudoephedrine was achieved by combined use of matrix excipients Comprital® 888 ATO (C) and Polyox® WSR 301 (P). Dissolution profiles of the tablets were evaluated using USP Method II Thickness of gel formation and area under the curve (AUC, product of the force the probe sensed and the distance the probe traveled) during drug dissolution were also recorded using a Texture Analyzer. The relationship between drug dissolution and polymer swelling was correlated and interpreted

Results: Drug dissolution within the first 90 minutes reduced with the increased proportion of C and P in tablet formulation However, drug dissolution completed in 6 hours due to the aqueous solubility of pseudoephedrine. Thickness of gel formation as well as the AUC increased linearly with the dissolution time, indicating first-order kinetics of water penetration into tablet matrix. Linear correlation was also observed between thickness of gel formation and square of drug release percentage.

Conclusions: There was a linear relationship between drug dissolution and polymer swelling of a controlled release matrix tablet of pseudoephedrine. The study demonstrated a unique application of Texture Analyzer in characterization of tablet quality control and drug dissolution
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Parametrical Stress-Strain Analysis of Homogeneously and Heterogeneously Crosslinked Matrices

K. Long1, J. Jackson1, J. Sweet1, M. Danckwerts2, V. Pillay2
1Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, USA, 2University of the
Witwatersrand, Department of Pharmacy and Pharmacology, Johannesburg, South Africa

Purpose: To compare the matrix yield value, deformation potential and capability to absorb mechanical energy for homogeneously and heterogeneously crosslinked alginate matrices

Methods: Crosslinked matrices were formulated by titrating polymer solutions of various alginates into aqueous media composed either of 1%w/v of zinc sulfate heptahydrate, calcium chloride, or their combination. Samples were hydrated in deionized water at

50 rpm and 37°C in an orbital shaker. Texture analysis was performed on both unhydrated and hydrated matrices using the TA.XT.plus Texture Analyzer to measure the matrix yield value, deformation potential, and the capability to absorb energy

Relationships among these parameters were derived through mathematical curve-fitting of data using non-linear regression

Results: Deformation potential of the unhydrated matrices increased in the order of decreasing MG ratios ranging from 29.76-44.82% for samples crosslinked in zinc, the combination, and calcium respectively. A similar relationship was derived from the matrix yield values which ranged from 67.17-91.23 N/mm in the order of zinc > combination >calcium. Absorbed energy values ranged from 0.008-0.013 Joules in a similar order. Systematic comparison of the textural properties of the crosslinked polymers revealed a directly proportional relationship between the matrix deformation and matrix tolerance. An inverse relationship existed between matrix tolerance and energy absorbed. In both cases an R2>0.90 was obtained

Conclusion:Alginates with different MG ratios display significantly differently textural properties which may be related to the different degrees of crosslinking facilitated by the MG ratios
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Roller Compaction of a Poorly Compressible Drug Substance Incompatible with Traditional Ductile Fillers
Z. Mahmoudi, F. Alvarez-Núñez
Pfizer Global R&D Michigan Laboratories, Pharmaceutical Sciences

Purpose. To evaluate the feasibility of manufacturing tablets via dry granulation of a poorly compressible drug substance incompatible with traditional ductile fillers.

Methods. Two formulations were tested. Both contained 25% of poorly compressible drug substance, lactose or lactose/mannitol as fillers and other functional excipients. Tablets of the above formulations were prepared as follows: blending of most ingredients, roller compaction of prepared blends, milling of manufactured ribbons, lubricating of obtained granules, and tableting. Process parameters were selected based on experiments conducting on placebos. An instrumented roller compactor was used for preparing ribbons. Press force and gap width were set at 7kN/cm and 2mm, respectively. Tensile strength (TS), solid fraction (SF), and porosity of the ribbons; particle size, bulk and tap density of the granules and tablet hardness were evaluated. Tensile strengths were measured using three –point beam bending method in a texture analyzer. Particle size distribution was evaluated using a laser diffraction particle size analyzer. A rotary tablet press was used to manufacture 100 mg tablets.

Results. TS and SF values of placebo ribbons of formulation containing lactose (2.17 MPa; 0.71) were slightly different than that of lactose/mannitol formulation

(2.20 MPa; 0.72). However, a significant decrease of TS values, due to the presence of the poorly compressible tested drug substance, was observed in both lactose (1.56 MPa) and lactose/mannitol (1.71 MPa) formulations

Granule evaluations indicated that bulk/tapped density values of lactose (0.65/0.89) were slightly different than that of lactose/mannitol (0.64/0.87) formulations. These density values were significantly higher than respective values of dry blends. Particle size analysis indicated that the mean volume diameter increased from 139 to 186 and from 135 to 166 µM in lactose and lactose/mannitol formulation, respectively. Tablet compression profiles indicated maximum hardness of 4.4 ±0.4 kp and 4±1.3 kp at similar compression forces for lactose and lactose/mannitol formulations, respectively.

Conclusion. Using proper roller compaction parameters it is feasible to manufacture dry granulation tablets of a poorly compressible drug substance incompatible with traditional ductile fillers
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Physical Properties of Bulk Insulin Powder for Inhalation
R. Malcolmson1, C. De Moor1, D. Miller1, Y. Liang1, C. Zhen1, Y. Kim1, J. Merchant1, D. Bennett1, I. Saracovan2, S. Sekulic2
1Nektar Therapeutics, 2Pfizer Inc

Purpose: To characterize the physical properties of Insulin Powder produced with various processing conditions. Analyses were performed to generate thorough product understanding

Methods: True density via helium pycnometry: Micromeritics AccuPycTM 1330 Pycnometer. Powder compressibility via uniaxial compaction: Stable Micro Systems TA-XT2i HR Texture Analyzer. Powder morphology via scanning electron microscopy (SEM); Phillips XL30 SEM. Surface area via nitrogen adsorption/BET analysis; Micromeritics Gemini III 2375 Surface Area Analyzer. Particle size via Sympatec Helos. Surface energy via inverse gas chromatography (IGC): Surface Measurement Systems IGC Analyzer, v1.5

Results: All powders measured had a true density of approximately 1.48 g/cc. Under uniaxially applied pressures of 0.1 to 100 psi, bulk densities ranged from 0.3-0.5 g/cc (untapped bulk density 0.2 g/cc). Particles have a rugous, xraisin-likex morphology and range from sub-micron to several microns in size. Specific surface area is typically 9 m2/g. Surface area varied with processing conditions and was a strong function of particle size distribution, as expected (typical median size was approximately 1.8 µm, range over the processing conditions was 1.4 – 2.8 µm). The dispersive and specific components of powder surface energy were similar across all lots, and were comparable to values from other spray-dried powders

Conclusions: Insulin powder for inhalation is a well-characterized pharmaceutical powder that exhibits a high degree of consistency in several physical properties when manufactured over a wide processing range. As expected, physical properties that relate to the primary particle size distribution do show variance over wide processing ranges
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Mechanical Properties of Hot-Melt Extruded Hydroxypropylcellulose Films Containing a Model Antifungal Drug
P. Mididoddi1, S. Prodduturi1, M. Repka2
1Department of Pharmaceutics, The University of Mississippi, University, MS, USA, 2Department of Pharmaceutics, The National Center for Natural Products Research, University, MS, USA

Purpose: To investigate the influence of tartaric acid (TTA) on the mechanical properties of drug- incorporated hydroxypropylcellulose (HPC) films produced by hot-melt extrusion

Methods: Two HPC film batches (300g) containing the antifungal drug ketoconazole (one without and one with TTA 4%) were prepared by hot-melt extrusion (HME) using a Killion extruder (Model KLB-100). The mechanical properties of these films were determined utilizing a Texture Analyzer® (TA.XT2i) equipped with Texture ExpertTM software. The standard test method for tensile properties of thin plastic sheeting by the American Society for Testing Materials, method D 882-95a, was utilized. Properties that were investigated included tensile strength and percent elongation (n=6/formulation). Moisture content of the HME films was determined using a Perkin-Elmer Pyris-1 TGA

Results: The mechanical properties of the HPC films were dependent on the composition of the formulations. After storage for two weeks (25°C/60%RH), the tensile strength determined for the films containing TTA was 8.3 MPa (±0.5), while for the films without tartaric acid was 13.8 MPa (±1.6). The percent elongation for the same films with tartaric acid was 51.9 (±2.2), while for the films without TTA was 30.8 (±1.3). After storage for 6 months (25°C/60%RH), both film formulations did not exhibit any significant change in the initial mechanical property findings. TGA data collected at the two-week and 6-month time intervals indicated higher moisture content for the tartaric acid-containing films than the HPC films without TTA

Conclusion: HME is a viable process to produce thin, flexible and stable drug-incorporated HPC films. Addition of tartaric acid within the film formulations significantly influenced the mechanical properties tested. However, the observed increase in moisture content within the TTA-containing films may play a role in this studyxs findings. The results of this investigation of HPC films are relevant to our ongoing development of improved formulations for topical drug delivery
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Influence of 'Etching' and Instrument Variables on the Bioadhesion of Hot-Melt Extruded Drug Delivery Systems for the Human Nail
P. Mididoddi1, M. Repka2
1Department of Pharmaceutics, The University of Mississippi, University, MS, USA, 2Department of Pharmaceutics, The National Center for Natural Products Research, University, MS, USA

Purpose: To determine the influence of xetchingx on the bioadhesion of hot-melt extruded (HME) drug delivery systems for the human nail

Methods: HME hydroxypropylcellulose films containing ketoconazole were prepared using a Killion extruder (Model KLB-100). The extruded films were applied to tip nail pieces of healthy volunteers (University of Mississippi, IRB#03-045). Bioadhesion tests were performed with these HME films using a Texture Analyzer®(TA.XT2i) equipped with Texture ExpertTM Software

The nail samples tested were either non-treated (control) or treated with phosphoric acid gel (PA). The instrument variables such as contact force, contact time and speed of withdrawal of the probe, were studied using these films. The parameters measured were peak adhesion force (PAF) and the area under the curve (AUC)

Results: PAF and AUC were determined to be greater for human nail samples treated with PA gel compared to that of the control for each of the instrument variables studied. At all contact forces employed, both the PAF and AUC correspondingly increased with increase in the contact time. For a contact force of 2.0 N and a contact time of 60 sec, the PAF and AUC were 3.5 N and 6.5 N-mm, respectively, for the treated samples compared to that of the control (0.9 N and 4.4 N-mm). In addition, the speed of withdrawal of 0.5 mm/s at a contact time of 180 sec resulted in a PAF of 1.3 N for the control vs. 4.0 N for the PA treated nail

Conclusion: Bioadhesive profiles of the HME films have demonstrated that nail samples treated with surface modifiers increase PAF and AUC values compared to that of the control. Thus, determination of differences in bioadhesion for the control and etched nail coupled with other studies is significant for the formulation, design and production of topical drug delivery systems for onychomycosis
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Influence of Formulation Variables on the Adhesion Characteristics of Clotrimazole Nail Lacquers
V. Nalamothu, J. Schwartz
Philadelphia College of Pharmacy, University of the Sciences in Philadelphia

Purpose: To investigate the adhesion characteristics of clotrimazole nail lacquers containing poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA or Gantrez®) polymer matrix systems using a Texture Analyzer

Methods: Nail lacquer formulations containing clotrimazole (4 to 12%) and various percentages of PVM/MA (Gantrez® ES-425) (10, 20, 30) and propylene glycol (tailing solvent) (2, 5, 8, 10) were prepared using ethyl acetate and ethyl alcohol as primary and coupling solvents respectively. The adhesion studies were performed using a Texture Analyzer® (TA.XT2 Plus) equipped with a Texture ExponentTM software. A TA-57 (7mm-1xR) probe was used in this study

Results: A reproducible method was developed for the adhesion studies using a model antifungal drug. Using this finalized method, i.e. contact time of 30 seconds and 10 g of applied force, the effects of concentration of drug, polymer and the tailing solvent

were evaluated. Formulations containing higher PVM/MA polymer exhibited a higher peak adhesive force (PAF) and area under the curve (AUC) value or work of adhesion compared to the formulations containing lower amounts of the polymer (132.7 g, 235.9 g and 332.7 g PAF for 10, 20 and 30% respectively and 6.224 g.sec 9.016 g.sec and 12.511 g.sec AUC for 10, 20 and 30% respectively). Similar trends were seen for increase in drug concentration and the tailing solvent

Conclusion:The adhesion studies of clotrimazole nail lacquers indicate that PAF and AUC values are a function of formulation variables Optimization of formulations and study of release properties for these nail lacquers is the subject of future studies
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Hot-melt extruded polymeric films for transmucosal drug delivery: Tailoring properties using polymer blends
S. Prodduturi1, R. Manek2, W. Kolling2, S. Stodghill1, M. Repka1
1Department of Pharmaceutics, University of Mississippi, 2Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe

OBJECTIVES: To study the effect of molecular weight and moisture content on the mechanical and bioadhesive properties, release characteristics, and stability of hot-melt extruded (HME) films containing clotrimazole (CT) and hydroxypropyl cellulose (HPC), or poly(ethylene oxide) (PEO) or polymer blends (HPC+PEO)

METHODS: A single-screw extruder was used to produce thin bioadhesive polymeric films. Moisture sorption isotherms were obtained using an SGA-100 Symmetric Vapor Sorption Analyzer. A TA.XT2i Texture analyzer equipped with TA-96 grips (mechanical studies), a TA-57R probe (bioadhesive studies), and Texture Expertx software was utilized for testing the films. Release studies were performed according to USP XXIII apparatus-5, paddle-over-disk method. Samples were analyzed by HPLC. Solid-state characterization studies were performed using Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD)

RESULTS: HPC films demonstrated higher moisture sorption than the PEO films. HPC films exhibited brittle fracture with higher tensile strength (63.5±1.9), and elastic modulus (19.9±1.1) and low percent elongation (3.9±0.2). In contrast, PEO films were flexible with low tensile strength (9.2±0.5), elastic modulus (6.3±0.3) and exceptionally high percent elongation (800%). PEO films demonstrated higher bioadhesivity than HPC films. The release of the drug from both of the films (HPC, PEO) followed zero-order profile. However, release from PEO films was faster than from the HPC-containing films

CT incorporated in both of the films was found to be in solid solution as indicated by DSC and XRD. However, CT incorporated in HPC films was found to be more stable than the CT/PEO films. Films prepared from polymer blends (HPC+PEO) demonstrated increased flexibility, ductility, and bioadhesivity as the PEO concentration was increased

CONCLUSIONS: Polymer blends of HPC and PEO were used successfully to tailor the properties of HME films without affecting drug stability. Films containing HPC:PEO:CT (55:35:10) demonstrated optimum mechanical, bioadhesive and release characteristics, while maintaining the stability of the drug within the films
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Impact of Drug Load on Thermal and Texture Parameters of Chewable Softgel Fills
H. Nasri
Banner Pharmacaps

Impact of Drug Load on Thermal and Texture Parameters of Chewable Softgel Fills

Purpose: To investigate the impact of dug load on the Glass Transition Temperature (Tg) as well as texture parameters like chewiness, hardness, and adhesivenss of chewable Softgel fills using Ibuprofen as a model drug

Methods: Five formulations were made by combining the appropriate amounts of chewable matrix and Ibuprofen at loads between 0% to 40% (w/w) DSC experiments: Samples (2-6 mg) were heated in sealed aluminum pans under nitrogen flow (20-cm3 min-1) at either a heating rate of 20 oC min-1, from 25 to 80 oC or a heating rate of 5 oC from 10 oC to 50 oC

Texture analysis experiments: Each formulation was tested for texture parameters such as chewiness, hardness, and adhesiveness using the Texture Expert Analyzer

Results: DSC measurements showed that increasing the drug content of the Chewables from 10% to 40%(w/w) resulted only in changing the Glass Transition Temperature (Tg) of the chewable matrix from 33 °C to 35 °C compared to the control (Chewable matrix with 0% drug load). Texture Analysis showed that increasing the drug load from 10% to 40% did not affect chewiness and cohesiveness but increased hardness

Conclusion:The DSC studies revealed that the Glass Transition Temperature (Tg) of the chewable matrix stayed between 33°C to 35°C Chewiness and cohesiveness of the chewable fill did not change with drug loads of up to 40% (w/w). The results of these studies support the possibility of using the chewable matrix as a base for formulating chewable softgel capsules without substantially affecting the physical parameters and texture of the fill.
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Topical Drug Release and Physicochemical Characterization of Acrylic and Silicone Adhesives
V. Raul, J. Cabala, P. Klykken, X. Thomas, G. Schalau II
Dow Corning Corp

Purpose: This study investigated the drug release and physicochemical properties of acrylic and silicone adhesives using vitamin B3 (niacinamide) as the model drug

Methods: Multiple levels of niacinamide ranging from 2 to 15% were loaded into acrylic and silicone adhesive matrices

A combination of Franz static diffusion cells and UV spectrophotometer analysis were used to evaluate the drug release kinetics. Viscoelastic parameters including elastic modulus (Gx), loss modulus (Gx), loss tangent (x) and dynamic viscosity (x) were evaluated using dynamic oscillatory frequency sweeps. The internal cohesiveness of the adhesive formulations was determined with a texture analyzer, and drug crystal characterizations were evaluated by scanning electron microscopy

Results: Release kinetics were dependent on the type of adhesive as well as the amount of drug loading. Near zero drug release rates could be obtained with all the adhesives tested. In comparison to the silicone adhesives, the more hydrophilic acrylic adhesives yielded lower drug release rates and smaller drug crystals. Viscoelastic properties of the acrylic adhesives did not significantly change with drug loading, whereas with the silicone adhesives, Gx, Gx, and x increased with drug loading

Conclusion:These studies underscore the ability to regulate drug release from acrylic and silicone adhesives. In comparison to creams, lotions and gels, which are applied repeatedly and in varying amounts, adhesives offer enhanced substantivity and overall control of drug exposure. Aesthetic properties such as visual transparency and gentleness to skin can also be formulated into adhesive drug delivery matrices in an effort to maximize therapeutic outcomes
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Characterisation of Powders by a Low-Pressure Compression Test
A. Soerensen1, J. Moeller-Sonnergaard1, L. Hovgaard1, S. Jepsen2, C. Larsen2, H. Lindner2
1Danish University of Pharmaceutical Sciences, 2Ferring Pharmaceuticals A/S

Purpose: To evaluate the precision and sensitivity of a compression test as an alternative to traditional tapped density measurements

Methods: Samples of 50 mg were compressed on a TA-XT2 Texture Analyser equipped with a 6 mm die and flat-faced punch. Data on punch position and force (50 points per second) were collected at a fixed punch speed of 0.2 mm/second

Compressed density was calculated from the mass of the powder plug and the sample volume at 0.2 MPa. Sample volume was corrected for the elastic deformation of the system

Tapped density of the powders was determined according to the European Pharmacopoeia (2.9.15) after 2500 taps using a settling apparatus equipped with a 250 ml graduated cylinder

Results: Twelve common pharmaceutical powders were included in the study. All experiments were made in triplicate. Compressed densities were in the range of 0.209 to 0.935 g/cm3 carrying standard deviations (repeatability) of 0.1-2.5 %. Tapped densities were in the range of 0.24 to 1.09 g/cm3 carrying standard deviations of 0.5-4.5 %. Compressed density and tapped density were linearly correlated with R2 = 0.81

The sensitivity of tapped density measurements is limited by the inaccurate reading of the sample volume to the nearest millilitre. Compressed densities can be determined with at least three significant digits because of the accuracy of the force measurements

Conclusions: The proposed low-pressure compression test allows sensitive and precise determinations of compressed density using very small amounts of powder. As compressed density is directly correlated to tapped density, the proposed test provides an excellent alternative to traditional tapped density measurements
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Experimental Design Strategy to Elucidate the Stress-Strain Moduli of Densified PLGA Scaffolds
J. Sweet1, F. Agbotse1, R. Khan1, M. Danckwerts2, V. Pillay2
1Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, USA, 2University of the Witwatersrand, Department of Pharmacy and Pharmacology, Johannesburg, South Africa

Purpose: To apply a rotatable Face-Centered Central Composite matrix to design densified poly(lactide-co-glycolide) (PLGA) complexes having physicomechanical moduli suitable for applications in tissue engineering

Methods: Twenty-six salted-out PLGA complexes were developed to study the effect of four independent variables: volume of water phase (10-100mL), molecular weight of polymer (55,000-116,000 Daltons), concentration of polymer (1-10%w/v) and salting-out time (2-24 hours). The dependent variables measured included the moduli for matrix resilience, energy absorption and gravimetric transitions. Complexes with constant surface area (1 mm2) were hydrated in phosphate buffered saline (PBS) of pH 7.4 over a 30-day period and analyzed at pre-determined time intervals to assess the response functions using macros created on Texture Exponent V3.2. The moduli for each response were computed from the AUC values obtained from non-linear curve-fitting applying a quadratic function in all cases (SigmaPlot V8.0, WinNonlin V3.2)

Results: An increase in the volume of the water phase markedly reduced the energy absorption modulus of the complexes (0.9-0.4 Joules/hour) upon hydration. On the other hand, increasing the PLGA molecular weight and salting-out reaction time did not produce any significant effect on the surface hardness (p=0.167, 95% CI). The overall modulus of resilience varied between 295.5-1199.60%/hour indicating a high interactions effect between the independent and dependent variables. A two-way ANOVA on the gravimetric transition modulus reflected significant variation (p=0.0021) from –24.0 to 25.4 hour-1. It was also observed that the physicochemical behavior of the salted-out co plexes could be strictly manipulated by varying the ionic strength of the PBS buffer system. In general, higher ion concentrations produced enhanced stress-strain resistance

Conclusion: The proposed Experimental Design provided a novel approach to develop PLGA scaffolds with significantly different physicomechanical properties and three-dimensional structures, which may prove to be useful in applications of tissue engineering such as cell seeding, adhesion and bone regeneration
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Evaluation of Drug Release and Performance Parameters for Metformin Commercial Tablets
L. Tutunji, R. Fassihi
School of pharmacy, Temple University, 3307 N Broad St, Philadelphia, PA 19140

Purpose: To evaluate the release of metformin from extended-release hydrophilic tablets and assessment of their swelling, textural, and erosional behavior during drug release process

Methods: Drug release from commercial tablets was assessed using USP 26 apparatus II (paddle) modified with insersion of a mesh in the dissolution vessel using both HCl/KCl buffer and phosphate buffer. The collected samples were diluted and the absorbance measured spectrophotometrically using HP 8453 UV spectrophotometer. The swelling and erosion behavior was investigated by textural analysis of the swollen tablets using a TA.XT2i texture analyzer

Results: Metformin release was independent of pH and drug transport was mainly based on diffusion from the dosage form. An initial burst effect was observed during the first two hours of the release profile. From 2 hours up to 12 hours, release followed linear kinetics. A tailing of release was observed from 14 to 24 hours. During dissolution, individual tablets were subjected to textural analysis and their resistance to probe penetration was determined. Results showed that the total work of penetration remained constant between 4 to 9 hours while swelling and water uptake increased during the same time period

Conclusions: It was observed that during dissolution, tablets were submerged in the medium, gently floating over the mesh till about 20 hours, after which time the tablets freely moved to the top of the dissolution medium in the vessels. At the beginning of the dissolution process, there was slow swelling followed by a more rapid increase in swelling after 4 hours of the dissolution

The rapid burst effect observed during the beginning of the dissolution process may be related to the slow swelling process, while the linear release during 2 to 9 hours is controlled by the gel layer formed during the corresponding time. The interrelationship between force-distance profiles, swelling, and release are discussed

Additional papers at the 2004 Annual Meeting were

T3100, Influence of Formation Variables on the Adhesion Characteristics of Clotrimazole Nail Lacquers; V. Nalamothu, J. Schwartz
T3149, Simultaneous Determination of Tensile Strength, Young's Modulus and Moisture Content for Roller Compacted Powdes by Near Infrared (NIR) Spectroscopy, A. Gupta, G. Peck, R. Miller, K. Morris
T3202, Improving Granule Strength of a Wet-Granulated Tablet Formation Without Changes in Composition, C. Yang, M. Telko, S. Panmai, B. Matuszewska, S. Karaborni
W5170, Development and Characterization of Matrix-Type Mucoadhesive Tablets of Buprenorphine for Sublingual Delivery, CN. Das, M . Surapaneni, L. Aburto, S. Sorenson, S. Das
W5244, Physicomechanical Characterization of Different Polymeric Materials and Core Substrates Employed in Formulation of Film-Coated Dosage Forms, S. Missaghi, R. Fassihi

The use of Texture Analysis in the physical characterisation of sputum from cystic fibrosis patients

Influence Of Water-soluble Polymeric Matrix Carriers On The Bioadhesive And Release Properties Of Hot-melt Extruded Films Containing A Water Insoluble Drug Purpose: To investigate the bioadhesive and release properties of hot-melt extruded films containing different ratios of the water-soluble polymers, hydroxypropyl cellulose and (HPC) and/or poly(ethylene oxide) (PEO) incorporated with clotrimazole, a AAPS PharmSci Vol. 5, No. 4, Abstract W4176 (2003)

Influence Of Excipients And In-situ Ph Variation On Release Kinetics Of Metronidazole And Tetracycline Hydrochloride From A Matrix Tablet Purpose: To investigate the combined effect of acidic/basic/neutral, ionic/nonionic, water soluble and water insoluble excipients and polymer type on the release kinetics of two antibiotics, metronidazole and tetracycline HCl. Methods: Drugs with AAPS PharmSci Vol. 5, No. 4, Abstract W4204 (2003)

Swelling And Erosion Characterization Of Hpmc And Peo Tablets During Dissolution Purpose: To investigate the swelling and erosion properties of hydroxypropyl methylcellulose (HPMC) and polyethylene oxide (PEO) as drug carrier. Methods: Plain HPMC (K100LV, K4M, K15M, and K100M) and PEO (Polyox WSR N60, WSR301, and WSR303) matrix AAPS PharmSci Vol. 5, No. 4, Abstract W4343 (2003)

Molecular Weight, Concentration And Thickness Of Hydroxypropylcellulose-containing Pharmaceutical Films As Determinants Of Dissolution Rate And Film Strength Purpose: The current study evaluated the influence of casting thickness, molecular weight and concentration of hydroxypropylcellulose in polymeric films on film strength and dissolution rate. Methods: Polymeric films containing different molecular AAPS PharmSci Vol. 5, No. 4, Abstract W5103 (2003)

Elucidation Of The Mechanisms Controlling Drug Release From Pellets Coated With Polymer Blends Purpose: To elucidate the mass transport mechanisms governing drug release from pellets coated with blends of enteric and GIT (gastro-intestinal-tract)-insoluble polymers. Methods: Propranolol hydrochloride-loaded pellets were coated with blends of AAPS PharmSci Vol. 5, No. 4, Abstract W5129 (2003)

Simulation Of Gastrointestinal Contractile Forces On Release Kinetics Of Swelling/eroding Matrices Purpose: To simulate and evaluate the effects of destructive mechanical forces of the gastrointestinal tract on matrix integrity and release kinetics of controlled release swellable tablets. Methods: Tetracycline tablets (100mg) were prepared by AAPS PharmSci Vol. 5, No. 4, Abstract R6104 (2003)

The Effect Of Processing Parameters On The Physical Characteristics Of Pellets Formed By Extrusion And Spheronization. Purpose: To study the effect of selected processing parameters, i.e., granulating fluid, mixing time and spheronization time, on morphology, viscoelastic properties and the dissolution profile of the extruded pellets. Methods: Pellets were made using AAPS PharmSci Vol. 5, No. 4, Abstract T3168 (2003)

Flavor Benchmarking Study Of The Leading Brands Of Over-the-counter Pediatric Analgesics Purpose: Flavor quality is key to compliance for many oral pharmaceuticals, which is an especially formidable challenge for pediatric formulations. Children have difficulty taking traditional solid dosage forms and respond dramatically to flavor, AAPS PharmSci Vol. 5, No. 4, Abstract T3267 (2003)

Influence Of Excipients And In-situ Ph Variation On Release Kinetics Of Metronidazole And Tetracycline Hydrochloride From A Matrix Tablet

Purpose: To investigate the combined effect of acidic/basic/neutral, ionic/nonionic, water soluble and water insoluble excipients and polymer type on the release kinetics of two antibiotics, metronidazole and tetracycline HCl. Methods: Drugs with

AAPS PharmSci Vol. 5, No. 4, Abstract W4204 (2003)
Swelling And Erosion Characterization Of Hpmc And Peo Tablets During Dissolution

Purpose: To investigate the swelling and erosion properties of hydroxypropyl methylcellulose (HPMC) and polyethylene oxide (PEO) as drug carrier. Methods: Plain HPMC (K100LV, K4M, K15M, and K100M) and PEO (Polyox WSR N60, WSR301, and WSR303) matrix

AAPS PharmSci Vol. 5, No. 4, Abstract W4343 (2003)
Influence Of Polyethylene Oxide Molecular Weight On Release Kinetics Of A Class-ii Drug: 4-androstene-3,17-dione

AAPS PharmSci Vol. 5, No. 4, Abstract W5164 (2003)
Evaluation And Comparison Of Dissolution Profiles For A Swelling And Eroding Dimenhydrinate Tablet Using Usp Apparatus I, Ii, And Iii

AAPS PharmSci Vol. 5, No. 4, Abstract W5202 (2003)
Simulation Of Gastrointestinal Contractile Forces On Release Kinetics Of Swelling/eroding Matrices

Purpose: To simulate and evaluate the effects of destructive mechanical forces of the gastrointestinal tract on matrix integrity and release kinetics of controlled release swellable tablets. Methods: Tetracycline tablets (100mg) were prepared by

AAPS PharmSci Vol. 5, No. 4, Abstract R6104 (2003)
Effect Of Non-ionizable Soluble And Insoluble Excipients On Release Kinetics From Hpmc Based Tablets

AAPS PharmSci Vol. 5, No. 4, Abstract T3039 (2003)
Development And Dissolution Kinetic Studies Of Ondansetron Hydrochloride From Hydrophilic Matrices Of Polyethylene Oxide

AAPS PharmSci Vol. 5, No. 4, Abstract T3180 (2003)
Design And Development Of A Gastroretentive Delivery System For Upper Gastrointestinal Tract Drug Delivery

Purpose: To develop a bilayer gastrofloatable delivery system for simultaneous controlled release of metronidazole and tetracycline HCl. Methods: Metronidazole, tetracycline HCl, microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC,

AAPS PharmSci Vol. 5, No. 4, Abstract T3216 (2003)
Formulation Development Of A Novel Self-correcting Controlled Release Matrix System Incorporating Film-forming Polymer Coatings

Purpose: To evaluate formulations of a novel self-correcting matrix system displaying bimodal and near zero-order release profiles incorporating coatings of film-forming polymers for the purpose of inducing dissolution lag time and improving

AAPS PharmSci Vol. 5, No. 4, Abstract W4121 (2003)
In Vitro Investigations Of Alternative Controlling Polymer Formulations Of A Novel, Self-correcting Controlled Release Matrix Displaying Ba/be To A Reference-listed Product

Purpose: To investigate the in vitro robustness, ruggedness and formulation flexibility of a novel, self-correcting controlled release matrix containing nicotinic acid capable of displaying in vivo bioequivalence to a reference listed drug product,

AAPS PharmSci Vol. 5, No. 4, Abstract W4122 (2003)

Textural Profiling And Statistical Optimization Of Crosslinked Polymeric Matrices Purpose. A 25 factorial design and artificial neural networks was employed to statistically evaluate the textural properties of a crosslinked calcium-alginate-pectinate-cellulose acetophthalate gelisphere system. Methods. In accordance with the AAPSPharmSci Vol. 4, No. 4, Abstract T3154 (2002)

Assessment Of Film Formation On Different Tablets Using Texture Analysis And Confocal Laser Scanning Microscopy
Purpose. To evaluate the nature of film formation on different tablets using confocal laser scanning microscopy (CLSM), and textural analysis of film layer and bonding efficiency. Methods. Three excipients, microcrystalline cellulose (MCC), spray
AAPSPharmSci Vol. 4, No. 4, Abstract T3190 (2002)

Physical And Mechanical Characterization Of Hydrophilic Films For Rapid Intra-oral Drug Delivery
Purpose. Water-soluble films that dissolve rapidly in the oral cavity release drug for absorption through the highly vascularized oral mucosae. The physical and mechanical characterization of such hydrophilic films facilitates the formulation of
AAPSPharmSci Vol. 4, No. 4, Abstract T3314 (2002)

Drug Content And Adhesive Uniformity Of Hot-melt Extruded Hydroxypropyl Cellulose Films Containing Clotrimazole
Purpose. To investigate the drug content, degradation, adhesion and content uniformity of hot-melt extruded (HME) hydroxypropyl cellulose (HPC) films containing clotrimazole. Methods. HPC films containing clotrimazole 10%, poly(ethylene oxide) (PEO)
AAPSPharmSci Vol. 4, No. 4, Abstract W4177 (2002)

Bioadhesive Properties Of Hot-melt Extruded Drug Delivery Systems On The Human Nail.
Purpose. To determine and compare the bioadhesive properties of hot-melt extruded drug delivery systems for onychomycosis on the dorsal human nail surface with and without surface modifier treatment. Methods. Hot-melt extruded films containing
AAPSPharmSci Vol. 4, No. 4, Abstract W4144 (2002)

The Suitability Of A Capsule Component For Use With A Pulsed Release Drug Delivery Device Purpose. To manufacture and assess the suitability of capsule components for the assembly of a pulsed release drug delivery system. Methods. Three types of capsule were prepared by coating size 0 hard gelatin capsules with ethyl cellulose: [A] Using AAPSPharmSci Vol. 4, No. 4, Abstract W4135 (2002)

Investigation Of Hydration Properties Of Lyophilised Nasal Formulations Purpose. Assessment of hydration and adhesion properties of lyophilised, bioadhesive nasal insert formulations. Methods. 1. Inserts were weighed, placed on a simulated nasal mucosa with limited water availability (agar), removed after a defined time, AAPSPharmSci Vol. 4, No. 4, Abstract W4140 (2002)

Determination Of Softgel Shell/fill Formulation Interactions Using Texture Analysis
Purpose. To identify potential softgel shell/fill formulation interactions by texture analysis. Methods. The following studies were conducted to investigate the migration of components in a softgel formulation: (1) The effect of
AAPSPharmSci Vol. 4, No. 4, Abstract W4196 (2002)

Physical Characterisation Of Hydro-alcoholic Cellulose Ether Gels
Purpose. This study examined the effect of model co-solvents, ethanol, propylene glycol and glycerol on the mechanical/rheological properties of hydroxyethylcellulose (HEC) gel systems. Methods. Gels were manufactured by dissolving HEC (1-5%w/w) in
AAPSPharmSci Vol. 4, No. 4, Abstract W5172 (2002)

Physical Evaluation Of Medicinal Nail Lacquers Using A Texture Analyzer
Purpose. There are no quantitative evaluation tools available to assess the medicinal nail lacquer at this time. Adhesion properties of any nail lacquer are not only critical in screening various formulations but also useful in selecting an ideal
AAPSPharmSci Vol. 4, No. 4, Abstract R6249 (2002)

Stability Analysis Of Granulated Metronidazole And Tetracycline Hcl By Hplc

Purpose. To evaluate the stabilities of combined granulation of metronidazole and tetracycline HCl. Methods. Granules of metronidazole and tetracycline HCl were made using wet granulation method by adding 5% polyvinylpyrrolidone (Plasdone K-25, PVP)

AAPSPharmSci Vol. 4, No. 4, Abstract W4384 (2002)



Design Of Novel N-propynyl Analogues Of ß-phenylethylidenehydrazine With Potential Monoamine Oxidase And ?-aminobutyric Acid Transferase (gaba-t) Inhibitory Activity

Purpose. Design, preparation and pharmacological evaluation of a group of phenyl substituted N-monopropynyl-&[beta]-phenylethylidenehydrazines and N,N´-dipropynyl-&[beta]-phenylethylidenehydrazines as inhibitors of MAO. These compounds were designed

AAPSPharmSci Vol. 4, No. 4, Abstract M1202 (2002)



Development Of Controlled Release Hydrophilic Matrix Tablets For Topical Colonic Delivery Of 5-aminosalicylic Acid

Purpose. To develop pectin based matrix tablets for controlled and local colonic delivery of 5-aminosalicylic acid (5-ASA) taking biopharmaceutical aspects into consideration. Methods. Two preliminary formulations were developed. In formulation

AAPSPharmSci Vol. 4, No. 4, Abstract W4161 (2002)



Novel Design Of A Monolithic Oral Controlled-release Delivery Formulation For Novasoy® Soy Isoflavone Concentrate

Purpose. To design a novel monolithic, solid oral dosage form capable of displaying improved 12- and 24-hour sustained release in vitro dissolution profiles of Novasoy® soy isoflavone concentrate (40%). Methods. Three formulations were developed to

AAPSPharmSci Vol. 4, No. 4, Abstract W4192 (2002)



Novel Design Of A Robust And Rugged Oral Monolithic Controlled Release Delivery System For Tramadol Hydrochloride.

Purpose. The purpose of this study was to design a robust and rugged monolithic, solid oral dosage forms capable of displaying 12- and 24-hour near zero-order in vitro dissolution profiles of tramadol hydrochloride in a novel self correcting matrix

AAPSPharmSci Vol. 4, No. 4, Abstract W4194 (2002)



In Vivo – In Vitro Correlation (ivivc) Of A Novel Monolithic Controlled Release Dosage Form

Purpose. To establish an in vivo – in vitro correlation for a novel monolithic controlled release readily manufacturable dosage form capable of displaying 12- and 24-hour near zero-order release of a BCS Class I compound. Methods. Three formulations

AAPSPharmSci Vol. 4, No. 4, Abstract W4203 (2002)



In-situ Solubilization Of Class Ii Drugs During The Hydrosol-gelation Phase In The Presence Of Amphoteric Amino Acids, Polysaccharides, And Polymers: A Novel Approach In Controlled Release Drug Delivery

IN-SITU SOLUBILIZATION OF CLASS II DRUGS DURING THE HYDROSOL-GELATION PHASE IN THE PRESENCE OF AMPHOTERIC AMINO ACIDS, POLYSACCHARIDES, AND POLYMERS: A NOVEL APPROACH IN CONTROLLED RELEASE DRUG DELIVERY REZA FASSIHI1, THOMAS DURIG1 AND STEVE TURNER

AAPSPharmSci Vol. 4, No. 4, Abstract W4208 (2002)



A Novel In Situ Solubilization For A ‘dissolution Rate Limited’ Drug Within The Hydrophilic Matrix For Controlled Release Delivery: Ondansetron Hydrochloride

Purpose. To develop and evaluate the release characteristics of Ondansetron HCl from hydrophilic based matrices using ionizable and nonionizable substances as solubilization and gelation modifiers within the swollen system. Methods. Hydrophilic

AAPSPharmSci Vol. 4, No. 4, Abstract W4148 (2002)



Design And Development Of A Controlled Release Formulation For "dissolution-rate Limited" Dimenhydrinate Via In-situ Interactions Of Charged Substances And Polymers

Purpose. To develop and evaluate a monolithic controlled release tablet formulation for dimenhydrinate (diphenhydramine: 8-chlorotheophylline; 1:1), as a cost-effective antiemetic dosage form. Methods. In this study, different controlled release

AAPSPharmSci Vol. 4, No. 4, Abstract W4115 (2002)

The use of Texture Analysis in the physical characterisation of sputum from cystic fibrosis patients
Joanne Barr,Susan A. Barker,Stuart Elborn.
Queen's University Belfast, Belfast, United Kingdom, Belfast City Hospital, Belfast, United Kingdom.

Purpose. To assess the use of Texture Analysis in the physical characterisation of sputum from cystic fibrosis (CF) patients. Methods. Sputum samples were voluntarily produced by five CF in-patients in Belfast City Hospital during their normal physiotherapy sessions. Samples were refrigerated immediately after expectoration until use and tested, unaltered, within 24 hours of production. A Stable Microsystems Texture Analyser TA.XT2 was used to test the samples in the "Adhesion" mode. The effect of treatment with the aerosolised mucolytic, rhDNase, on sputum properties was assessed in four additional patients. Five repeats were made for each measurement. Results. The "adhesiveness" of the sample is measured by the force required to detach a probe from the sample and the "cohesiveness" of the sample is measured by the distance travelled before separation of the probe and the sample. A correlation was observed between the adhesion force, the distance travelled and the condition of the sputum. For example, patient 2 produced thin but smooth sputum, which showed an adhesion force of 0.70 ± 0.05 g and a travel of 16.8 ± 7.6 mm. Sputum from patient 5 was very thick and difficult to manipulate and showed an adhesion force of 1.42 ± 0.07 g and a travel of 53.4 ± 4.6 mm. Following treatment with rhDNAse, two patients showed statistically significant (p<0.05) decreases in both parameters, but, unexpectedly, two patients exhibited statistically significant increases in these parameters. Conclusions. These results have shown that it is possible that the TA.TX2 may be developed to give a "numerical" description of the state of the sputum from CF patients, allowing assessment of disease progression and effectiveness of clinical therapy. Additionally, the data have shown that the effect of aerosolised rhDNase is not predictable.

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Application of a Dual Crosslinking Reaction for Development of a Multiple-Unit Binary Polymeric System Designed for Constant Drug Release Rate
Viness Pillay,1Nivriti Hurbans,2Cassim M. Dangor,2Reza Fassihi.3
1University of the Witwatersrand, Johannesburg, South Africa, 2University of Durban-Westville, Durban, South Africa, 3Temple University, Philadelphia, USA.

Purpose. To evaluate the physicochemical properties of a novel crosslinked cellulose acetate hydrogen phthalate-sodium alginate (CAHPSA) pellet system developed for linear drug release. Methods. A two-step crosslinking reaction was employed by titrating a diclophenac sodium-loaded CAHPSA suspension into acetic acid followed by curing in aqueous calcium chloride to produce 5 formulations having 97.45%, 97.24%, 95.34%, 75.48% and 71.11% (F1, F2, F3, F4, F5) drug encapsulation efficiencies. Curing conditions were optimized using the Central Composite Design (Design-Expert 6.0.3). Dissolution and matrix erosion were evaluated by the USP-24 rotating paddle method (phosphate buffer pH 6.8). Release kinetics was modeled with Power Law variants by the Guassian-Newton approach (WinNonlin 3.1). Matrix swelling was assessed by changes in sphere volume. Rupture and resilience tests were performed on dry and hydrated pellets using 50 and 95% strain (Texture Analyzer, Texture Technologies, NY). Results. Based on pellet sphericity, dissolution rate (T50%) and drug encapsulation, optimal curing conditions included 24 hours in 15% acetic acid and 2% calcium chloride solutions followed by air-drying at 21°C. Drug release suppression was observed as encapsulation decreased (T50%: F1 and F5 = 2.5 and 5 hours). Modeling indicated that lower encapsulation provided ideal linear kinetics (r2 for F5>0.98). Matrix swelling was significantly reduced at lower encapsulation (p<0.05) (diametral increase after 2 hours: 1.25-fold for F5 versus 3-fold for F3). Resilience plateaued at »10% after 1.5 hours of hydration while rupture testing revealed greater matrix plasticity at lower drug encapsulation (work of rupture: F4=1.68J, F5=1.1J). Due to plasticity, F5 showed greater erosion (88.27%) after 8 hours as opposed to 65% for F1. Conclusions. Matrix swelling, erosion, texture and drug release potential were significantly influenced by drug encapsulation. This may be due to changes in matrix water distribution pattern as a result of its varying affinity for drug and polymer molecules.

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Effects Of Excipients On Adhesion Properties Of Transdermal Pressure Sensitive Adhesives
Hock S. Tan, Suresh Borsadia.
Lavipharm Laboratories Inc., East Windsor, NJ, USA.

Purpose. To study the effects of pharmaceutical excipients on adhesion properties of acrylic pressure sensitive adhesives (PSAs) for transdermal systems. Methods. The adhesives studied were two transdermal acrylic PSAs, one with carboxylic (-COOH) functionality (TA-COOH), and another with hydroxyl (-OH) functionality (TA-OH). Three commonly used pharmaceutical excipients, polyvinylpyrrolidones Kollidon 30 (K30) and Kollidon 90F (K-90), and a copolymer of vinylpyrrolidone and vinyl acetate Kollidon VA 64 (KVA-64), were incorporated into the PSAs to effect adhesion properties. Adhesive formulations were coated on polyethylene film and dried according to conventional transdermal patch preparation procedure. Peel adhesion and shear resistance were evaluated using standard PSA test methods, and tack was measured using Texture Analyzer. Results. PSA properties of TA-COOH were significantly affected by addition of the excipients. In general, excipients caused increase in cohesion in the order of K-90 > K-30 > KVA-64 > no excipients, and decrease in peel in the order of no excipients > K-30 > K-90 > KVA-64. Tack was little affected. For TA-OH, the excipients significantly reduced the peel adhesion in the order no excipients > KVA-64 > K-90 > K-30. Tack and shear of TA-OH were not significantly affected by addition of K-30, K-90 and KVA-64. Conclusion. This study indicated that TA-COOH may be crosslinked with the vinylpyrrolidone polymers/copolymer, which resulted in an increase in cohesive strength of the adhesive, and decrease in adhesion. Adhesion of TA-OH was reduced by the excipients, while cohesion changed little.

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Inhibition of rupture of pellets containing disintegrant and PEG
Bee Koen K. Low,1Alex B. Mullen,2Howard N. Stevens.2
1University Of Strathclyde, Glasgow, United Kingdom, 2University of Strathclyde, Glasgow, United Kingdom.

Purpose. To investigate the influence of Polyethylene Glycol 3350 (PEG) on inhibition of rupture of a pellet formulation containing a disintegrant (LH-21). Methods. Core pellets (65% low-substituted hydroxypropylcellulose (LH-21), 25% PEG and 10% acetaminophen) were prepared by melt granulation, size fractionation and warm spheronisation (Model 120 Spheroniser, Caleva) then coated with ethyl cellulose (EC) (3% w/v in acetone/isopropyl alcohol 50/50) using fluid bed (Wurster) technology. The rate of release of acetaminophen from pellets (150mg) was determined (USP XXIII dissolution apparatus 2, 37°C, 50 rpm) in distilled water. The swelling force of model LH-21 tablets (120mg, hardness 6-8kp) was measured in aqueous PEG solutions (10-70% w/v) using a Texture Analyser (Stable Microsystems TA-TX2) in HDLL mode (force relaxation) and in dextrose solutions of the same concentration. The swelling of other model tablets containing LH-21 and PEG in various ratios was similarly examined in water. Results. The drug dissolution profile showed that pellets with thin EC coats (<4.4% w/w) ruptured rapidly, while those coated with 5-8.4% w/w ruptured progressively, but at higher EC levels (>10% w/w) drug was released by diffusion through the coat without evidence of pellet rupture. Results obtained from the Texture Analyser on the model tablets showed that LH-21 swelling force reduced as PEG concentration increased above 10% w/v and also at dextrose concentrations above 40% w/v. Similarly, the swelling of tablets containing different ratios of LH-21 and PEG, when measured in water showed that increasing PEG content was found to inhibit the swelling of the tablet. Conclusions. These studies suggest that PEG is an inappropriate excipient when combined with LH-21 to produce a pulsatile release system relying on swelling of disintegrant to rupture the pellet coat. Competition for free water reduces the swelling capacity of LH-21.

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Bioadhesive and Chemical Properties of Hydroxypropyl Cellulose Hot-Melt Extruded Films Containing Nystatin and Clotrimazole
Michael A. Repka,1,2Suneela Prodduturi.1
1The University of Mississippi, University, MS, USA, 2National Center for Natural Products Research, University, MS, USA.

Purpose. To investigate the bioadhesive and chemical properties of hydroxypropyl cellulose (HPC) films containing two model antifungal drugs and various polymer additives. Methods. HPC films containing nystatin 10% or clotrimazole 10%, polyethylene oxide and/or hydroxypropyl methylcellulose (HPMC) and a polycarbophil 5% (Noveon® AA-1) were prepared by hot-melt extrusion utilizing a Killion extruder (Model #KLB-100). A TA.XT2i Texture Analyzer equipped with Texture ExpertÔ software was used for bioadhesion testing to produce force-deflection profiles. Data from these profiles were utilized to determine peak adhesive force (PAF), elongation at adhesive failure (EAF), and area under the curve (AUC) for the films tested. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms were recorded to determine drug solubility and water content within the extruded films, in addition to glass transition temperatures (Tg). High-pressure liquid chromatography (HPLC) was utilized to determine the formulations’ pre and post extrusion drug content. Dissolution profiles were also determined using USP apparatus 5. Results. Differences were observed in PAF and AUC between the films containing the two model drugs. The nystatin-containing films exhibited a higher PAF and greater AUC than the films incorporated with clotrimazole (276.4 vs. 249.1 g and 87.1 vs. 63.7 g×mm, respectively). In addition, DSC thermograms indicated that within all of the HPC extruded film formulations containing nystatin, the model drug was in a solid solution state. Conclusions. Force-deflection profiles obtained from these experiments indicate that PAF and AUC are not only a function of the polymer additives within the HPC extruded films, but a function of the model drug incorporated as well. Also, nystatin was determined to be completely solubilized within the HPC matrix films. These experimental results are applicable to the development of bioadhesive antifungal delivery systems.

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Physical and Chemical Properties of Transmucosal Hydroxypropyl Cellulose and Hydroxypropyl Methylcellulose Films Containing Lidocaine
Michael A. Repka,1,2Manish Munjal,1Kavitha Gutta.1
1The University of Mississippi, University, MS, USA, 2National Center for Natural Products Research, University, MS, USA.

Purpose. To compare the physical and chemical properties of lidocaine-incorporated transmucosal bioadhesive films containing hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) polymer matrix systems. Methods. Film formulations containing HPC and HPC:HPMC polymer matrices incorporated with the model drug lidocaine 10% and the bioadhesive Noveon® AA-1 5% were prepared by cast molding and hot-melt extrusion utilizing a Killion extruder (Model KLB-100). Bioadhesion tests were performed using a TA.XT2i Texture Analyzer equipped with Texture ExpertÔ software. In addition, dissolution profiles were obtained using USP apparatus 5 and post-production drug content was determined by high-pressure liquid chromatography (HPLC). Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms were also recorded. Results. The film formulations incorporated with the HPC-only polymer matrix exhibited a higher peak adhesive force (PAF) and area under the curve value (AUC) compared to the formulations containing HPC:HPMC (80:20) (188.2 vs. 125.3 g and 84.3 vs. 28.4 g×mm, respectively). In addition, the film formulations containing a HPC:HPMC (80:20) matrix exhibited slower drug release than the films containing the HPC-only matrix. Conclusions. Bioadhesion tests and dissolution profiles from these experiments indicate that PAF, AUC and drug release rates from the films are a function of the films’ polymer matrix. The results of our studies with HPC/HPMC films are relevant to the ongoing development of transmucosal drug delivery systems.

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Metered dose Dermal Drug Delivery: PandermalTM Tablets
Sharon Mills, John Staniforth, Mike Tobyn.
Vectura Limited, Bath, United Kingdom.

Purpose. The purpose of the PandermalTM unit dose tablet is to provide an accurately metered dose of topical drug to the skin whilst avoiding unnecessary use of preservatives. Although previous attempts have been made to standardise the dosage of topical medications (e.g. the finger tip unit) they have comparatively poor reproducibility. Methods. Drug was dispersed or dissolved in a molten wax material (which is currently used in a wide range of topical and other presentations) at a relatively low temperature with additional materials to aid solubility and penetration of the drug, as appropriate. The resultant formulation was solidified and dry granulated under ambient conditions or at slightly lowered temperatures. The granules were tableted using conventional technology although where necessary low temperature tableting and Zirconia tooling was employed. Weight uniformity and failure behaviour (using the Stable Micro Systems Texture Analyser, TAXT2i) was evaluated. Results. Initial studies using the Texture analyser indicated that a number of physical characteristics influenced their suitability as both topical bases and as materials suitable for tableting. Incorporation of drugs into the matrix was efficient and initial studies indicated chemical and physical compatibility. Production of tablets and granules at low temperature was carried out and proof of principle was demonstrated. Weight and content uniformities were equivalent to, or better than, pharmacopeial specifications for tablets for oral use. Hardnesses at low temperature were in a narrow range but, as designed, there was considerable softening at room and skin temperatures. Inclusion of agents to modify skinfeel and spreadability improved these parameters without impacting on the ability to tablet at room or low temperatures. Conclusions. Tableting of systems intended for topical use was successfully demonstrated. The tablets produced had good weight and content uniformity and were readily dispersed on contact with the skin.

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Mechanical and drug release properties of freeze-dried chitosan-alginate sponges
Asad Abu Khalil, Hui L. Lai, Duncan Craig.
School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.

Purpose: To investigate the effect of admixing alginate with chitosan on the structural, mechanical and release properties of the resultant sponges after freeze-drying, with a view to examining the potential use of these materials as wound dressings. Methods: Chitosan (Fluka) was mixed with different proportions of alginate (Fluka) to yield 1% w/v solutions and 10% w/v paracetamol added then freeze-dried to prepare the sponges. Dissolution studies (Caleva 8ST, G.B.Caleva Ltd) were used to evaluate the release of paracetamol. Scanning electron microscopy was performed using a Jeol 6400 SEM. Mechanical properties were tested using a Texture Analyser (TA-XT2, Stable Micro Systems). Results: The sponges were found to control the release of paracetamol as compared to a standard tablet formulation, with the most effective retardation being found for chitosan alone (50% release over 680 minutes). SEM studies indicated that the sponges composed of alginate or chitosan alone had well defined fibrillar structures, while the mixed systems had irregular morphologies. This was reflected by the mechanical assessment whereby the force required to rupture the sponges on extension was found to be 12.2N and 9.1N for the chitosan and alginate alone but only a maximum of 5.0N for the mixed systems. The force required to compress the sponge by 4mm was also measured, with the chitosan sponges again showing the greatest strength (5.6N) and with all the sponges containing alginate having values <1N. Conclusions: Chitosan and alginate were found to form effective sponges for the controlled release of paracetamol. It was anticipated that the mixed systems may show favourable properties compared to the polysaccharides alone. However, it was noted that chitosan alone showed the most favourable properties in terms of release mechanical strength and morphological regularity.

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Fast- and High-Swelling Polymeric Excipient Derived from Poly(ethylene oxide) and Cationic Derivatives
Y. L. Fan, R. L. Schmitt, D. H. Donabedian, C. Chien.
The Dow Chemical Company, Bound Brook, NJ, USA.

Purpose. Poly(ethylene oxide) (I) is used as a polymeric excipient in many controlled release oral dosage formulations. This investigation is to examine some unusual swelling characteristics of blends made from high m. wt. (I) and a class of cationic cellulosic polymers (II). Methods. Polymer blends were prepared by mixing (I) with different loading of (II) and formulated into tablets by compression molding. The swelling rate and degree of swelling of the tablets in 0.1 N HCl were measured at 37°C using a Texture Analyzer Model TA-X2i and supplemented with a precision ruler. The dissolution profiles of drugs released from these tablets were determined using a Disteck Dissolution System Model 2100B according to the USP procedure. Results. Tablets formulated with 80/20 weight ratio of (I)/(II) exhibited a faster rate and higher degree of swelling than (I) alone. Tablet containing more than 50/50 of (II) disintegrated too ready during the test. Tablets prepared using blends containing 7 MM m. wt. (I) and different m. wt. (II) but of identical cationic charge density, the degree of swelling increased with increasing m. wt. of (II). With identical m. wt. but different charge densities, the degree of swelling of the tablets increased with increasing charge density in (II). The dissolution profiles of Riboflavin or caffeine from tablets formulated with these polymer blends follow those of tablets formulated with the high m. wt. (I) only. In both cases, the release rates follow fairly closely to a zero-order profile.

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Response Surface Analysis For Waxes In Semi-Solid Products
Sauwaluxana Tongaree, Frank Nowaczyk, Jr..
Whitehall-Robins Global PR&D, Richmond, VA, USA.

Purpose. To examine the effects of variable wax content and composition on the physical properties (penetration, melting point and spreadability) of semi-solid products by Response Surface Analysis. Methods. JMP statistical software was used to generate a Box-Behnken design. Three factors evaluated were ozokerite (0-5% w/w), candelilla wax (0-10% w/w) and beeswax (0-5% w/w). Responses were hardness (as related to penetration value), melting point and spreadability (inversely related to applied peak force and peak area). An Instron 5500R, Fisher-John Melting Point Apparatus, and TA-XT2i texture analyzer were used to determine hardness, melting point and spreadability of each sample, respectively. Results. Candelilla (quadratic term) was found to be the most significant factor for peak force, peak area and penetration (p < 0.001). It significantly increased hardness and reduced spreadability of the products. Ozokerite in combination with beeswax or candelilla was also found to increase hardness, peak area and peak force. Beeswax (quadratic term) and a cross product between ozokerite and candelilla were found to have a statistically significant effect on sample hardness. All terms were significant at p <0.05. For melting point, ozokerite and candelilla were found to be significant factors in the model. Both increased melting points of samples as their levels increased. In addition a cross product between ozokerite, candelilla and beeswax was found to significantly improve the model for melting point. Spreadability of the product (peak force or peak area) was found to have good correlation with penetration. Conclusions. Response surface analysis provides useful information for choosing combinations of waxes within the region of experimentation that optimize the end product desired attributes.

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Textural and torque-based procedure to determine the degree of powder mixing and lubrication efficiency for scale up tableting
Charumathy V. Navaneethan,1Shahrzad Missaghi,1Rahmat Talukder,1Marc Johnson,2Reza Fassihi.1
1Temple University School of Pharmacy, Philadelphia, PA, USA, 2Texture Technologies Corp., Scarsdale, NY, USA.

Purpose. To understand the behavior of the powder under different conditions of shear dynamic before and after lubrication and its performance on a high-speed rotary press. Methods. Three drug powders, metronidazole, bismuth citrate and tetracycline were chosen as model drugs representing non-cohesive and cohesive properties. Each powder was individually granulated with 5% PVP in deionized water and passed through an oscillating granulator and dried. The granules were blended with 2% Ac-Di-Sol using a V-blender. One portion from each granulation was lubricated with 0.5% magnesium stearate for 5 minutes. The powder characterization was performed on the plain powders, non-lubricated and lubricated granules using the texture analyzer, TA.XT2i equipped with ManUmit Powder Rheometer. Tablets were made using a high-speed rotary press, Stokes B2. Results. The profiles of interaction of shear stress, strain and density during the shear test indicate that powder compresses, expands and shears many times in a test cycle. Test profiles also clearly reveal existence of significant differences between cohesive and cohesion less powders. In all cases lubrication normalized the overall interactive nature of the powder according to the shear dynamic condition and reduced the frictional effect by approximately 65%. Acceptable tablets in respect of physical characteristics, weight and content uniformity manufactured on a rotary press were obtained when lubricated powders had comparable shear profiles. Conclusions. Behavior of the powders during handling and flow conditions is of paramount importance. Adoption of shear test conditions to various powders demonstrated that standard test procedures for evaluation of various interactive forces during powder handling should be applied in order to have reliable test results. It is also shown that when different powders have comparable shear profiles their flow behavior is predictable during scale up operation.

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Investigation of bioadhesive properties of linear and cross-linked sodium hyaluronate gels
Helene Hägerström, Katarina Edsman.
Department of Pharmacy, Uppsala University, Uppsala, Sweden.

Purpose. To investigate the bioadhesive properties of gels prepared from linear and cross-linked sodium hyaluronate. Methods. The bioadhesive properties of linear and cross-linked sodium hyaluronate and cross-linked polyacrylic acid (Carbopol 934P) gel preparations were assessed using a tensile strength method, utilizing a TA.HD texture analyzer and porcine nasal mucosa. The contact time was 2 min and the withdrawal speed was 0.1 mm/s. As an indicator of bioadhesive strength and for comparison of the different gel preparations the work of adhesion was used, recorded as the area under the force-distance curve. Rheological characterization of the gels was performed with a Bohlin VOR rheometer. Results. The cross-linked polyacrylic acid gels were used as a reference, since they are generally considered to have good bioadhesive properties. For these gels the measured work of adhesion was dependent on the polymer concentration. In the concentration range 0.5-2% (w/w) the 2% gel showed the largest work of adhesion (0.068±0.014 mJ, mean±95% C.I.). For the preparations based on the linear sodium hyaluronate (0.5-2%, w/w) we observed a similar increase of the work of adhesion with increasing concentration. However, the 1.5% preparation exhibited a higher work of adhesion (0.185±0.016 mJ) than the 2% preparation (0.128±0.022 mJ). Overall, the values obtained were higher than for the polyacrylic acid gels. Moreover, three cross-linked sodium hyaluronate gels were investigated, all with a concentration of 2% (w/w) but differing in gel particle size. The preparations with the largest gel particles exhibited a work of adhesion that was not significantly different from that of the 2% linear sodium hyaluronate, whereas the work obtained for the preparation with the smallest particle size was approximately the same as for the 2% cross-linked polyacrylic acid. Conclusions. Linear and cross-linked sodium hyaluronate gels appear to have equally strong or stronger bioadhesive properties than cross-linked polyacrylic acid gels.

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Effect of actives on the properties of a quick dissolving intraoral film
Li-Lan H. Chen,1Li Tao,2William Pfister.3
1Lavipharm Laboratories, Inc., East Windsor, USA, 2BMS, New Brunswick, USA, 3Newmed, Robbinsville, USA.

Purpose: To develop a novel intraoral delivery system and investigate the effects of actives on film properties and release profiles. Methods: Water-soluble cellulose ether was used as a film former. The quick dissolving intraoral delivery system was formed by a solvent casting method. The mechanical properties were measured using an Instron instrument according to ASTM D882. A Texture Analyzer was used to measure film bioadhesion (dry tack and wet tack). The disintegration and dissolving times of films was performed in a dissolution apparatus. Paddle over disc method was used to measure the dissolution of films with actives. Results: Hydrophilic actives with a relatively high loading dose were found to increase the dry tack of the films. Hydrophobic actives had no effect on the dry tack; however, they reduced the wet tack of the films and also made them stiffer than placebo films by increasing the modulus of the films. On the other hand, hydrophilic actives enhanced the wet tack of the films and softened the films by decreasing the modulus of the films. The tensile strength of the films with actives was observed to be lower than placebo films. However, the elongation was found to be the same for both placebo films and films with actives. The disintegration and dissolving time were prolonged for the films with hydrophobic actives. Hydrophilic drugs were released immediately and the release was complete within two minutes, unlike films with hydrophobic actives that had one and half minutes of lag time. Conclusions: The physicochemical properties and the loading dose of actives significantly affected the performance of the quick dissolving intraoral film. Therefore, addition of excipients with different physicochemical properties other than the active and selection of proper molecular weight polymers are necessary to obtain a quick dissolving intraoral film with desired properties.

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Quantification of adhesion of lyophilised HPMC formulations using a novel dynamic adhesion test
Fiona McInnes,1A. J. Baillie,2H. N. Stevens.1
1University of Strathclyde, Glasgow, United Kingdom, 2Propharma, Glasgow, United Kingdom.

Purpose. Development of an in vitro adhesion assay for lyophilised formulations intended for nasal administration, modelling hydration on the nasal mucosa and the subsequent sliding force due to mucocilliary clearance. Methods. Discs lyophilised from 0.6ml of test material were applied near the top of a 25cm x 25cm agar plate (synthetic mucosal surface) with a force of 5g for 1 minute. The plate was tilted to an 80° angle and the formulations allowed to slide down the agar surface. The distance travelled by the sliding discs was recorded at regular intervals. The inverse of the slope obtained by plotting the square root of distance against time provided a quantitative measure of adhesion. Lyophilised discs of test material were also examined using a Texture Analyser (TA.XT2) in adhesion mode. Results. TA data were variable and could not discriminate among different formulations. Results obtained from the newly developed method were more reproducible and detected significant differences among many of the formulations tested. Increasing K4MP content in the lyophilised disc significantly (p<0.05) decreased rate of travel down the plate (an increase in adhesion) with values (1/slope) obtained for lyophilised 1%, 2% and 3% K4MP formulations (in 1% mannitol) being 32.65, 45.69 and 61.16 respectively. Increasing mannitol, sucrose or lactose content in lyophilised 2% K4MP formulations did not significantly affect adhesion. Increasing PVP 10,000 content in lyophilised 2% K4MP formulations decreased adhesion. Values (1/slope) obtained for 1%, 2% and 3% PVP 10,000 were 46.20, 45.84 and 40.94 respectively. PVP 44,000 and 700,000 gave similar results. Conclusions. This novel method for the characterisation of lyophilised nasal inserts provides reliable results and more accurately represents the hydration and subsequent adhesion of such formulations encountered in the nasal cavity. Results suggest the HPMC component of these formulations positively influences adhesion while sugars and PVP content does not.

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Role of Lubrication Efficiency on Release Reproducibility From Dry Blend and Wet Granulated Low Drug Load Tablets.
Rahmat M. Talukder,1Reza Fassihi,1Marc I. Johnson.2
1Temple University School of Pharmacy, Philadelphia, PA, USA, 2Texture Technologies Corp., Hamilton, MA, USA.

Purpose. To demonstrate the influence of dry blending and wet granulation on powder flow, lubrication efficiency, content uniformity, weight variation, manufacturability, and dissolution characteristics of low drug load (<1.5% active drug) tablets manufactured on a high-speed rotary press. Methods. Riboflavin, microcrystalline cellulose (MCC), Ac-Di-Sol, and magnesium stearate were used in both dry blend and granules. Wet granulation was done by using PVP K-25 and an oscillating granulator. Powder rheology was characterized by using Texture Analyserâ TA-XT2i equipped with a ManUnit. Content uniformity was assessed spectrophotometrically. Tablet dissolution was carried out in accordance with USP 23. Results. The relative standard deviations (RSD) of tablet weight variations and content uniformity in dry blend and wet granulation methods were found to be 1.74% and 1.46%, and 2.94% and 2.22% respectively. The release profiles for dry blended tablets in 40 minutes showed 73.2% drug release with 14.3% RSD whereas the wet granulation resulted in 78.9% drug release with 1.5 RSD. Flow, torque, and rheological properties were studied to determine the relationship between circumferential velocity of the blade, consolidation stress, and displacement. The total area under the curves (force-displacement g.cm) for MCC alone, dry blend after lubrication, granules before and after lubrication were 1186.8, 809, 706.8, and 466.9 respectively. Conclusions. Weight variation and content uniformity were within the acceptable limit in both processes. However, the dissolution and rheological profiles exhibited differences. When wet granulation is done, the interparticulate friction is reduced and reproducibility in release profiles is enhanced (RSD 1.5). The lubrication efficiency also appears to be approximately 40% higher with granulation process. In addition to favorable physical properties, higher lubrication efficiency may impact the release reproducibility by providing more uniform and consistent substrate for wetting and solubilization.

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Development and Evaluation of a Miniaturized Procedure for Determining the Indices of Tableting Performance
Kimberly A. Lamey,1,2Joseph B. Schwartz,2Francis X. Muller.1
1GlaxoSmithKline, King of Prussia, PA, USA, 2University of the Sciences in Philadelphia, Philadelphia, PA, USA.

Purpose. Comparison between standard compaction simulator methods and a miniaturized procedure for determination of the Indices of Tableting Performance was executed to compare their ability to predict a material’s compaction properties. Methods. Tableting properties of single excipients, direct compression or dry granulation placebo formulations and drug substances, varying widely in ductile to brittle characteristics, were determined by using a compaction simulator equipped with 10 mm round, flat-faced tooling with or without a 1mm core rod and a Texture Analyser TA-XT2I. Materials were compacted to an in-die thickness of 3.0 + 0.05 mm, and Indices of Tableting Performance, indentation hardness, Young’s modulus, yield pressure, strain rate sensitivity (SRS) and tensile strength were calculated based upon previously reported equations. Results. Young’s modulus values were in agreement with ductile to brittle material characteristics as 2 to 81 GPa, respectively. Correlation between bonding index and Young’s modulus appeared to follow a polynomial model with a decrease from the uppermost ductile region to the lowermost brittle fracture region. Reported indentation hardness values appeared to be greater for more brittle materials (i.e. 340 - 470 MPa), and correlation between indentation hardness and yield pressure supported equivalent resolution of a material’s resistance to local deformation. A lower brittle fracture index (BFI) correlated with a higher out-of-die tensile strength (e.g. BFI = 0.09 and TS = 7.4 MPa) while elastic strain and time-dependent material properties were linked by determination of strain index (SI) and SRS. Materials possessing higher SRS normally exhibited higher values for calculated SI (e.g. SRS = 47% and SI = 1.9). Conclusions. Statistical analysis of standard compaction simulator values determined using both in-die and out-of-die calculation procedures versus the Indices of Tableting Performance values generated using miniaturized procedures resulted in significant correlation between the two procedures, thus providing an alternate means for characterizing compaction properties.

Instrumental Evaluation of Sensory Attributes of Lip Balm Formulations
S. Tongaree, E. M. Morefield
Whitehall-Robins Healthcare: Richmond, VA United States

Purpose. To characterize and differentiate between lip balm formulations using a texture analyzer. Methods. A TA-XT2i texture analyzer was used for penetration testing for several lip balm formulas. The penetration test was performed using a 2-mm diameter punch probe driven into the samples at a speed of 0.5 mm/sec for a distance of 4.0 mm. The degree of internal variations was used as a measure of the “graininess” of the sample. Adhesive peak force and work of adhesion were used to explain the oiliness, greasiness and stickiness of the formulas. Sensory data were obtained from 10-14 staff members trained in the evaluation techniques of the Spectrum Skinfeel Descriptive Method. Samples were presented randomly with all panelists seeing all samples for two repetitions. Results. From the texture analyzerresults, sample #510 was found to exhibit the least smoothness, greatest hardness, lowest adhesive peak force and work of adhesion. Sensory evaluation results also indicated that sample #510 was significantly different from the other samples. It showed more dryness/roughness, the least ease of application, slipperiness, oiliness and the highest waxiness and greasiness. Sample #710 had the least internal variations and was perceived by the end user as being the smoothest product with the lease residue. Conclusions. Differences among lip balm formulas can be detected by texture analysis. Although no absolute relationship was found between both methods, texture analysisis a useful tool for initial screening of lip balm products prior to sensory evaluation, and may be useful for quality control.

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Characterization of in vitro Disintegration of Fast Dissolving Tablets Using a Texture Analyzer and Correlation with in vivo Disintegration Time and Mouthfeel
K. Abu-Izza1, V. Li1, J. M. Edwards2, G. Petherick2, P. Thompson2
1Whitehall-Robins: Richmond, VA United States ; 2Whitehall International: Havant, United Kingdom

Purpose. To characterize the in vitro disintegration behavior of fast dissolving tablets, and correlate the results with in vivo disintegration time and mouthfeel attributes obtained from a sensory study. Methods. In vitro disintegration test was performed on 4 formulations (A, B, C and D) using a texture analyzer. The displacement versus time and force versus time profiles were recorded. The time for disintegration onset (T1) and total disintegration time (T2) were calculated. The same formulations were evaluated for in vivo disintegration time and mouthfeel in a sensory study that included 34 subjects. Results. Good correlation was found between T2 and in vivo disintegration times of formulations B, C and D. For formulation A, which was the most gritty, in vivo disintegration time was significantly longer than the in vitro time due to undissolved particles. By analyzing the force vs. time and displacement vs. time profiles simultaneously, in vitro failure behaviors that correlate with different mouthfeels (gritty, chalky, smooth) could be identified. A grittiness index was calculated from the AUC of the force-time curve during disintegration. The calculated index correlated with the in vivo grittiness score.

Conclusions. The texture analyzer is a useful tool for comparing disintegration times of fast dissolving tablets and for in vitro characterization of different mouthfeels.
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Different Methods to Characterize Rheological Changes in "Lanae Alcoholes Unguentum cum Aqua" (DAB 1999)
B. Moeller1, B. W. Mueller2
1Christian Albrecht University Kiel: Kiel, Germany ; 2Christian Albrecht University Kiel: Kiel, Germany

Purpose. The aim of this study was to investigate different methods to characterize rheological changes in unguentum alcoholum lanae aquosum (Eucerin) when using different types of petrolatum and paraffins. Methods. Six different Eucerin batches with three different petrolatum types and two different paraffins (all materials provided by Merkur, Hamburg, Germany) were prepared. The rheological behaviour was determined by using a rheometer MCR 200 (PHYSICA, Stuttgart, Germany). Furthermore, the oil factor was measured (performed by using a method according to the DAB 1999). In addition, a three-months-stability-testing at a temperature range between –18 °C and +40 °C ( temperature cycling) of those six different ointments was carried out. The texture profile analysis has been investigated by using a texture analyser TA-XT 2 with a conus of defined dimensions. Results.It can be shown that different types of petrolatum effect the texture profile and the rheological behaviour of the ointments - directly after production and after storage -, whereas it was not possible to distinguish these preparations by the oil factor. All measured rheograms exhibit the characteristics of typical petrolatum flow curves. Discussion and Conclusion. Although the oil factor is commonly used to distinguish different petrolatum types, it becomes difficult to use this parameter to characterize different types of ointments containing petrolatum. The other methods mentioned above seem to be more capable regarding this problem, because not only petrolatum but also ointments can be distinguished. In addition, the results of the study demonstrate that the determination of the oil factor is less stringent than texture analysis and rheological measurements. The latter two methods could be used to control the required consistency of a product and to follow changes associated with emulsions under various conditions.

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Bonding Index for Commercially Available Excipients Utilizing a Miniaturized Approach
K. A. Lamey1,2, J. B. Schwartz2, F. X. Muller1, R. Wigent2, P. Angiolillo2
1SmithKline Beecham: King of Prussia, PA United States ; 2University of the Sciences in Philadelphia: Philadelphia, PA United States

PURPOSE. To develop equations and a small-scale method for determination of the bonding index for commonly utilized excipients. METHODS. Tablets are compressed via an instrumented Manesty Betapress equipped with 2 sets of 10mm Round Flat-Faced tooling. Tablet weight ranges from 340 mg to 510 mg based upon the true density of the material. Tensile Strength and Indentation Hardness (n=10) are determined after physical testing with the Texture Analyser TA-XT2I. Indentation diameter (d) is measured with an optical microscope equipped with a graduated ocular under light incidence or calculated via a derived equation. Physical testing is also performed with an analytical balance and digital caliper. RESULTS. In pre-formulation studies, drug substance is often available in small quantities making it difficult to determine bonding indices utilizing conventional techniques. Thus, equations and miniaturized methods were derived to determine the bonding index of commonly utilized excipients to segue into predictable methods for pre-formulation evaluation. Results below indicate that the equations and methods capture the intrinsic compaction properties of materials varying in the ductile to brittle transition with Avicel PH-102 > Fast-Flo Lactose 316 > Emcompress.

CONCLUSIONS. To date, large scale models have been utilized to determine the bonding indices of pharmaceutical excipients and drug substances; hence, equations were derived and miniaturized methods developed for indentation hardness and tensile strength. This approach may be capable of predicting potential compression issues encountered with a pharmaceutical material during pre-formulation evaluation.

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Mechanical Properties of Hydrogel Co-Polymers, Designed as Medical Device Coatings
D. S. Jones, L. M. Byers, C. G. Adair, S. P. Gorman
The Queen's University of Belfast: Belfast, United Kingdom

Purpose. To characterise the mechanical and thermorheological properties of co-polymers of hydroxyethlmethacrylate (HEMA) and methacrylic acid (MA), designed for use as medical device coatings. Methods. Polymers and co-polymers were synthesised by free radical polymerisation at 60°C for 18 h. using AIBN (0.5% w/w). Tensile analysis of the hydrated polymers was performed using a SMS texture analyser in tensile mode (cross-head speed 1mm s-1 ). From the resultant stress-strain plot the ultimate tensile strength (UTS) and % elongation (% E) were determined. The thermorheological properties (storage modulus G’, glass transition temperature Tg and the loss tangent) were determined by DTMA, using a fixed frequency (1Hz) and a heating rate of 2°C min-1. Results. As the % of MA was increased, the UTS, % E, G’ (@37°C) increased. However, no significant alterations in the mechanical damping parameter (at 37°C) were observed. Furthermore, the Tg of the co-polymers was significantly greater than that of pHEMA and sequentialy increased as the % of MA was increased. Following hydration, Tg of all materials dropped to circa 0°C, due to plasticisation with water.

Conclusion. This study has shown that the mechanical properties of pHEMA, a problem that restricts its clinical usage, may be improved by co-polymerisation with MA. These materials are currently undergoing clinical assessment as medical device coatings.

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Rheological and Textural Properties of Poly(acrylic acid) Organogels
D. S. Jones, B. C. O. Muldoon, A. D. Woolfson
The Queen's University of Belfast: Belfast, United Kingdom

Purpose. To examine the rheological properties of poly(acrylic acid) (PAA) organogels, formulated using a range of polyhydroxy and polyethoxy solvents. Methods. Formulations were prepared by dissolving PAA in either propylene glycol (PG), ethylene glycol (EG), glycerol (Gly) or poly(ethylene glycols) (PEG) with stirring. The rheological properties of the gels were evaluated using a parallel plate rheometer in oscillation mode at 20±0.1°C (4cm plate diameter, 1mm plate gap) and over a defined frequency range (0.01-1.0Hz). Texture profile analysis was performed by twice depressing an analytical probe into each sample at a defined rate (10 mm s-1) and to a defined depth (15mm), allowing 15s between successive depressions. Results. The storage modulus (G'), and tan d increased as frequency was increased, whereas dynamic viscosity (h') decreased. Increasing concentration of PAA significantly increased G', G'', h', hardness and compressibility and decreased tan d. Furthermore, the non-solvent type statistically influenced the textural and viscoelastic properties, with glycerol exhibiting the most pronounced effects. These observations confirm differences in hydrogen bonding as a primary mechanism for changes in rheological properties. The effects of glycerol on the rheological/textural properties may be accredited to the tri-hydroxy functionality and formation of a hydrogen bonded 3-dimensional network with PAA.

Conclusion. This study has described the effects of non-aqueous solvents on the rheological properties of PAA. The substantially elastic nature of these systems offers possibilities for their use as drug delivery vehicles.

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Rheological Stability of Hydroxyethylcellulose Gels in the Presence of Redox Agents
D. S. Jones, B. C. O. Muldoon, A. D. Woolfson
The Queen's University of Belfast: Belfast, United Kingdom

Purpose. To examine the effects of a model redox agent (iron 2 oxide) on the rheological stability of hydroxyethylcellulose (HEC) gels. Methods. Gels were prepared by dissolving HEC (2, 3, 4% w/w) in distilled water. When required, iron (0.1% w/w, as the oxide) was added and mixed until homogeneous. Samples were either analysed one week following preparation or stored for one month at 37ºC and 0ºC prior to analysis. Texture profile analysis was performed by twice depressing an analytical probe into each sample at a defined rate (10 mm s-1) and to a defined depth (15mm), allowing a 15s delay between successive depressions. Flow rheograms were performed at 20±0.1ºC using a parallel plate (4cm) rheometer (plate gap 1.0mm). The zero rate viscosity of each formulation was derived form the upward flow curves using the Cross Model. Results. The presence of FeO in freshly-prepared HEC gels had no significant effects on textural or rheological properties. Conversely, in stored samples FeO significantly compromised these properties, particularly at higher concentrations of HEC. As HEC is a cellulose derivative, the observed effects of FeO may be attributed to an oxidative depolymerisation occurring via hydrogen abstraction mediated by iron. Table 1. Textural properties of HEC (4% w/w) gels containing 0.1% iron, as the oxide Formulation

Conclusion. This study has demonstrated that the rheological performance of HEC gels may be altered by the presence of redox agents. As many drugs and excipients possess this ability, these observations may have further implications for formulation design of HEC gel systems.

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Rheological and Mucoadhesive Properties of Metronidazole-Containing Semi-Solids
D. S. Jones, M. S. Lawlor, A. D. Woolfson
The Queen's University of Belfast: Belfast, United Kingdom

Purpose. To characterise the rheological and mucoadhesive properties of metronidazole-containing semi-solids designed for the treatment of periodontal disease. Methods. Formulations were manufactured containing polymethylvinylether-maleic anhydride (PVMEMA; 15% w/w) polyvinylpyrrolidone (PVP; 0-9% w/w) and metronidazole (Met; 0-25% w/w). Oscillatory rheometry was performed at 20.0±0.1°C over a frequency range of 0.01-1.0Hz using a 6cm dia. parallel plate geometry (1mm plate gap) and a defined strain (0.04). Mucoadhesion was characterised using a SMS texture analyser in tensile mode and was measured as the force to break the bond between the formulation and a hydrated mucin disc.Results. Increased conc. of PVP and/or Met significantly increased the storage modulus (G’) and mucoadhesion yet decreased the loss tangent. The effects of PVP on the rheological properties of PVMEMA were synergistic, indicative of potential complex formation. The rheological effects of Met may be accredited to increased semi-solid behaviour associated with increased conc. of dispersed solid drug particles. The maximum mucoadhesive force was observed with the formulation containing 15% PVMEMA/9% PVP/25% Met (0.7±0.0N).

Conclusion. In this study, structured semi-solids were formulated that possessed wide ranges of elasticity and mucoadhesive properties. In light of the clinical importance of these properties, formulations containing 15% PVMEMA and 9% PVP would be expected to be clinically useful.

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Guar Based Matrix Tablets: Effect of Excipients on Gel Properties and Drug Release
T. Durig, R. Fassihi
Temple University: Philadelphia, PA United States

Purpose. To investigate the effect of excipients on drug release and swelling and erosion behavior of guar based controlled release matrix tablets. Methods. Verapamil HCL, guar (Supercol G3) and the appropriate additive (18% of final mix) were combined by wet granulation, then vacuum dried and compressed. The additives included lactose, sucrose, microcrystalline cellulose (MCC), dicalcium phosphate (DCP), NaCl, CaCl2, glycine and citric acid. Tablet dissolution, erosion and water uptake studies were carried out using a modified USP 23 Apparatus 2 method in pH 1.5 buffer. In addition the gel strength of uniaxially swollen tablets was measured (TA.XT2. Texture Analyzer). Results. Near linear drug release over 24 hours was obtained from formulations containing NaCl and glycine. The contribution of Fickian release to overall drug release was lowest for these formulations (rate constants 16.9 and 13.4 %h-0.43 respectively) and was correlated with greater gel strength and lower water uptake (350% vs. 400% for control (no additive) in 6 hours). This may be due to “salting out” of the polymer and reduced solubility of the drug in the presence of highly soluble electrolytes. DCP and CaCl2 yielded profiles that were similar to the control formulation (Fickian rate constants~19-20.5 %h-0.43). For soluble sugars (lactose and sucrose) the Fickian contribution to overall drug release was large (rate const. 21.5 and 23.17 %h-0.43 respectively). Consequently curved profiles with rapid initial release were obtained. Water uptake was greatest for these additives (450% in 6 hours). The lowest water uptake and matrix erosion was observed for MCC. Release from this formulation was predominantely Fickian. This may be due to hydrogen bonding between the cis-OH groups of guar and the hydrated surfaces of the insoluble cellulose particles. Conclusion. The physico-chemical nature of added excipients significantly influences the release kinetics from guar based formulations. Ionic, watersoluble materials (NaCl, glycine) have the ability to limit the initial rapid diffusion of drug and to sustain near linear release over 24 hours.

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Comparing the Dynamics of Matrix Densification Associated with HPMC and PEO Systems
V. Pillay1, B. Johnson2, R. Fassihi1
1Temple University: Philadelphia, PA United States ; 2Texture Technologies: Scarsdale, NY United States

Purpose. To probe the mechanisms associated with matrix stiffening/ densification via textural analysis as a consequence of in situ electrolyte interactions within hydroxypropylmethylcellulose (HPMC) and polyethylene oxide (PEO) matrices in relation to its role in controlling the release of moderate to highly soluble bioactives such as verapamil, diltiazem and metoprolol. Methods. Monolithic formulations containing polymer, drug and/ or electrolytes were manufactured on a Carver Press with flat-faced punches at a compression of 500 lbs. Dissolution rate studies and erosion dynamics were evaluated using the USP 24 Apparatus 2 in USP-recommended buffers (pH1.5, 900mL, 37±0.1°C, 50 rpm, N=3). Drug analysis was performed by UV spectroscopy. Phase tracking of hydrated polymer matrices were achieved via textural profiling (Texture Analyzer, Stable Micro Systems) in order to establish glassy/ rubbery phase transitions associated with medium infiltration and electrolyte dissociation. In addition, a novel approach of coupled electrolyte conductivity and textural analyses were performed within the swelling microenvironment of the matrix in order to assess diffusional dynamics. Results. The modified rates of HPMC and PEO matrix swelling as a consequence of the disposition of selected electrolytes utilized for the induction of zero order drug release rates for a range of bioactives from simple monolithic designs are presented. Through tracking boundary movements, the process of continuously shifting peripheral matrix densification toward matrix core was observed in a manner dependent on electrolyte content, polymer type and hydration time. Matrix erosion for HPMC and PEO controls (i.e. without electrolyte) follow linear dissolution kinetics (r2>0.97), while formulations with electrolyte characteristically undergo a square-root of time decline in weight. The swelling potential of the electrolyte-containing matrices, reflected significant suppression during the first 2 hours of exposure to medium due to polymer dehydration and salting-out phenomenon. Simultaneous measurements in textural transitions and electrolyte conductivity showed that PEO has a higher affinity for water molecules as opposed to HPMC. In addition, conductivity was largely dependent on molecular weight and size of electrolytic ions. Conclusions. Electrolyte-inclusion significantly alters the hydration dynamics of HPMC and PEO.
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