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Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009)
Umang Shah
Page 1 of 9
Posters (AAPS Annual Meeting...
Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009)
Umang Shah
Page 2 of 9
Conclusion
Accurate filling ...
Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009)
Umang Shah
Page 3 of 9
analyzer). A first order rat...
Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009)
Umang Shah
Page 4 of 9
Methods
Targeting Korsch XL-...
Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009)
Umang Shah
Page 5 of 9
Concentrated solutions of HP...
Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009)
Umang Shah
Page 6 of 9
Three placebo granulations (...
Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009)
Umang Shah
Page 7 of 9
Methods
To demonstrate feasi...
Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009)
Umang Shah
Page 8 of 9
Results: Particle size analy...
Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009)
Umang Shah
Page 9 of 9
Methods
Physical properties ...
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Umang Shah Poster Presentations AAPS 1994-2009 (2)

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Umang Shah Poster Presentations AAPS 1994-2009 (2)

  1. 1. Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009) Umang Shah Page 1 of 9 Posters (AAPS Annual Meeting)  Dynamic Vapor Sorption as a PAT Tool to Assess Tablet Coating (2009) Authors: J. Vieta, D. Dubash, A. R. Garcia, D. Burnett, B. Clark, U. Shah Purpose Employ Dynamic Vapor Sorption (DVS-Intrinsic, Surface Measurement Systems) as a PAT tool to assess the moisture protection imparted by various tablet film coatings at various process parameters examined. Methods Opadry AMB and Opadry II (Colorcon, Inc) coating materials provide moisture barrier characteristics to coated tablets and can hence protect moisture sensitive drug substance. The film-coating process requires identification and control of critical process parameters to ensure uniform coating and hence reliable barrier to moisture penetration. Four separate coating trials were conducted at Colorcon, West Point, PA to assess the effect of various coating parameters (wet vs. dry process conditions, with and without sub-coats) on the quality of the resultant film-coat of placebo tablets. The atomizing and pattern air pressure, pan speed, and airflow were the critical process parameters examined. Dynamic Vapor Sorption (DVS) and Scanning Electron Microscopy (SEM) were employed to assess quality of the coated tablets. The water uptake and kinetics were measured at 25 °C / 60% RH using the DVS. Water vapor diffusion coefficients were calculated using Fick’s Law and coating thickness determined using SEM imaging. Coated tablets were also tested for weight gain and water content after exposing them to 40°C / 75% RH for about 2 months. Results Isotherms of trial and control tablets using Opadry AMB and II were generated and compared. The moisture content and weight gain of the coated tablets was also compared to the DVS isotherms. Based on the isotherms generated tablets coated with Opadry II demonstrated better moisture protection over the tablets coated with Opadry AMB. Change in percentage of mass for Opadry AMB coated tablets and core tablets were similar but significantly higher compared to Opadry II coated tablet. Conclusion DVS as a PAT tool demonstrates that Opadry II provides better moisture protection over Opadry AMB (coating material employed for currently developed product). This study suggests that DVS can be successfully employed to assess design space and critical process parameters during development of coating parameters to ensure moisture protection.  Evaluation of Capsule Filling Capability using a Quantos Automated Powder Dosator (2009) Authors: A. Melendez, U. Shah Purpose The objective of this study was to evaluate Quantos Powder Dosator to assess capability of filling various levels of API directly into hard gelatin capsules. Capsule sizes 0, 1, 2 and 3 were employed since they are commonly employed for clinical trials. The Quantos dosing system from Mettler-Toledo is an automatic balance capable of delivering micro doses of powders. It contains an intelligent dosing head that includes a radio frequency identification chip (RFID) that controls dosing and stores data. The dosing heads are disposable and the equipment continuously mixes the powder with its unique stirring mechanism while providing an antistatic mechanism during filling. Adapters to fill hard shell capsules were developed for this system to allow filling single capsules. Methods For each excipient/filler evaluated a total of fifty empty capsules were weighed, filled by Quantos and then re- weighed to determine amount delivered. Limit of variation was set at NMT 5%. Target dispensed amounts were 100 mg, 10 mg and 1mg. Results Density, flow, particle size, shape and distribution for six fillers examined were correlated to filling capability. Results were analyzed by performing multiple comparison statistical analysis. Filling 100 mg and 10 mg was feasible within a tolerance of 2.5% within 5 decimal places of accuracy. The RSD was less than 2% for 100 mg and between 1-7% for 10 mg. The variation for filling 1 mg was relatively higher at greater than 20% and environmental controls are required.
  2. 2. Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009) Umang Shah Page 2 of 9 Conclusion Accurate filling of 10 mg and 100 mg into capsule size “0” using free flowing powders is feasible. It is inferred that filling sizes 1 and 2 will be difficult since the dosator beak is wider than the capsule body. Filling size 3 capsules is difficult and time consuming unless a guide is used that positions the capsule accurately and consistently every time. Filling of cohesive powders like colloidal silicon dioxide and magnesium stearate was difficult to attain. Currently this device can be used for filling capsule size zero and bigger. For filling smaller capsule sizes, the dosator beak has to be modified in order to ensure dispensed powder falls into the capsule body  Comparison of Various Dispersion Techniques to Assess Particle Size, Distribution and Shape of a Micronized, Highly Cohesive Powder using Malvern G3 Image Analyzer (2009) Authors: M. Scoggins, G. Sando, U. Shah Purpose This study compares particle size, shape and distribution data using several dispersion conditions including dispersion pressure, foil thickness, dispersion apparatus, and evaporative techniques for testing of a micronized, highly cohesive drug substance manufactured at different sites. Methods Several dispersion methods were assessed to achieve reliable and reproducible data using image analysis and compared with optical microscopy and laser light scattering results. Parameters studied included dispersion pressure and foil thickness in the Sample Dispersion Unit (SDU), utilization of Malvern’s Sample Preparation Device (SPD), and an evaporative technique. Two different lots of the drug substance were examined. Results With 6 μm foils and the SDU at various dispersion pressures, CE Diameter ranged from 10.6 μm – 14.0 μm. Shape factors of circularity and aspect ratio increased while elongation decreased as dispersion pressure increased. When using 25 μm foils, CE Diameter ranged from 12.0 μm – 13.1 μm. Data were filtered using the convexity shape factor to exclude agglomerates from the data analysis that did not disperse during sample preparation. When employing the SPD, CE Diameter data was less reproducible. Data ranged from 6.4 μm – 11.7 μm. For the evaporative method, CE Diameter ranged from 7.2 μm – 18.2 μm. Shape factors were consistent with SDU (varying elongated particles reported) possibly indicating a larger number of agglomerates still remaining in the dispersion. Conclusion The samples were found to be equivalent when comparing data generated for the Malvern Morphologi G3 image analyzer at the two sites. While the data did not completely agree with those reported in COA, this is to be expected when employing orthogonal techniques. Overall size and shape data trending shows consistent measurements across dispersion parameters employed with the SDU. Utilization of the three dispersion techniques studied demonstrate that method development is critical when determining techniques and parameters necessary to generate reproducible and accurate data. The ability to selectively filter data is a useful tool to ensure analyses is performed on primary particles while excluding agglomerated material not adequately separated during sample preparation which can easily be assessed using an image analyzer such as the Malvern G3.  Fluid Bed Granulation: Identifying Critical Process Parameters and Developing Design Space (2009) Authors: S. Sathigari, S. Wilson, H. Vera, M. Scoggins, A. Melendez, B. Clark, U. Shah Purpose The purpose of this study was to identify critical granulation parameters by utilizing in-process moisture analyzer and to develop a design space for the critical process parameters identified. Methods The granulation experiments were performed in a pilot-scale fluid bed granulator (Fluid Air, Inc) for a modified release formulation. A body centered cubic statistical design of experiment (DoE) was employed using statistical software (Statgraphics Centurion XV) to evaluate the critical process parameters. Process Analytical Technology (PAT) tool such as the Near Infrared Spectroscopy (NIR) technique (FOSS XDS Interactance optic probe) was employed to monitor the real time moisture and to create a design space for the moisture trajectory in the process. For NIR model development, NIR spectrum and loss on drying data were collected every 2 minutes for three batches. The NIR model was validated by tracking the granule moisture level during each of the DoE trial. Granules were evaluated for bulk and tap densities, flow characteristics and particle size (sieve analysis and digital image
  3. 3. Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009) Umang Shah Page 3 of 9 analyzer). A first order rate equation was assumed for the granule growth kinetics during the initial phase of the granulation. Results For the formulation employed, the Pareto charts reveal that, the spray rate and air flow are the critical process parameters that affect granule characteristics. An initial high spray rate with less air flow is needed to achieve the desired bulk density and flow for the granules. The NIR model was able to determine moisture content accurately at low moisture levels but failed at higher moisture levels. Composite model using the NIR + 20% model was able to measure the moisture trajectory at higher moisture levels. A Design Space for the process with the required end point granule characteristics was constructed based on the moisture trajectories of DoE runs. Conclusion An on-line and off-line PAT tool and DoE were successfully employed to determine fluid-bed critical process parameters and also develop design-space for the modified release formulation.  A Novel Approach to Address Segregation Challenges in Directly Compressible Formulations (2008) Authors: M. Scoggins and U. Shah Purpose Assess formation of ordered dry blend utilizing morphological variations in crospovidone, NF (varying intraparticular porosities) to overcome segregation potential and tablet potency trending of a DC formulation Methods Twenty two experiments including process and formulation variables were examined to overcome segregation potential of a directly compressible low dose combination formulation. Variables employed included process variations (high vs. low shear mixing to prevent surface charge formation), pre-blending of the active with select excipients, roller compaction, and type and grades of excipients employed to preferentially bind the active to form an ordered blend. Blends were subjected to sieving to assess binding potential. The difference in drug substance (DS) on the screen and the pan represented the bound fraction (binding potential) for a given variable examined. Results The studies conducted suggest that the lower strength DS (DS 1) possesses strong demixing/segregation potential. Blend discharge, down stream material handling, and flow from the hopper (funnel flow) during tableting indicated a serious concern for the lower strength DS due to potency trending observed during tableting. No statistical differences in binding potential were observed when low vs. high shear mixing was examined. Roller compaction of active blends provided marginal improvements in binding potential. Blends made using Polyplasdone XL vs.Polyplasdone XL 10 (possessing varying particle morphologies, i.e. intraparticular porosity and surface roughness) demonstrated superior binding potential which resisted flow and material handling induced segregation (p =0.05) suggesting utilization of appropriate particle morphology to prevent blend segregation typically observed in DC formulations. Conclusion Blend segregation in DC formulations can occur during blending, discharge, and down stream material handling. In addition, segregation can also occur in a tablet hopper which exhibits funnel flow. A novel and simple approach to overcome this phenomenon was to employ excipients possessing high surface roughness and intraparticular porosity to trap the active, thus forming an ordered blend which eliminated potency trending on pilot scale batches. (Patent Filed)  Application of Tangential and Vertical Velocities as Scale-up Parameters for Directly Compressible Tablets – 2 case studies (2008) Authors: R. Conjeevaram, D. Dubash, A. Melendez, R. Malladi, B. Clark, U. Shah Purpose Evaluation of tangential velocity (TV) and vertical velocity (VV) as a scalability tool on instrumented tablet presses using placebo blends of two different formulations.
  4. 4. Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009) Umang Shah Page 4 of 9 Methods Targeting Korsch XL-200 (25-stations), as a model production press, corresponding tangential (TV) and vertical velocities (VV) for the Piccola (Lab scale, 10-stations) and Manesty (Pilot scale, 16 stations) presses were computed using the SMI Director Software. Experiments were conducted using 0.25” (placebo 1) and 0.3125” (placebo 2), round, standard concave, domed tooling. Tablets resulting from each study were tested for weight, thickness, hardness and diameter. Strain rate (SR) sensitivity and compression force (CF) plots were generated to assess scalability. Results 1. CF studies revealed that the Piccola is scalable to the Manesty Beta Press based on both vertical and tangential velocities. 2. SR studies also showed that the formulae are scalable from Piccola to Manesty, and further gives a very good indication of it’s scalability to the Korsch XL200 press up to a speed of 75 RPM (TV of 1119mm/sec.). Conclusion For the two formulations tested, data suggests that either TV or VV can be used as a scalability tool.  Enhancing Bioavailability via Nanoparticle Formation Using a Modular High-Pressure System (HPS) (2006) Authors: C. Vemavarapu and U. Shah Purpose Dimensional control of particulate solids is a critical control parameter for pharmacokinetics and bioavailability for poorly soluble compounds. A novel modular high-pressure system was evaluated to form and stabilize nanoparticles in the 200-400 nm range followed by conversion to redispersible solid dosage form. The objective was to increase the AUC and Cmax while lowering the tmax. Methods Coarse suspension was processed using various HPS cell configurations. Characterization of nano particles was performed using orthogonal characterization approaches. Zeta potential measurements were employed to determine the type and concentration of stabilizers required to stabilize the nanoparticles. Wet granulation or spray drying was employed to form redispersible powder followed by addition of extra-granular excipients to form solid dosage form. Results By employing complementary particle size characterization techniques it was determined that stable submicron particles having narrow particle size distribution (mean volume diameter < 200 nm) could be formed using the HPS by varying the equipment geometry and process duration at concentrations as high as 60% w/w. Increasing the drug concentration enhanced particle size reduction due to particle-particle impact, attrition and shear. A 4-10 folds increase in AUC, 7-12 folds increase in Cmax, 5-8 fold increase in initial rate and 1-1.5 decrease in tmax was observed for the nanoformulations over the micronized dosage form. Conclusion While current industry practices for mechanical size reduction in the nanometer range is dominated by piston gap homogenizing and media milling, a new alternative is the modular high-pressure system (HPS). Unlike piston gap homogenization (primary force - cavitation and secondary forces - impact or shear) or wet milling (primary forces - impactand shear), the modular high-pressure system is capable of individually controlling impact, cavitation, shear and flow (turbulent or laminar) to accommodate different solid fracture characteristics to achieve nanoparticles in the 200-400 nm range.  Rheology of Concentrated Aqueous Solutions of Hydroxypropyl Cellulose Utilized as Binders for Wet Granulation (2006) Authors: C. Vemavarapu, W. M. Polak, M. Lodaya, and M. J. Mollan and U. Shah Purpose Rheological characterization of concentrated aqueous solutions of hydroxypropyl cellulose (HPC) to aid in reproducible manufacturing and metering of the binder solutions. Methods
  5. 5. Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009) Umang Shah Page 5 of 9 Concentrated solutions of HPC (Klucel-EXF, MW=80,000, Hercules) were made by dissolving the polymer in water using a rotor-stator type mixer. Freshly made solutions appeared milky white due to the air entrapped during mixing. Complete deaeration and hydration turned these gels into optically clear solutions. This process took anywhere between 6 hours (10 %) to 4 days (30% w/w gel). Rheological characterization of these gels was performed at 25°C using a controlled stress rheometer (AR2000, TA Instruments). Results Flow analysis of these gels indicated that all concentrations (10 to 30, % w/w) were equally shear-thinning, with the rateindex of Cross-model averaging at 1. Zero-shear viscosity values were determined in flow-mode using Cross- model and were further verified from the corresponding dynamic viscosities in oscillatory-mode at low frequencies. An exponential relation was established (Viscosity = 61.028*e^0.2396*Weight-percent) between the zero-shear viscosity of the hydrogels and their concentration. The effect of thermal stress on the viscosity of HPC gels at 25°C was examined. An Arrhenius-dependent increase in instantaneous viscosities was seen in gels exposed to 35-65°C. The viscosities, however, reverted back to normal values over time. Viscoelastic analysis at 1Hz revealed that at all concentrations, G”>>G’, indicating a moderate elastic contribution. The crossover frequency for these gels was found to be >40Hz. Oscillatory time sweep studies indicated that the gels build structure over time under moderate stress, with corresponding increase in both the storage and loss moduli. Conclusion Concentrated solutions of HPC exhibit shear-thinning behavior. Moderate elastic contribution makes pumping and high-shear mixing of the gels possible even at very high concentrations. The effect of temperature needs to be closely examined to make reproducible gels from both the hot and cold methods.  Biopharmaceutical Properties that Impact the Successful Prediction of In Vivo Performance of Oral Dosage Forms (2006) Authors: S. Sutton, M. amEnde, L. Appel, R. Beihn, J. Bennett, T. Boyden, B. Caldwell, M. Chidlaw, J. Cook, J. Crison, L. Evans, R. Gaskin, S. Herbig, S. LeMott, P. Luner, J. McCarthy, L. Miller, A. Mutchler, K. Norton, E. Novak, P. Patel, M. Puz, B. Ramos, J. Ringling, K. Sagawa, J. Scavone, U. Shah, R. Shanker, S. Smith, D. Supplee, A. Thombre, D. West, S. Zugel Abstract: The formulation scientist needs to have confidence that the formulation will perform as expected in the clinic. When in vitro dissolution methods no longer provide that confidence, preclinical surrogates have been met with varying degrees of successful prediction of formulation performance in the clinic. A review of Pfizer experience during recent history provided the substrate for this analysis. Formulation types examined were controlled release (CR), immediate release (IR), enteric, eroding, non-eroding, tablets, multiparticulates, suspensions, etc. Actives included representation from all four Biopharmaceutic Classification Schema (BCS). Clinical performance of IR formulations containing highly soluble (HS) and highly permeable (HP) compounds was always predicted from dog studies. Most formulations of LS/HP-LP compounds utilized various solubility enabling strategies that effectively made the compounds behave as if they were HS/HP-LP. In vitro – in vivo relationships (IVIVr) for formulations of HS/LP compounds were established in the dog, and these predicted their performance in humans. For example, Cmax in dogs & humans roughly correlated (r2=0.85) for six solubility enabling formulations (SEDDS, oil –incapsule, etc). For truly LS compounds, several dog models were presented and compared to gamma scintigraphic/PK studies. In conclusion, with the species differences in GI physiology kept in mind, and the study carefully planned, the dog predicted the clinical performance of the formulation when the formulation controlled the rate limiting process in the kinetics of dissolution and absorption.  Evaluation of a Universal Mill for Continuous Particle Size Reduction of Granulations Possessing Different Fracture Characteristics (2005) Authors: Umang Shah and Vanessa Askins Purpose For a continuous processing system, size reduction is an essential component after wet granulation drying and it is important that the rate of milling equals the rate of drying. To maintain a high-throughput while accommodating a wide range of granule characteristics a Universal Mill (UPZ 60) equipped with a range of easily interchangeable size reduction elements was evaluated. The possibilities of the mill configuration include a pin mill or a beater mill with beater disc, swing or plate beater unit with various grinding tracks or sieve insert options. Methods
  6. 6. Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009) Umang Shah Page 6 of 9 Three placebo granulations (microcrystalline cellulose, lactose, and dicalcium phosphate) having different fracture characteristics were evaluated. A pin mill configuration was initially assessed followed by the swing beater disc configuration. Process parameters such as the peripheral disc rate, feed rate, differential temperature between the inlet and outlet (grinding chamber temperature build-up), motor amperage and nitrogen gas flow-rate were monitored. Both types of mill configurations could process the granulations at average output rates of 50 kg/h or higher to achieve the desired particle size distribution. During extended runs the pin mill configuration yielded closer to desired particle size distribution (PSD) with some material build-up indicating potential problems in continuous operation. No appreciable build-up was observed using the swing beater disc configuration however the PSD was coarser than desired. This is potentially due to lower energy imparted by the beater disc versus the pin mill configuration. Based on these studies certain process modifications are recommended for milling plastically deforming materials when using the pin mill configuration. Conclusions These studies indicate that for a continuous operation the Universal Mill offers several advantages including ease of changeover to the several different types of milling elements while accommodating a wide variety of materials to achieve higher throughput rates at the target particle size and distribution.  Use of Multiple Loss-In-Weight Feeders for Wet Granulations Prepared by Twin-Screw Mixer. (2005) Authors: U. Shah, W. Polak, V. Askins Purpose Benefits of continuous wet granulation include reduced capital investment, flexibility of batch size and ease of automation. However one of the challenges of continuous processing is accurate feeding of poorly flowing powder components. The objective of this study was to evaluate the effect of multiple feeders on the content uniformity (CU) of granulations prepared using a continuous twin-screw extruder (TSE). Methods Twin-screw LWF are typically employed for powders that exhibit poor flow properties. LWF consists of a feeding module, feeder hopper, weighing device and a control system. LWF estimates the mass-flow rate by dividing the weight reduction by the time interval. To compensate for the difference between the set-point and the current measured value of mass flow, motor rotation speed is continuously modified. A series of experiments were conducted to evaluate the effect of multiple LWF on the content uniformity (CU) of granulations prepared using the continuous twin-screw extruder. Results Two feeders, one containing the API and the other a preblend of excipients, were employed. The total dry feed rate was maintained at 10 lb/hr and the API feed rate was varied between 0.05 to 6.0 lb/hr. Within the feed range of API (0.05-6.0 lb/hr), nine experiments were conducted. The corresponding API levels varied between 0.5%- 60%. Six samples were collected for each experiment at different time points. Assay of the tray-dried granulation indicated that at the 0.5 lb/hr (5% API level) and higher feed rates the average CU was 98% to 111% (%RSD: 0.45-1.43), however variability was higher at feed rates below 0.5 lb/hr (average CU: 85%-129%, %RSD: 10.38-19.33). Conclusion Preliminary results indicate the feasibility of metering individual components directly into the continuous TSE thus eliminating the need for a preblend step. Modification of feeder screw, hopper and agitators may be necessary to achieve the desired CU for very low feed rates.  Utilization of a Modified Twin-Screw Mixer to Develop a High-Strength Protease Inhibitor Tablet Dosage Form. (2004) Authors: Umang Shah and Matthew Mollan Purpose In an effort to reduce patient pill burden, development of a higher strength tablet dosage form was evaluated by employing a modified a twin-screw mixer (TSM). The use of a modular twin-screw high shear wet granulator is a new technology that works on first in, first out principle and is capable of providing a higher and more uniform level of shear and mixing. The objective was to demonstrate feasibility of utilization of a modified TSM to achieve higher drug loading, acceptable tablet characteristics and meeting bioequivalence requirements of the lower strength multi dose product.
  7. 7. Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009) Umang Shah Page 7 of 9 Methods To demonstrate feasibility of employing a co-rotating and inter-meshing TSM several equipment and process modifications were implemented. The equipment modifications included employment of side-stuffer, removal of die plate and determination of location/s for the injection of granulating liquid. Additional variables studied included screw element geometry and position; pre blend feed rate, screw rpm and process temperature. The screw elements evaluated included classical mixing (dispersive and distributive), combing and forwarding elements. The side- stuffer was employed to predensify, dearate and pressure feed preblend. The formulation variables evaluated included increasing the active concentration, reducing inter and intra granular excipient levels, varying both the binder level and granulating liquid injection rate and quantity. The impact of these variables was used to assess the final blend and tablet characteristics (density, flow, particle size distribution, tablet weight, hardness, friability, disintegration and dissolution etc). Torque and output rates were also monitored for both the process and formulation variables examined. Tablet dissolution profiles were generated in standard vessels, 50 rpm paddle speed with sampling at 10, 30, 45, 60 and 90-minute time points. Results By employing a modified TSM the tablet weight was decreased by 35% and active concentration increased from 47% to 66%. Placing a zoning element at the exit of the mixer resulted in uniformly sized granulations. Injection of granulating solutions at 2 ports versus 1 port eliminated torque excursions. Screw configuration played a critical role in obtaining high and consistent output. By varying the screw design the output could be varied between 3 kg/hr to 11 kg/hr on the pilot scale equipment. The choice of screw design employed resulted in tablet disintegration ranging between 4-15 minutes and the bulk density varying between 0.35 to 0.60 g/cc (Table I). The amount of energy required to granulate (specific energy) and the residence time was used as criteria for scale-up from 10 kg (pilot scale) to 1000 kg (manufacturing scale) batch size. Experiment Screw Design Screw RPM Bulk Density (g/cc) Torque Output (kg/hr) % Dissolution (Q45) 1 A 250 0.35 6 3.3 79 2 B 230 0.60 5 3.3 77 3 C 300 0.51 5 10.9 74 4 D 275 0.47 4 8.5 80 5 D 350 0.49 15 50 80 Note: Experiments 1-4 are on pilot scale and Exp. 5 on production scale equipment Conclusions: Although the drug substance is spray dried and possesses very low bulk density and where conventional techniques such as high-shear granulation and roller compaction failed, the modified TSM process was able to sufficiently densify the drug substance to achieve the target tablet weight, disintegration and dissolution characteristics and meet the bioequivalence criteria. Since twin-screw parameters that govern scale-up are well understood scale-up from a few kilos to hundreds of kilos can be easily achieved. This novel process provides several advantages such as feasibility of continuous processibility and modularity of the screw design that can address specific requirements of the drug substance. (Reference: WO0189679 A2)  Comparative Study of Bovine vs. Non-Bovine Grades of Magnesium Stearate, NF. (2004) Authors: U. Shah Purpose Factors such as surface area, particle size, hydration/crystal form and mixing time affect the lubricant properties of magnesium stearate. It was observed that addition of vegetable grade magnesium stearate in the absence of colloidal silicon dioxide (glidant) resulted in clump formation in a 42 L bin blender. A factorial design study was conducted to determine functional equivalence between vegetable (VS) and bovine (BS) sources of magnesium stearate. Methods For the study, variables examined were– type of magnesium stearate (BS or VS), blending time (10 min vs 20 min) and method of glidant addition (with or without magnesium stearate). Glidant was added directly to the preblend when not added with magnesium stearate. The response variables studied were tablet hardness, ejection force, disintegration time and friability. Particle size analysis, X-ray diffraction (XRD), DSC, TGA and photomicrography (SEM) were also conducted on both sources of magnesium stearate.
  8. 8. Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009) Umang Shah Page 8 of 9 Results: Particle size analysis indicated that BS has larger particle size. The SEM revealed that the VS particles were more clustered then BS. The surface area of the VS was also determined to be higher than BS. The VS XRD profile appears to have well defined peaks between 21 variables studied indicated no significant functional differences between the sources. Additionally, no clump formation was observed when glidant was not added with magnesium stearate using the 8 qt blender. Conclusions Although differences in particle size and surface area were observed between the two sources, the experimental design did not reveal any functional differences. It is believed that this could be a function of the size and type of blender employed or the characteristics of the formulation examined.  Simethicone Chewable Tablets: Product Development and Process Optimization Using Response Surface Design. (1999) Authors: U Shah and V Dhopeshwarkar Purpose To develop simethicone chewable tablet formulation using Response Surface Design. Methods The highly viscous and sticky nature of simethicone makes it difficult to incorporate into a tablet formulation due to unacceptable blend flow, non blend uniformity, tablet hardness and mouth-feel. Unacceptably low tablet hardness causes breakage of tablets during packaging and on removal from blister pack. A three level and three factor response surface design (33 experiments) was conducted to develop an optimal formulation. Maltodextrin was chosen as an adsorbate for simethicone. Several grades of maltodextrin were evaluated based on surface area, surface morphology and particle size distribution. 3 grades of maltodextrin were chosen for the optimization study. Three variables chosen for the optimization were: base concentration of the adsorbate (35%, 45% and 55%), surface area of the adsorbate (high, medium and low) and duration of high shear mixing (5 minutes, 1 minute and 0 minute). The total blending time (ploughs only/low shear mixing) was kept constant at 5 minutes. Duration of high shear mixing (choppers also) was chosen as a process variable because preliminary studies had indicated that under or over-mixing led to variability in content uniformity or clump formations (requiring an additional step of sizing during manufacture). Dependent variables studied were content uniformity of the blend, hardness, production rate and mouth-feel of the tablets. Results Maltodextrin Surface Area (m2/g) Content Uniformity % Hardness (kP) Tablets/hour M 100 0.25 94.0 ± 7 3.0 (± 1.0) 100,000 M QD 500 0.56 98.5 ± 4 6.0 (± 1.5) 160,000 M QD 510 0.36 97.5 ± 5 6.5 (± 2.5) 145,000 Conditions: 45% maltodextrin and 1-min. high shear mixing Conclusions Based on the results from the response surface design M QD 500 grade maltodextrin was chosen as the adsorbate. The tablet production rate, hardness and mouth-feel were found to be optimal at 1 minute of high shear mixing which also eliminated an extra step of sizing.  Effect of Differences in Porosities between Different Grades and Sources of Crospovidone NF on Disintegrant Functionality (1998) Authors: U Shah and L.L. Augsburger Purpose Since several grades and sources of Crospovidone NF are now available, the first objective was to identify differences in physical properties thought to be related to functionality. The second objective was to develop a Standard Performance Test to determine relationship between any physical differences and disintegrant functionality.
  9. 9. Umang S. Shah Ph.D.; Selected Poster Presentations at AAPS (1994-2009) Umang Shah Page 9 of 9 Methods Physical properties examined were particle size and distribution, surface area, porosity and surface morphology. Disintegration and dissolution on a directly compressible tablet formulation (Active : Hydrochlorothiazide) containing an insoluble filler (Dicalcium Phosphate Dihydrate) were performed using the USP procedure. The three Standard Performance Tests studied were measurement of initial rate as well as final extent of liquid uptake and settling volumes on the pure disintegrants & simultaneous measurement of axial as well as radial disintegrating forces on pure disintegrant compacts. Results Disintegrant Porosity (%) Extent of Liquid Uptake (g) Disintegration Time (s) Dissolution 25 min. (%) Polyplasdone XL 79.9 1.03 480 48.7 Polyplasdone XL-10 64.6 0.79 726 40.2 Kollidon CL 60.3 0.65 900 28.9 Crospovidone M 56.8 0.46 1833 12.8 Conclusions Results suggest that porosity plays an important role in disintegration and dissolution of formulations containing an insoluble filler. Extent of liquid uptake is recommended as a Standard Performance Test to determine functional differences of different sources and grades of Crospovidone NF.  Effect of Scale-Up on Dissolution and Water Uptake Profiles of Propranolol HCl Tablet Formulations. (1995) (unable to locate abstract; file lost)  Evaluation of the Functional Equivalence of Different Sources of Super-Disintegrants in Pharmaceutical Tablets. (1994) (unable to locate abstract; file lost) Link: http://www.aapsj.org/abstracts/am_abstracts2008.asp

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