Investigation of Cellulose Acetate Polymer Viscosity and Coating Solution
`Concentration on Performance of Push-Pull Osmotic Pump (PPOP) Tablets
`
`Lawrence Martin, Hua Deng, Shahrzad Missaghi, Thomas P. Farrell and
`Ali R. Rajabi-Siahboomi
`
`Poster Reprint
`CRS 2012
`
`Abstract Summary
`This study investigated the effect of cellulose acetate (CA) viscosity and coating solution concentration (solids
`content) on the properties of Opadry® CA ready formulated osmotic coating system and performance of push-pull
`osmotic pump (PPOP) tablets. Variations in solids content of the coating solutions significantly impacted solution
`viscosity and film opacity but did not affect drug release profiles. Variations in cellulose acetate viscosity grade did
`not affect the viscosity of the coating solutions or the performance of PPOP tablets.
`
`Introduction
`Cellulose acetate has been commonly used as the water-insoluble, semipermeable membrane (SPM) in osmotic
`dosage development. Polyethylene glycol (PEG) 3350 is the most commonly used plasticizer and/or pore-former in
`SPMs. These two components are typically dissolved in a co-solvent mix of acetone/water and prepared in a range
`of solution concentrations. Varying the relative amounts of CA and PEG in the film coating influences the permeability
`of the film, changing the rate of media ingress into the core and potentially altering drug release rate.1
`This study investigated whether variations in cellulose acetate viscosity or coating solution concentration can influence
`the performance of PPOP tablets, in terms of drug release profiles and coating quality.
`
`Experimental Methods
`Opadry® CA, a ready formulated SPM coating system comprising CA and PEG3350, was used in this study with a
`co-solvent mixture of acetone (90% w/w) and water (10% w/w) for coating solution preparation. An experimental
`design with 2 variables, at 3 levels, for a total of 9 coating trials (Table 1) was used. CA grades with low, medium
`and high range of the product viscosity specification were examined, and coating solutions were prepared at low,
`medium and high solids content. Coating solutions were applied to bilayer tablets containing a low dose (10 mg)
`and practically insoluble model drug. Solution viscosity was measured using a rheometer with concentric cylinder
`geometry (AR-G2, TA Instruments, USA). Pull and push layer formulations (Table 2)2 were produced using a high-
`shear, hydro-alcoholic granulation process (P/VAC-10, Diosna, Germany) (1.5 kg batch size). The granules were
`lubricated and compressed into bilayer tablets using an instrumented rotary press (Piccola, Riva, Argentina) with
`standard round concave tooling (9.5 mm) at the target weight of 330 mg (pull:push layer, ~2:1 w/w). The Opadry
`CA solutions were coated onto the bilayer tablets to a theoretical weight gain of 10% w/w using a 2.5 L side-vented
`coating pan (LDCS, Vector, USA). The coating parameters are listed in Table 3. Coated tablets were dried in a vacuum
`oven at 40°C for 24 hours. A 0.5 mm delivery orifice was laser-drilled (Cobalt 250, InkCupsNow, USA) through the
`film coating on the pull layer side of each PPOP tablet.
`Opadry CA film coating opacity was determined by measuring the contrast ratio of coatings removed from flat-faced
`tablets, on black and white backgrounds using a spectrophotometer (Model 600, Datacolor, USA) at the wavelength
`range of 400 – 700 nm. Dissolution studies were conducted in simulated intestinal fluid (SIF) at pH 7.5 without
`enzymes, using USP Apparatus II with sinkers at 50 rpm. Drug release profiles were measured spectrophotometrically
`(Agilent Technologies, USA) using 10 mm path length quartz flow-through cells. The drug release rate constant k,
`(%/hour) was obtained by calculating the slope of the linear section of the dissolution profiles in the range of 5-80%
`of drug release. The morphology of the SPM was examined using a Hitachi Field Emission Scanning Electron
`Microscopy (FE-SEM) (vs4300, Hitachi High-Tech, Japan).
`
`OPADRY® CA/POLYOX™
`
`-1-
`
`Amerigen Ex. 1039, p. 1
`
`

`
`Table 1.Experimental Design
`
`Variables
`
`CA viscosity (sec.a)
`Solids content (% w/w)
`
`Low
`8.3
`5.5
`
`Level
`Medium
`10.5
`7.0
`
`High
`12.5
`8.5
`
`a Specification: 8.0 s to 13.0 s (ASTM-A falling ball viscosity).
`
`Table 2.Formulation of Pull and Push Layers for PPOP Tablets of Model Drug Y
`
`Pull Layer – Ingredients
`
`Supplier
`
`Drug Y
`Polyethylene oxide (POLYOX™
`WSR N-80)
`Magnesium stearate
`Total
`Push Layer – Ingredients
`
`Polyethylene oxide (POLYOX™
`WSR Coagulant)
`Sodium chloride
`Pigment, red iron oxide
`
`Magnesium stearate
`Total
`
`-
`The Dow Chemical
`Company, USA
`Mallinckrodt, USA
`
`Supplier
`
`The Dow Chemical
`Company, USA
`Mallinckrodt, USA
`Rockwood Pigments,
`Italy
`Mallinckrodt, USA
`
`Quantity
`(%w/w)
`5.6
`93.9
`
`0.5
`100
`Quantity
`(%w/w)
`64.0
`
`35.0
`0.5
`
`0.5
`100
`
`Table 3.Coating Process Parameters
`
`Parameters
`
`Inlet temperature (°C)
`
`Exhaust temperature (°C)
`
`Product temperature (°C)
`Airflow (cfm)
`Fluid delivery rate (g/min)
`Atomizing air pressure (psi)
`Pattern air pressure (psi)
`Pan speed (rpm)
`Batch size (kg)
`
`41 - 43
`
`31 - 32
`
`27 - 28
`80
`28 - 30
`21.0
`7.5
`18
`1.5
`
`OPADRY® CA/POLYOX™
`
`-2-
`
`Amerigen Ex. 1039, p. 2
`
`

`
`Results and Discussion
`Solution Viscosity
`Samples of CA within viscosity specification (low, medium and high) had no significant impact on coating solution
`viscosity (Figure 1) in this study. However, increasing the solution concentration from 5.5 to 8.5% w/w resulted in
`large increases in solution viscosity. Opadry CA coating solutions showed the behavior of Newtonian fluids, where
`the viscosity was generally independent of shear rate.
`
`10
`
`Shear rate (1/sec)
`
`100
`
`1000
`
`Figure 1. Viscosity of Coating Solutions
`
`100
`
`Viscosity (cPs)
`
`10
`
`1
`
`Low viscosity, Low solids
`
`Medium viscosity, Low solids
`
`High viscosity, Low solids
`
`Low viscosity, Medium solids
`
`Medium viscosity, Medium solids
`
`High viscosity, Medium solids
`
`Low viscosity, High solids
`
`Medium viscosity, High solids
`
`High viscosity, High solids
`
`Drug Release Profiles
`Similar zero order drug release profiles (f2 = 64-98) were obtained for Opadry CA formulations evaluated in this
`study, and the release constant (k) was in the range of 7.3-8.2 %/hour (R2 = 1.0) (Figure 2). The linear regression
`model was applied to examine the relationship between release constant (k) and polymer viscosity/solids content,
`and the results indicated a statistically insignificant relationship. Therefore, variations in either CA viscosity or coating
`solution concentration had minimal influence on the rate of drug release from the PPOP tablets.
`
`Figure 2. Dissolution Profiles of PPOP Tablets
`Dissolution condition: SIF pH 7.5, Apparatus II, 50 rpm (k, rate constant, %/hr).
`
`Low viscosity, Low solids (k=7.26)
`Medium viscosity, Low solids (k=7.65)
`High viscosity, Low solids (k=7.55)
`Low viscosity, Medium solids (k=8.03)
`Medium viscosity, Medium solids (k=7.29)
`High viscosity, Medium solids (k=8.21)
`Low viscosity, High solids (k=8.24)
`Medium viscosity, High solids (k=7.88)
`High viscosity, High solids (k=7.39)
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`Time (hrs)
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`% Drug Y dissolved
`
`OPADRY® CA/POLYOX™
`
`-3-
`
`Amerigen Ex. 1039, p. 3
`
`

`
`Figure 3. Appearance of PPOP Tablets: Push Layer Side at
`Varying Polymer Viscosity and Solution Concentration
`
`Coating Quality
`Opadry CA film coatings became more opaque with
`increasing solution concentration from 5.5% to 8.5% w/w
`(Figure 3). A similar trend was observed through
`spectrophotometric opacity measurement (Figure 4).
`SEM images confirmed that increases in film opacity were
`a result of greater porosity in films formed from the
`coating solutions of higher concentration (Figure 5).
`Although all 9 coating trials had similar yields (≥ 95%),
`the more porous films were found to be thicker (129 μm
`vs. 98 μm) and, therefore, could be expected to have
`longer diffusion paths.
`
`
`Increasing Opacity
`
`
`
`Figure 4. Opacity of Semipermeable Membranes
`
`Figure 5. . SEM Images of SPM Coated onto Bilayer Tablets at
`Varying Solution Concentrationsb
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Opacity (%)
`
`400
`
`500
`
`600
`
`700
`
`Wavelength (nm)
`
`Low viscosity, Low Solids
`
`Medium viscosity, Low Solids
`
`High viscosity, Low solids
`
`Low viscosity, Medium solids
`
`Medium viscosity, Medium solids
`
`High viscosity, Medium solids
`
`Low viscosity, High solids
`
`Medium viscosity, High solids
`
`High viscosity, High solids
`
`b CA viscosity = 10.5 s; 5.5%, 7.0% and 8.5% solids content displayed at left, center and
`right, respectively.
`
`
`
`Conclusions
`Variations in CA viscosity, or solution concentration, had no significant effect on the drug release profiles from PPOP
`tablets coated with Opadry CA system, indicating the robustness of PPOP dosage forms. However, the solids content
`of coating solutions impacted the film opacity, an important quality attribute of PPOP tablets. This evaluation identifies
`the critical material attributes and process parameters for future consideration on the development of osmotic pumps
`coated with Opadry CA.
`
`References
`1.
`Malaterrea,V, Ogorka,J, Loggia N, et al. Approach to design push–pull osmotic pumps. Int J Pharm. 2009 Jul 6;376(1-2):56-62
`Patel P, Liu Q, Missaghi S, et al. Effect of Semipermeable Coating Composition and Opadry® Top-Coating Systems on Performance
`2.
`of Push-Pull Osmotic Pump Tablets of a Practically Water Insoluble Model Drug. AAPS annual meeting and exposition, 2011.
`
`The information contained herein, to the best of Colorcon, Inc.’s knowledge is true and accurate. Any recommendations or suggestions of
`Colorcon, Inc. with regard to the products provided by Colorcon, Inc. are made without warranty, either implied or expressed, because of
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`
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`
`© BPSI Holdings LLC, 2012.
`
`The information contained in this document
`is proprietary to Colorcon and may not be
`used or disseminated inappropriately.
`
`All trademarks, except where noted, are
`property of BPSI Holdings, LLC.
`
`POLYOX™ is a trademark of the Dow
`Chemical Company
`
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`
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`
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`
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`
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`
`Amerigen Ex. 1039, p. 4
`
`CRS_2012_Missaghi_PPOP_visc_OYCA