Formulation and Characterization of a Compacted Multiparticulate System for Modified Release of Water-Soluble Drugs—Part II Theophylline and Cimetidine

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  Formulation and Characterization of a Compacted Multiparticulate System for Modified Release of Water-Soluble Drugs—Part II Theophylline and Cimetidine
   Drug Development and Industrial Pharmacy , 35:568–582, 2009Copyright © Informa UK, Ltd.ISSN: 0363-9045 print / 1520-5762 online DOI: 10.1080/03639040802459460 568 LDDI Formulation and Characterization of a Compacted Multiparticulate System for Modified Release of Water-Soluble Drugs—Part II Theophylline and Cimetidine Formulation and Characterization of a Compacted Multiparticulate System Stuart L. Cantor  ICON Development Solutions, Ellicott City, MD, USA Stephen W. Hoag and Larry L. Augsburger School of Pharmacy, University of Maryland, Baltimore, MD, USA The purpose was to investigate the effectiveness of an ethylcel-lulose (EC) bead matrix and different film-coating polymers indelaying drug release from compacted multiparticulate systems.Formulations containing theophylline or cimetidine granulatedwith Eudragit ®  RS 30D were developed and beads were producedby extrusion–spheronization. Drug beads were coated using 15%wt/wt Surelease ®  or Eudragit ®  NE 30D and were evaluated fortrue density, particle size, and sphericity. Lipid-based placebobeads and drug beads were blended together and compacted onan instrumented Stokes B2 rotary tablet press. Although placebobeads were significantly less spherical, their true density of 1.21 g/cm 3 and size of 855 m  m were quite close to Surelease ® -coated drugbeads. Curing improved the crushing strength and friability val-ues for theophylline tablets containing Surelease ® -coated beads;5.7  ±   1.0 kP and 0.26  ±   0.07%, respectively. Dissolution profilesshowed that the EC matrix only provided 3 h of drug release.Although tablets containing Surelease ® -coated theophylline beadsreleased drug fastest overall (  t  44.2%  = 8 h), profiles showed thatcoating damage was still minimal. Size and density differencesindicated a minimal segregation potential during tableting forblends containing Surelease ® -coated drug beads. Although modi-fied release profiles >8 h were achievable in tablets for both drugsusing either coating polymer, Surelease ® -coated theophyllinebeads released drug fastest overall. This is likely because of theincreased solubility of theophylline and the intrinsic properties of the Surelease ®  films. Furthermore, the lipid-based placebosserved as effective cushioning agents by protecting coating integ-rity of drug beads under a number of different conditions whiletableting.Keywords multiparticulate system; modified release; hydrophobicmatrix; ethylcellulose; extrusion–spheronization INTRODUCTION Creating a multiparticulate, modified release dosage formcontaining a water-soluble drug involves several stages of development and evaluation in order to determine suitableexcipient usage levels and processing parameters. Althoughformulation strategies such as the use of a hydrophobic matrixand/or film coating can be employed to attain a certain level of drug release, each technique would require optimization andneed to be examined separately to determine its level of effec-tiveness in the dosage form.Beads produced by extrusion–spheronization offer potentialtherapeutic advantages of reproducibility of drug blood levels,improved bioavailability, and a lowered risk of side effects bypreventing dose dumping (Bechgaard & Nielsen, 1978). More-over, beads can be manufactured with higher drug loads, a nar-row particle size distribution, spherical shape, good flowproperties, and low friability (Vervaet, Baert, & Remon, 1995).Beads with similar densities and particle sizes will show alesser tendency toward segregation during tableting and thiscan decrease problems, such as weight variation and contentuniformity (Aulton, Dyer, & Khan, 1994).Theophylline and cimetidine are highly water-soluble drugsand were chosen for this study as they are less soluble than ace-taminophen and therefore, their release profiles can be bettercontrolled within the constraints of this multiparticulate system(Cantor, Hoag, & Augsburger, 2008). Drugs that are good can-didates for modified release would be those with high aqueoussolubility, relatively short half-lives, and narrow therapeuticindices (Buckton, Ganderton, & Shah, 1988). By using a com-bination of a hydrophobic matrix, acrylic-based granulatingagent, and polymeric barrier film coatings, formulations con-taining highly water-soluble drugs can be made dissolution ratelimited for extended release (>8 h); and this can ultimatelybenefit patients by reducing dosing frequency.Although much has been published on the topic of hydro-philic matrices in tablets, to our knowledge, no work to date Address correspondence to Stephen W. Hoag, School of Pharmacy, University of Maryland, 20 N. Pine Street, Baltimore, MD21201, USA. E-mail:    D  r  u  g   D  e  v  e   l  o  p  m  e  n   t  a  n   d   I  n   d  u  s   t  r   i  a   l   P   h  a  r  m  a  c  y   D  o  w  n   l  o  a   d  e   d   f  r  o  m    i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m    b  y   P   f   i  z  e  r   L   t   d   (   A  c   t   i  v  e   )  o  n   0   2   /   0   3   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .  FORMULATION AND CHARACTERIZATION OF A COMPACTED MULTIPARTICULATE SYSTEM 569has examined the potential role of micronized ethylcellulose(EC) powder as a hydrophobic matrix in extruded drug-loadedbeads, except for the acetaminophen research that was previ-ously discussed by Cantor et al. (2008). Additionally, littlework has also been published examining what effect multiplerelease retardant techniques in combination with an EC matrixmay have on drug-release profiles (Tiwari, Murthy, Pai,Mehta, & Chowdary, 2003). EC can yield a variety of releaseprofiles dependent on many factors, such as total polymerlevel, viscosity, particle size, and so forth. A relatively newproduct, the low viscosity (7 cP) micronized grade of EC(mean particle size: 9 µ m) was selected for this work becauseof its proven success in granulation whereas coarse gradeswere unsuccessful (Agrawal, Manek, Kolling, & Neau, 2003).The large surface area of the micronized EC powder shouldenable it to uniquely participate in the bead matrix to delaydrug release. Hydrophobic polymers such as EC can also pro-vide several advantages, ranging from good stability to varyingmoisture and pH levels, the latter because of its non-ionicnature. EC is also cost effective and has broad regulatoryacceptance in the pharmaceutical industry.Acrylic polymers can also be used alone or in conjunction withEC to delay release of water-soluble drugs. Eudragit ®  RS 30D is alow permeability aqueous dispersion of a pH-independentmethacrylate copolymer that has been used successfully in filmcoating for beads (Heng, Hao, Chan, & Chew, 2004; Zhu, Mehta, & McGinity, 2006), tablets (Alkhatib & Sakr, 2003;Lee, Ryu, & Cui, 1999), as a tablet matrix during direct com-pression when used in its powdered form (Rey, Wagner,Wehrle, & Schmidt, 2000), and infrequently as a wet granula-tion binder (Wang et al., 1997). Another alternative in filmcoating of drug beads is to use an aqueous pseudolatex disper-sion of plasticized EC known as Surelease ® . This polymer hasbeen previously used to coat phenylpropanolamine HCl beadsand the authors found that increasing the coating level from 10to 15% wt/wt lowered the mean pore diameter and porosity of the coating layer to delay drug release of this highly water-soluble drug salt (Vuppala, Parikh, & Bhagat, 1997).The drawback for preparing tablets from drug beads whichhave received a modified release coating is that the compres-sive stress can cause the coating to develop cracks and rupture,thus destroying the extended release effect. This is manifestedas an increase in the drug dissolution rate. Different placebocushioning agents with varying particle sizes, material proper-ties (plastic or brittle) or bulk densities have been previouslyused in trying to overcome this obstacle such as Avicel ®  PH-200 powder (Dashevsky, Kolter, & Bodmeier, 2004), freeze-dried beads (Habib, Augsburger, & Shangraw, 2002), waxbeads (Debunne, Vervaet, Mangelings, & Remon, 2004;Vergote, Kiekens, Vervaet, & Remon, 2002; Zhou, Vervaet, &Remon, 1996; Zhou, Vervaet, Schelkens, Lefebvre, & Remon,1998), and beads composed of microcrystalline cellulose alone(Celik & Maganti, 1994), in combination with a soft waxymaterial such as polyethylene glycol (Nicklasson & Alderborn,1999a; Torrado & Augsburger, 1994), or with other excipients such as lactose (Aulton et al., 1994); or dibasic calcium phos-phate dihydrate (Nicklasson & Alderborn, 1999b). Moreover,Debunne et al. (2004) and Vergote et al. (2002) compacted mixtures of paraffin wax beads with coated drug beads anddemonstrated through cross-sectional scanning electron micro-graphs of tablets that this was a viable dosage form by showingintact drug beads embedded in the wax matrix.However, with all the variables mentioned earlier, the drug-release data is largely dependent not only on the polymericcoating and levels used on the drug beads, but also on the phys-ical and mechanical properties of both the drug and placebobeads themselves. Furthermore, segregation during mixing andtableting remains a potential problem when blending coateddrug beads with Avicel ®  powders (Aulton et al., 1994;Dashevsky et al., 2004) or with low bulk density beads pre-pared by freeze drying (Habib et al., 2002).For example, previous work has shown that compression of beads coated with EC pseudolatexes from either Aquacoat ® (Dashevsky et al., 2004) or Surelease ®  (Chang & Rudnic,1991; Palmieri & Wehrle, 1997) resulted in the rupture of the coating as evidenced by a high dissolution rate. Celik andMaganti (1994) used propranolol HCl beads coated with Sure-lease ®  at 10% wt/wt, 15% wt/wt, and 20% wt/wt and foundthat regardless of the amount of coating applied, the beads losttheir sustained release properties upon application of relativelylow compression pressures. Additionally, more recent work also indicated that EC films were more brittle than the acrylicfilms (i.e., Eudragit ®  RS/RL 30D or Eudragit ®  NE 30D) andthat EC films also showed large cracks under strain (Bussemer,Peppas, & Bodmeier, 2003). On the other hand, while com-pacted propanolol HCl beads coated with an acrylic dispersionof Kollicoat ®  SR 30D also showed coating rupture during dis-solution, adding 10% wt/wt triethyl citrate (TEC) as a plasti-cizer successfully prevented coating damage from occurringbecause of the increased flexibility of the film (Dashevskyetal., 2004).The composition of the cushioning placebo beads also playsa major role in preventing coating damage to the drug beads.Although placebos composed of Avicel ®  and lactose wereineffective cushioning agents because of their strength and lack of plasticity (Aulton et al., 1994), Salako, Podczeck, and Newton(1998) found that beads containing glyceryl monostearate(GMS) were more deformable during compaction than beadsprepared from harder materials. Blending GMS beads withcoated drug beads prior to compaction can assist in maintain-ing the sustained drug-release effect; this is because the GMSbeads function as lubricants to reduce interparticle and die wallfriction as well as facilitate interparticle packing during tablet-ing (Lundqvist, Podczeck, & Newton, 1998; Pinto, Podczeck, & Newton, 1997). However, it is important to keep in mindthat during dissolution, high levels of such hydrophobic mate-rials can cause liquid penetration into the tablet matrix to be therate-limiting step. Moreover, some authors believe that the    D  r  u  g   D  e  v  e   l  o  p  m  e  n   t  a  n   d   I  n   d  u  s   t  r   i  a   l   P   h  a  r  m  a  c  y   D  o  w  n   l  o  a   d  e   d   f  r  o  m    i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m    b  y   P   f   i  z  e  r   L   t   d   (   A  c   t   i  v  e   )  o  n   0   2   /   0   3   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .  570 S. L. CANTOR ET AL. plastic materials present in placebo beads, such as GMS, canactually increase tablet compactability. This effect from com-pacted GMS beads is believed to be because of their moredeformable nature, which can allow for a high degree of inter-particle bonding and thus, an increase in tablet tensile strength(Iloanusi & Schwartz, 1998; Lundqvist, Podczeck, & Newton, 1997; Mount & Schwartz, 1996). The overall objective of this research is to develop modifiedrelease tablet formulations of different water-soluble drugswith in vitro release profiles greater than 8 h. Moreover, it wasalso desired to study (a) the effectiveness that each differentformulation variable (i.e., EC level in matrix, RS/RL ratio,type of bead coating polymer used, and so forth) had on thesuppression of drug release, (b) the protective cushioningeffect of the different placebo beads, and (c) how release wasaffected by the differences in drug solubility. MATERIALS AND METHODSMaterials Fine particle EC 7 cP viscosity grade (Ethocel 7-FP Pre-mium) with an ethoxyl content of 48.0–49.5% was a gift fromDow Chemical Company (Midland, MI, USA). Microcrystal-line cellulose NF was supplied by FMC Corp., Princeton, NJ,USA. Talc (Imperial 500 USP) was used in bead coating for-mulations and supplied by Luzenac (Greenwood Village, CO,USA).Cimetidine USP, theophylline anhydrous USP, and glycerolmonostearate flakes were purchased from Spectrum Chemicals(New Brunswick, NJ, USA). Milled calcium phosphate dibasicanhydrous was obtained from Innophos (Cranbury, NJ, USA).Sodium Starch Glycolate NF was supplied by JRS Pharma,Patterson, NY, USA; Starch 1500 NF and Surelease ®  (ECpseudolatex dispersion) were supplied by Colorcon (WestPoint, PA, USA); Eudragit ®  RS 30D (Ammonio methacrylatecopolymer “type B”) and Eudragit ®  NE 30D (Methacrylicester copolymer) were supplied by Degussa Pharma Polymers(Piscataway, NJ, USA). TEC, used as a plasticizer, was sup-plied by Morflex, Inc. (Greensboro, NC, USA). Bead Manufacture: Theophylline or Cimetidine Beads and Lipid-Based Placebos All powders for drug bead formulations were mixed in a16-quart twin-shell blender (Patterson-Kelley Co., EastStroudsburg, PA, USA) for 10 min. Batches of 1,500 g weregranulated in a planetary mixer (Model KU-1, Erweka,Heusenstamm, Germany) using Eudragit ®  RS 30D polymersolution. Distilled water (q.s.) was also added in order to obtainthe correct consistency for extrusion; and mixing continueduntil individual moist drug granules appeared (Table 1). Con-trol formulations were prepared with calcium phosphate diba-sic anhydrous in place of EC. However, the control batches didnot readily absorb moisture and granulate well even aftermixing, therefore, these batches were dried on stainless steeltrays for approximately 3 h at 50°C. This mass was thenreturned to the planetary mixer to obtain granules before pro-ceeding. After the wet mass was prepared, it was extruded at37 rpm using a single-screw extruder (Model # EXKS-7, FujiPaudal Co., Osaka, Japan) fitted with a screen of 1-mm aper-ture size. The extrudates were then immediately spheronizedfor 1 min at 500 rpm using a spheronizer (Model 15, GB Cal-eva Ltd., Ascot, UK) equipped with a 375 mm diameter cross-hatched plate. The drug beads were dried for 24 h at 50 ° C to afinal moisture content of <1.0% using a tray drier (Model1018E, Colton, Detroit, MI, USA).The lipid-based placebo beads used excipients listed inTable 2. All powders were initially dry blended together.Batches of 1,300 g were prepared by first heating the GMS to80 ° C in a stainless steel beaker on a double boiler. All pow-ders were then slowly added into the GMS while the mixturewas being continuously stirred with a metal spatula. Once thepowder blend was added, the mixture was subsequentlyhomogenized using a high shear homogenizer (Model PT 10/ 35, Polytron ®  Kinematica AG, Brinkmann Instruments,Westbury, NY, USA) at 22,000 rpm for an additional 10 min.An ice bath was used to cool the mixture to 50 ° C, and thenthe material was hand sieved through a #12 screen and thebeads were immediately spheronized at 550 rpm for 25 s. Thematerial was again sieved on a #30 screen and the finesdiscarded.TABLE 1 Drug Bead Formulations for Theophylline or CimetidineComponent a Ethylcellulose (EC)ControlTheophylline or Cimetidine (15 mg)8.68.6Avicel ®  PH-10115.415.4Ca 2 HPO 4 , anhydrous0.058.0Eudragit ®  RS 30D18.018.0Ethylcellulose, 7cP58.00.0Distilled water b 20.032.0 a All quantities are in % wt/wt. b Calculated on a dry weight basis. TABLE 2 Placebo Wax Bead FormulationComponent a %Glycerol monostearate50.0Starch 150042.0Sodium Starch Glycolate8.0 a All quantities are in wt/wt.    D  r  u  g   D  e  v  e   l  o  p  m  e  n   t  a  n   d   I  n   d  u  s   t  r   i  a   l   P   h  a  r  m  a  c  y   D  o  w  n   l  o  a   d  e   d   f  r  o  m    i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m    b  y   P   f   i  z  e  r   L   t   d   (   A  c   t   i  v  e   )  o  n   0   2   /   0   3   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .  FORMULATION AND CHARACTERIZATION OF A COMPACTED MULTIPARTICULATE SYSTEM 571 Particle Size and Shape Analysis Bead particle size was determined in duplicate by sieveanalysis and was performed with a 6–9 g sample using anAllen Bradley ATM Model L3P Sonic Sifter ®  (Milwaukee,WI, USA). The screen sizes used were #18, #20, #25, #30, #35,and #40. All tests were run for 5 min with amplitude and pulsesettings of five.Graphical analysis showed the particle size distributions tobe log-normal since the logarithmic transformation decreasedthe skewness of the distribution. The percentage by weightretained on each sieve was determined and the geometric meandiameter, labeled as GMD or d  g , and geometric SD , s  g , of theparticle size distributions were calculated using the followingequations (Fan et al., 2005):where n i  is the weight percentage of particles in the i th interval,for all n i ; and d  i  is equal to the midpoint of the diameter of thesize interval in the i th interval, for all d  i .A two-dimensional shape factor was measured using aNikon Eclipse ME600 optical microscope (Nikon, Inc.,Melville, NY, USA) coupled with SPOT v. 3.5.6 image analy-sis software (Diagnostic Instruments, Inc., Sterling Heights,MI, USA). Illumination was achieved via transmission; thetotal magnification was 50 × . The calculation used the follow-ing equation with a value of 1 indicating a perfect sphere, andany value less than that reflecting a deviation from sphericity(Debunne et al., 2004): True Density True density was measured using a helium displacement pyc-nometer (Accupyc 1330, Micromeritics, Norcross, GA, USA)according to the USP 29 general chapter <699> on density of sol-ids. The densities reported are the average of five determinations. Moisture and Bulk Density All batches were dried to a loss on drying (LOD) <1.0% withan endpoint rate set at <0.01%/min. LOD was determined on driedbatches using a Computrac Max 2000XL Moisture Analyzer(Arizona Instruments, Tempe, AZ, USA). Bulk densities of beadswere determined in duplicate using a powder funnel to gently fillbeads up to the 60-mL mark on a 100-mL graduated cylinder. Coating of Theophylline and Cimetidine Beads Coating trials were performed at UPM Pharmaceuticals,Inc. (Baltimore, MD, USA). Batches of 400 g of beads contain-ing either theophylline or cimetidine were coated to a 15% wt/ wt theoretical weight gain with either Surelease ®  or Eudragit ® NE 30D using a Glatt GPCG-2 fluid bed processor (Binzen,Germany) equipped with an 0.8-mm nozzle. Surelease ®  wasdiluted from a 25% wt/wt dispersion to 15% solids with waterbefore beginning the coating operation. Bottom spraying wasperformed using a 10 in. Wurster insert (3.625 in. diameter), aMaster Flex LS peristaltic pump, and an atomizing air pressureof 1 bar. For Surelease ®  coating, the inlet air temperature wasapproximately 60–65 ° C, product temperature 40 ° C, andexhaust air temperature was 39 ° C. The beads were then driedin the same apparatus for 5 min at the same temperatures.Coating of beads using Eudragit ®  NE 30D was performedaccording to the following formulation:The Eudragit ®  NE 30D dispersion was first passed througha #20 screen and accurately weighed into a stainless steelbeaker; then the appropriate amount of water was added. Thissolution was subsequently homogenized on low speed (setting 1)using an IKA Ultra Turrax T-25 homogenizer (IKA Works,Inc., Wilmington, NC, USA). Talc was then slowly added andmixing continued for an additional 1 min. The coating condi-tions for Eudragit ®  NE 30D are as follows: the inlet air temper-ature was approximately 35 ° C, product temperature 26 ° C, andexhaust air temperature was 25 ° C. The beads were then driedin the same apparatus for 5 min at the same temperatures. Tableting and Tablet Evaluation For manual tableting studies, 10 g of a combination of drugand placebo beads in various ratios were added to a plastic bagand mixed for 3 min. For automatic tableting studies, 400 g of a combination of drug beads and placebo beads in variousratios were added to a plastic bag and mixed for 3 min. Asingle-station instrumented Stokes B2 rotary tablet press (oper-ating at 30 rpm) equipped with an instrumented eye bolt forcompression force and an ejection cam for ejection force wasused with 8.7 mm round, concave punches. Beads were accu-rately weighed and manually filled into the die to achieve tar-get tablet weights of 350 ±  5 mg. Tablet crushing strength log(*log), d nd n iii g  =  ∑∑ (1) log(log),  /  s  giii nd n = ∑∑ 212 (2) Sphericity=projectedarea(perimeter)().4 2 p  ⋅ (3)Ingredient%Eudragit ®  NE 30D74.90Talc 500 USP9.98Water15.12    D  r  u  g   D  e  v  e   l  o  p  m  e  n   t  a  n   d   I  n   d  u  s   t  r   i  a   l   P   h  a  r  m  a  c  y   D  o  w  n   l  o  a   d  e   d   f  r  o  m    i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m    b  y   P   f   i  z  e  r   L   t   d   (   A  c   t   i  v  e   )  o  n   0   2   /   0   3   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .  572 S. L. CANTOR ET AL. (hardness) was determined by diametric compression using ahardness tester (Model HT-300, Key International, Inc.,Englishtown, NJ, USA). All tablets were allowed to stay atambient temperature for 24 h before hardness testing to allowfor elastic recovery. Eighteen tablets were subjected to 100rotations in a friabilator (Model TA, Erweka, GmbH,Germany) rotating at 25 rpm following USP 24 Method<1216>. To improve tablet crushing strength, tablets wereheated for 24 h at 50 ° C using an oven. Dissolution Testing Dissolution testing of tablets or beads was performed in900mL distilled water at 37 ±  0.5 ° C using USP apparatus IIat 50 rpm (Vankel VK 7000, VanKel Industries, Inc., Cary,NC, USA). The temperature was maintained using a bathheater (Model VK 750D, VanKel, Edison, NJ, USA). Sam-ples (1.5mL) were manually withdrawn at specified timeintervals and replaced by new media. The samples wereplaced in Eppendorf  ®  centrifuge tubes and spun using aEppendorf  ®  5415C centrifuge (Brinkmann Instruments, Inc.,Westbury, NY, USA) at 13,000 rpm for 2 min. This wasfound to be more effective than filtration and led to more sta-ble spectrophotometric readings. The cimetidine andtheophlline samples were spectrophotometrically analyzedaccording to USP 24, at 219 and 270 nm, respectively, usinga Spectronic Genesys 2 UV/VIS spectrophotometer (ThermoElectron Corp., Waltham, MA, USA). The weight of tabletsused was 350 mg, and when beads were studied, an amountcorresponding to the equivalent drug amount from tabletswas used. All dissolution testing was performed under sink conditions and profiles are the mean of six replicates. Stan-dard curves (  R 2   ≥  .999) were generated for each drug and theamount of dissolved drug was normalized based on theamount present in the tablet or bead.The similarity factor,  f  2 , was used to determine if dissolu-tion profiles were different; generally an  f  2  value between 50and 100 is taken as the criterion for equivalence. The  f  2  metricequation is a logarithmic transformation of the sum of thesquared error (Guidance for Industry, 2000) and is expressed aswhere n  is the number of time points,  R t   and T  t   are the percentdrug dissolved for the reference and test products, respectively,at each time point t  . Dissolution data time points below 85%drug release and only one sampling time point above 85% wereused in the calculations of the  f  2  metric, since the use of addi-tional data points above 85% release (i.e., after the dissolutionplateau has been reached) has been previously shown to biasthe similarity factor and introduce error (Shah, Tsong, Sathe, &Liu, 1998). This pair-wise method of comparing dissolutionprofiles has been suggested by SUPAC for immediate releasesolid oral dosage forms to determine bioequivalence (Guidancefor Industry, 1995), but is also suitable when making compari-sons among modified release dosages as well. Statistical Analysis Statistical analysis of the data was performed using analysisof variance (ANOVA) with least significant difference (LSD)as the post hoc test. A  p- value of less than .05 was consideredsignificant (SPSS v.12, Chicago, IL). RESULTS AND DISCUSSIONCharacterization of Uncoated and Coated Drug Beads and Lipid-Based Placebo Beads The characterization of some physical properties of uncoated and coated theophylline–EC and cimetidine–ECbeads and their controls along with the lipid-based placebobeads is shown in Tables 3 and 4. Although the uncoated con-trol beads were similar in particle size they were significantly  f n RT  tt t n 22=1 =50log1+1()        − × ∑ − 05 100 . , (4)TABLE 3 Bulk and True Densities, Particle Size and Sphericity for Uncoated Theophylline and Cimetidine BeadsSampleBulk Density a  (g/cm 3 )True Density b  (g/cm 3 )Particle Size d  g   ±   s  g c  ( µ m)Sphericity d Cimetidine–EC0.63 ±  0.03 e 1.21 ±  0.00 e 812.1 ±  1.20.93 ±  0.03 e Cimetidine control1.00 ±  0.04 e 1.93 ±  0.00 e 798.2 ±  1.20.92 ±  0.05Theophylline–EC0.59 ±  0.01 e 1.22 ±  0.00 e 793.9 ±  1.50.89 ±  0.05 v Theophylline control1.00 ±  0.04 e 1.96 ±  0.00 e 809.4 ±  1.20.87 ±  0.05 e a  M    ±   SD ; n  = 2. b  M    ±   SD ; n  = 5. c Geometric mean diameter ±  geometric SD , n  = 2. d  M    ±   SD ; n  = 30. e Means are significantly different within each column by one-way ANOVA with LSD as the post hoc test (  p <.05).    D  r  u  g   D  e  v  e   l  o  p  m  e  n   t  a  n   d   I  n   d  u  s   t  r   i  a   l   P   h  a  r  m  a  c  y   D  o  w  n   l  o  a   d  e   d   f  r  o  m    i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m    b  y   P   f   i  z  e  r   L   t   d   (   A  c   t   i  v  e   )  o  n   0   2   /   0   3   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .
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