Drug Development and Industrial Pharmacy
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`ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: https://www.tandfonline.com/loi/iddi20
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`Oral medication delivery in impaired swallowing:
`thickening liquid medications for safe swallowing
`alters dissolution characteristics
`
`Yady J. Manrique, Arron M. Sparkes, Julie A.Y. Cichero, Jason R. Stokes, Lisa
`M. Nissen & Kathryn J. Steadman
`
`To cite this article: Yady J. Manrique, Arron M. Sparkes, Julie A.Y. Cichero, Jason R. Stokes, Lisa
`M. Nissen & Kathryn J. Steadman (2016) Oral medication delivery in impaired swallowing:
`thickening liquid medications for safe swallowing alters dissolution characteristics, Drug
`Development and Industrial Pharmacy, 42:9, 1537-1544, DOI: 10.3109/03639045.2016.1151033
`
`To link to this article: https://doi.org/10.3109/03639045.2016.1151033
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`Published online: 02 Mar 2016.
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`DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 2016
`VOL. 42, NO. 9, 1537–1544
`http://dx.doi.org/10.3109/03639045.2016.1151033
`
`RESEARCH ARTICLE
`
`Oral medication delivery in impaired swallowing: thickening liquid medications for
`safe swallowing alters dissolution characteristics
`
`Yady J. Manriquea, Arron M. Sparkesa, Julie A.Y. Cicheroa, Jason R. Stokesb, Lisa M. Nissenc and Kathryn J. Steadmana
`aSchool of Pharmacy, The University of Queensland, Brisbane, Australia; bSchool of Chemical Engineering, The University of Queensland, Brisbane,
`Australia; cSchool of Clinical Sciences, Queensland University of Technology, Brisbane, Australia
`
`ABSTRACT
`Acetaminophen (paracetamol) is available in a wide range of oral formulations designed to meet the needs
`of the population across the age-spectrum, but for people with impaired swallowing, i.e. dysphagia, both
`solid and liquid medications can be difficult to swallow without modification. The effect of a commercial
`polysaccharide thickener, designed to be added to fluids to promote safe swallowing by dysphagic patients,
`on rheology and acetaminophen dissolution was tested using crushed immediate-release tablets in water,
`effervescent tablets in water, elixir and suspension. The inclusion of the thickener, comprised of xanthan
`gum and maltodextrin, had a considerable impact on dissolution; acetaminophen release from modified
`medications reached 12–50% in 30 min, which did not reflect the pharmacopeia specification for immediate
`release preparations. Flow curves reflect the high zero-shear viscosity and the apparent yield stress of the
`thickened products. The weak gel nature, in combination with high G’ values compared to G’’ (viscoelasti-
`city) and high apparent yield stress, impact drug release. The restriction on drug release from these formu-
`lations is not influenced by the theoretical state of the drug (dissolved or dispersed), and the approach
`typically used in clinical practice (mixing crushed tablets into pre-prepared thickened fluid) cannot be
`improved by altering the order of incorporation or mixing method.
`
`ARTICLE HISTORY
`Received 10 October 2015
`Revised 20 January 2016
`Accepted 25 January 2016
`Published online 1 March
`2016
`
`KEYWORDS
`Acetaminophen; dissolution;
`dysphagia;
`rheology;
`viscosity
`
`Introduction
`
`from solids such as
`The range of oral dosage forms available,
`tablets and capsules to liquids such as elixirs and suspensions, are
`designed to address the therapeutic needs of the majority of the
`population including infants, adults and the elderly. However,
`patients with impaired ability to swallow (i.e. dysphagia) vary in
`their ability to swallow food and fluids without aspiration into the
`airways1. Whole tablets and capsules should be avoided for people
`with swallowing impairments due to the risk of aspiration and
`penetration into the airway2. Oral
`liquid dose forms represent an
`alternative to the use of solid dose forms for people with swallow-
`ing issues, but thin fluids leave dysphagic patients at risk of aspir-
`ation as a consequence of the poor control of
`liquids.
`In the
`absence of alternatives, the most common solution to the medica-
`tion delivery dilemma for dysphagic patients is to crush tablets
`and open capsules, and mix the powder with food3,4, thickened
`fluid or naturally thick food vehicles, such as yoghurt, jam or pud-
`ding5–7. The use of thickeners to facilitate safe swallowing of fluids
`is a result of the rheological properties of these agents8 as the
`increased viscosity of the fluid leads to better control over the tim-
`ing of opening of the valves involved in swallowing, reducing the
`chance of transit straight into the airway9.
`Previous research has demonstrated that water thickened with
`commercial polysaccharide thickeners, has the potential to nega-
`tively impact the release of conventional crushed tablets when they
`are used in replacement of water. The effects were thickener and
`viscosity-dependent, with products containing xanthan gum and
`higher thicknesses causing the greatest restriction in drug release10.
`The aim of this research is to determine whether the state of
`drug aggregation within the thickened water (i.e. dissolved or
`
`of drug release.
`an important determinant
`is
`dispersed)
`Acetaminophen (paracetamol) is a good example of an active ingre-
`dient available in several solid and liquid oral
`formulations.
`Acetaminophen tablets are the most commonly modified medicine
`for adults and children in Australian hospitals5 and most commonly
`cited as being difficult to swallow11. It is available in dosage forms
`that provide paracetamol in solution (syrup and dissolved efferves-
`cent tablets) and dispersed state (suspension, crushed immediate
`release tablets in water). The hypothesis to be tested is that the limi-
`tation on drug release is reduced when the acetaminophen is dis-
`solved rather
`than dispersed within the thickened water. Two
`approaches can be applied to test this hypothesis, firstly to vary the
`order of adding the components to allow acetaminophen to dis-
`solve in water and then mix into thickened water, as opposed to
`the standard clinical practice of dispersing crushed tablet powder
`into pre-thickened water. The second approach is to compare the
`effect on drug release of thickening commercial products that have
`acetaminophen dissolved (effervescent tablet, elixir) or dispersed
`(suspension). Additionally, detailed rheological characterization of
`the thickened products was carried out to consider the contribution
`of viscoelasticity and yield stress to restriction on drug release.
`
`Material and methods
`
`Materials
`
`The dosage forms studied were available in Australia in 2012 when
`this work was conducted: Panadol
`immediate release tablets
`500 mg, round and film coated (marketed in Australia with state-
`ments declaring these forms do not have any ingredient that
`improves absorption), Panadol rapid soluble effervescent tablets
`
`CONTACT Kathryn J. Steadman
`k.steadman@uq.edu.au
`ß 2016 Informa UK Limited, trading as Taylor & Francis Group
`
`School of Pharmacy, The University of Queensland, Brisbane, Qld 4072, Australia
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`1538
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`Y. J. MANRIQUE ET AL.
`
`raspberry flavor elixir
`500 mg, Panadol children’s 5–12 years
`(48 mg/mL), and Panadol children’s 5–12 years color-free orange
`flavor suspension (48 mg/mL). Deionized water or deionized water
`thickened with Easythick (Flavour Creations, Brisbane, Australia)
`was used as the drug delivery vehicle. Easythick (contents: malto-
`dextrin, xanthan gum, sodium chloride) was prepared using the
`quantity indicated by the manufacturer to produce the thickest
`level described by the Australian National Standards for dysphagic
`patients12,13, level 900, which indicates that the apparent viscosity
`at a shear rate of 501 should be greater than 900 mPas. Spoon
`measurements of the thickener were converted to weight to pro-
`vide the desired percentage (%w/v). To produce thickened water
`at level 900, each 185 mL of water required 5 teaspoons of the
`thickener, equivalent to 13.5 g (7.3% w/v), so for 15 mL of water
`1.1 g of thickener was added.
`
`Experimental design
`
`the method used to incorporate
`The role in drug release of
`crushed tablets into the thickened water was investigated by vary-
`ing both the order of addition of the three components, crushed
`tablet, water and thickener powder, and the technique used to
`add the medication (manually with a spatula versus mechanical
`high speed stirrer). The variations in the order of addition were:
`
` Variant 1: thickener þ water, then crushed tablet (i.e. the water
`was thickened before the crushed tablet was mixed in)
` Variant 2: crushed tablet þ water,
`the
`(i.e.
`then thickener
`crushed acetaminophen tablet was suspended in the water
`before the water was thickened)
` Variant 3: crushed tablet þ thickener,
`the
`(i.e.
`then water
`crushed tablet was mixed with the thickener powder before
`the water was thickened)
`
`to thicken commercially available
`the potential
`Additionally,
`liquid dosage forms was investigated using acetaminophen in solu-
`tion (i.e. effervescent
`tablet, elixir) and suspension. The entire
`experiment was replicated three times.
`
`Sample preparation
`
`Preparation of solid formulations by manual incorporation
`For variant 1, which represents standard clinical practice5–7, one
`immediate release acetaminophen tablet was crushed in a mortar
`and pestle and the contents transferred to a 30 mL disposable plas-
`tic cup. Thickened water was prepared by adding 3.6 g of thickener
`powder to 50 mL water and mixed with a hand stick blender
`(Tiffany 200W) with stainless steel shaft at stirring level 2 for 1 min
`until a uniform mass was formed, then 15 g of this thickened water
`was added to the cup containing one crushed tablet and manually
`mixed with a metallic spatula for 3 min.
`For variant 2, one acetaminophen tablet was crushed and trans-
`ferred to weighing paper, then to a 30 mL disposable cup. The
`mortar and pestle and weighing paper were rinsed with 10 and
`5 mL (15 mL total) of deionized water and added into the cup.
`1.1 g thickener powder was gradually incorporated and stirred until
`homogeneous.
`For variant 3, one acetaminophen tablet was crushed and trans-
`ferred to weighing paper, then to a 30 mL disposable cup. 1.1 g of
`thickener powder was added to the cup containing the crushed
`tablet and stirred. Then the mortar and pestle and weighing paper
`were rinsed with 10 and 5 mL (15 mL total) of deionized water and
`added into the cup and mixed.
`
`All samples were manually mixed with a stainless steel spatula
`for 5 min until the mixture was visually homogeneous. To allow full
`hydration and swelling, after the thickener and water were mixed,
`samples were covered with a double layer of ParafilmVR M (Sigma-
`Aldrich, Pty. Ltd., Sydney, Australia) and kept at 4 C overnight prior
`to dissolution testing; once swelling is complete, gum-based thick-
`eners do not change viscosity14. For variant 3, the thickened water
`prepared overnight was manually mixed with the crushed tablet
`15 min before dissolution testing.
`Weights of the intact tablet, mortar and pestle with and without
`residuals, empty disposable cup and disposable cup with crushed
`contents were noted.
`
`Preparation of solid formulations by mechanical incorporation
`In order to use an overhead stirrer for mechanical incorporation, the
`quantity prepared was up-scaled to produce an appropriate volume.
`Three and half acetaminophen tablets were crushed in a mortar and
`pestle and the solid transferred into a 100 mL glass beaker.
`For variant 1, thickened water was prepared by adding 3.6 g of
`thickener powder to 50 mL of deionized water in a measuring
`cylinder and mixed.
`For variant 2, 50 mL water was added to the beaker containing
`crushed tablets, and then 3.6 g thickener powder was added and
`mixed.
`For variant 3, 3.6 g thickener powder was added to the beaker
`containing crushed tablets, and then a volume of 50 mL of water
`was added and mixed.
`All the samples were mixed using an IKAVR RW20 digital over-
`head stirrer, with a crossed blade impellor (Thermo Fisher Scientific
`Australia Pty Ltd, Scoresby, Australia) at 400 rpm for 5 min. For the
`purpose of de-aeration, 30 g of mechanically mixed samples and
`thickened water used in variant 1 were transferred to 50 mL centri-
`fuge tubes and centrifuged (Eppendorf Centrifuge 5804 R, VWR
`International, Pty Ltd, Brisbane, Australia) at 2000 rpm for 2 min at
`20 C. These were then covered with a double layer of ParafilmVR M
`kept at 4 C overnight prior to dissolution testing to allow full
`hydration and swelling. For variant 1, the thickened water was
`recombined in a glass beaker after removal from refrigerated stor-
`age and mixed with the crushed tablets. 15 g of samples (equiva-
`lent to 1 crushed tablet) were weighed into a 30 mL disposable
`plastic cup 15 min before dissolution testing.
`Weights of the intact tablet, mortar and pestle with and without
`residuals, empty disposable cup and disposable cup with crushed
`contents were noted.
`
`Preparation of liquid formulations
`The quantity of thickener added to liquid formulations was the
`quantity required to thicken water to level 900. A dose of 15 mL of
`elixir or suspension formulations were measured, placed into a
`30 mL disposable plastic cup, and 1.1 g of thickener powder was
`added and mixed with a stainless steel spatula for 5 min to ensure
`the thickener was well dispersed. One effervescent tablet was dis-
`solved in 100 mL water, and 7.3 g of thickener powder was added
`and mixed until a thick solution free of powder was formed.
`Thickened samples were covered with a double layer of ParafilmVR
`M and kept at 4 C overnight.
`
`Methods
`
`Drug release and dissolution
`For the dissolution studies, prepared samples were removed from
`refrigeration and allowed to sit at room temperature for 15 min
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`prior to starting dissolution testing. The samples were tested using
`USP dissolution apparatus II
`(VK7000, Varian, Mulgrave, Victoria,
`Australia) with 900 mL of simulated gastric fluid (SGF) pH 1.2 with-
`out enzymes15 at 37 C and paddle speed of 50 rpm. 3 mL samples
`were collected at 1, 3, 5, 10, 25, 30, 60, 90, 120, 150, 180 min
`through stainless steel cannula assembled with flow filter (10 lm,
`Varian) into 3 mL plastic syringes and 3 mL of fresh SGF was added
`at every sampling point16. In this study, we used one dissolution
`environment to allow direct comparison of multiple dosage forms.
`Samples were filtered through 0.45 lm nylon membranes
`(Grace Davison Discovery Sciences, Alltech Associates Pty Ltd,
`Victoria, Australia) and diluted to obtain the desired concentrations
`to enable readings using UV spectroscopy. A calibration curve was
`constructed and the absorbance of acetaminophen samples was
`measured at 244 nm Hitachi U-1900 Spectrophotometer (Hitachi
`Australia Pty, Ltd, Sydney, Australia). Whole tablet in 15 mL water,
`crushed tablet in 15 mL water (dispersed by agitation with a metal-
`lic spatula), the elixir, suspension and dissolved effervescent medi-
`cations without
`thickener were performed for
`comparison.
`Thickened water without medication was measured as control. To
`account for background absorbance associated with the thickener,
`absorbance readings for the control (always < 0.015) were sub-
`tracted from the absorbance of
`the samples containing drug.
`Cumulative dissolution of acetaminophen was plotted against time
`and analyzed for differences in dissolution at 30 min with one-way
`ANOVA (p < 0.05) and a Bonferroni post-hoc test using GraphPad
`Prism version 6 (GraphPad software, San Diego, CA); all data tested
`complied with the assumptions of ANOVA for normality and equal-
`ity of variance.
`The Korsmeyer–Peppas model was fitted to the cumulative
`release versus time plots using SigmaPlot 12.0 (Systat Software, Inc.
`San Jose, CA). The Korsmeyer–Peppas is an empirical equation that
`correlates the amount of the drug released (Mt) and the exponen-
`tial function of the release profile:
`ð1Þ
`Mt=M1 ¼ ktn
`is the amount of drug release at time t, M1 is the total
`where Mt
`drug released over the duration of the experiment, k is the kinetic
`constant, and n is the release exponent17. Cumulative release pro-
`18.
`files were compared using the similarity factor, f2
`
`Rheological measurements
`Samples were prepared following the same conditions and at the
`same time as for dissolution testing. Rheological attributes of the
`elixir and dissolved effervescent
`tablet without
`thickener were
`measured in a stress controlled rheometer G2 (TA instruments C/O
`Waters Australia, Pty, Ltd, Sydney, Australia) using cone and plate
`titanium 40 mm, 2 deg, 63 lm truncation attachment at 37 C.
`Samples were equilibrated for 2 min prior to measuring. The cone
`and plate was used to give constant shear rate throughout the
`sample, so the viscosity does not vary within the geometry.
`Thickened samples were also measured in the cone and plate, but
`for several measurements artefacts arose including slip, and con-
`finement of undissolved particulates from the comminuted tablets;
`such phenomena are described in detail by Davies and Stokes19.
`To overcome these particular issues, a vane-in-cup geometry was
`used, which is appropriate to characterize the rheology of struc-
`tured fluids with characteristics of a weak gel that contains yield
`stress, as described by Stokes and Telford20. Thickened water, sus-
`pension, thickened liquid dosage forms and one crushed tablet
`manually mixed into thickened water (variant 1) were prepared,
`equilibrated at 37 C for 30 min and the measurements taken in a
`AR 1500ex stress controlled rheometer (TA instruments C/O Waters
`
`DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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`
`Australia, Pty, Ltd, Sydney, Australia) with a large aluminium vane
`at 37 C. The linear viscoelasticity of the samples were character-
`ized using small amplitude oscillatory testing: the viscous (loss
`modulus, G’’) and elastic properties (storage modulus, G’) were
`obtained as a function of frequency. Small oscillatory measure-
`ments were carried out on the prepared samples. Stress sweep
`tests were first performed from 0.1 to 100 Pa, with 1 Hz frequency
`value at 37 C, to determine the linear viscoelastic region. The
`stress was linear with strain across a brand frequency range at 1 Pa
`and therefore frequency sweep tests were performed from 10.0 to
`0.1 Hz, with 1 Pa constant stress at 37 C.
`
`Results
`
`Based on the weight of powder contained in the cups prior to mix-
`ing with thickened water and assuming that 100% corresponded
`to 500 mg of the content declared in one tablet, between 3% to
`4% of drug was lost during the crushing, weighing and transfer
`into the cups with no difference between method variants. This
`loss has not been accounted for in the results, but indicates that
`the total % dissolution that could be obtained from the crushed
`tablets could reach a maximum of 96 to 97%.
`
`Dissolution experiments
`
`Acetaminophen is classified in the Biopharmaceutical Scheme as
`BCS class III, but possesses some attributes of the BCS class I sub-
`stances21.
`Its solubility is not pH dependent within physiological
`range, having a pKa value of 9.5, so adjusting the dissolution
`media pH used in this study would not be expected to affect dis-
`solution. Acetaminophen whole and crushed tablets delivered with
`water exhibited rapid and complete dissolution in SGF with over
`96% of the drug released and measured in the first 30 min (Figure
`1A, Table 1). Similarly, acetaminophen was immediately released
`from the elixir and the effervescent
`tablet
`(Figure 2A and B,
`Table 2).
`In contrast, the suspension exhibited moderate release
`under
`the conditions of
`this dissolution test, with only 30%
`released in 30 min (Figure 2C, Table 2).
`
`Modified solid dosage forms
`
`Using crushed tablets, the effect of the state of drug aggregation
`(dissolved or dispersed), the order of adding components, and mix-
`ing method were investigated. The standard clinical method of
`preparation, in which crushed tablets were mixed into 15 g of pre-
`thickened water (variant 1), resulted in only 36% acetaminophen
`being dissolved in the first 30 min (Table 1). Thickener slowed dis-
`solution for all formulations involving crushed tablets, irrespective
`of whether manual or mechanical mixing was used or the order of
`incorporation of the components (Figure 1B and C, Table 1). The
`manual mixing method produced formulations with faster release
`of acetaminophen than mechanical mixing (p < 0.001) with differ-
`ences of 9.5, 15.2 and 13.7% at 30 min for variants 1, 2 and 3,
`respectively (Table 1).
`The dissolution profiles for the crushed tablets in thickened
`fluid were compared to the intact dosage form by the similarity
`18. All medications delivered with thickened water invari-
`factor f2
`ably resulted in f2 of less than 50 (Table 1), which confirms that
`the dissolution profiles were dissimilar and predicts that differences
`are likely to occur in vivo. The Korsmeyer–Peppas model fitted the
`dissolution profiles well (r2 ¼ 0.98–0.99; Table 1). The release expo-
`nent n was 0.41 to 0.49,
`indicating primarily Fickian diffusion-
`controlled release.
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`Table 1. The percentage dissolution (mean 6 standard error, n ¼ 3) in simulated
`gastric fluid at 30 min for acetaminophen immediate release whole and crushed
`tablets delivered with 15 mL of water and crushed tablets with 15 g of thickened
`water using two mixing methods (manual, mechanical) and three order of add-
`ition variants (1, 2, 3).
`
`Similarity
`factor f2
`
`Korsmeyer–Peppas
`r2 (SE)
`
`n (SE)
`
`% Dissolved
`at 30 min
`96.7 6 1.3%b
`
`98.3 6 0.2%b
`
`Formulation
`Whole tablet
`Crushed tablet in:
`Water
`Thickened water
`Manual
`Variant 1a
`Variant 2
`Variant 3
`Mechanical
`26.8 6 1.8%ec
`0.99 (1.60)
`0.47 (0.018)
`15.4
`Variant 1
`24.9 6 1.1%ec
`0.99 (1.33)
`0.42 (0.014)
`14.3
`Variant 2
`21.6 6 3.2%e
`0.99 (0.74)
`0.42 (0.009)
`13.0
`Variant 3
`Values of % dissolution with different superscript alphabalic symbols are signifi-
`cantly different (p < 0.05). Similarity factor (f2) with respect to the whole tablet
`and Kosmeyer–Peppas release exponent n (6SE) and r2 (6SE) were calculated.
`aStandard method used in clinical practice.
`
`36.3 6 2.8%cd
`40.1 6 2.3%c
`35.3 6 1.7%cd
`
`19.1
`20.5
`18.6
`
`0.49 (0.018)
`0.41 (0.013)
`0.43 (0.028)
`
`0.99 (2.18)
`0.99 (1.80)
`0.98 (3.44)
`
`The Korsmeyer–Peppas model was fitted to the dissolution pro-
`files (r2¼ 0.97-0.99; Table 2) except the unthickened effervescent
`tablet and unthickened elixir because the acetaminophen was
`already in solution in these formulations before the dissolution test
`started. The release exponent n was close to 0.5, indicating primar-
`ily Fickian diffusion-controlled release, though it varied to a greater
`extent for the thickened liquid formulations (0.34 to 0.58) than the
`thickened crushed tablet formulations (0.41 to 0.49).
`
`Rheology of the thickened medications
`
`All samples containing thickener exhibited non-Newtonian shear-
`thinning behavior with viscosity values dependent on the shear
`stress applied to the sample (Figure 3). Unthickened acetamino-
`phen suspension also exhibited non-Newtonian behavior, reflecting
`the structured vehicle contained in the suspension. The viscosity of
`the elixir and dissolved effervescent tablet was very low and similar
`to water and remained invariable with stress (data not shown), typ-
`ical of Newtonian behavior.
`A shear rate of 50 s1 was chosen for comparison as it is com-
`monly used in evaluation of fluid foods as an indicator of the dom-
`inant shear rate operating in the oral cavity22 and is the shear rate
`used for the number category system for texture-modified fluids in
`the US and Australia23. The elixir and effervescent tablet with no
`thickener exhibited low viscosity of 15 and 8 mPas (Table 3). Water
`thickened to level 900 was indeed characteristic of
`its texture-
`modified fluid category with a viscosity of 917 mPas, while add-
`ition of a crushed tablet to the thickened water reduced viscosity
`to 625 mPas but addition of thickener to the effervescent tablet in
`water increased viscosity to 1540 mPas, presumably associated
`with different excipients contained in the immediate release and
`effervescent tablets. With a viscosity of 403 mPas, the suspension
`may be categorized as level 400, but addition of thickener resulted
`in a very thick liquid (4380 mPas); the thickened elixir was also
`very thick (3650 mPas) despite the primary formulation having
`very low viscosity and Newtonian behavior.
`in zero-
`Relative differences between formulations (Table 3)
`shear viscosity (i.e. at very low shear rate, <1 Pa) and infinite-shear
`viscosity values (i.e. at high shear stress >100 Pa) largely echoed
`the relationships observed in viscosity at 50 s1, except that the
`crushed immediate release tablet in thickened water was more
`similar to the effervescent tablet in thickened water at low and
`
`Whole
`Crushed
`
`123
`
`231
`
`1540
`
`Y. J. MANRIQUE ET AL.
`
`(A)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`100
`
`(B)
`
`80
`
`60
`
`40
`
`20
`
`Paracetamol dissolution (%)
`
`0
`100
`
`(C)
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`50
`
`150
`
`200
`
`100
`Time (min)
`Figure 1. Dissolution of whole and crushed acetaminophen tablets delivered with
`15 mL water (A), and crushed tablets delivered in 15 g thickened water (B, C). The
`crushed tablet was incorporated into the thickened water by manual
`(B) and
`mechanical mixing (C) with three different variants 1, 2 and 3. The data shows
`mean 6 se for three replicates for dissolution tests performed in SGF at 37 C and
`50 rpm. The lines in (B) and (C) are fits to the Korsmeyer–Peppas model.
`
`Modified liquid dosage forms
`
`The quantity of thickener required to thicken water to level 900
`was added to acetaminophen elixir, dissolved effervescent tablet
`and suspension, resulting in a significant change in dissolution pro-
`file in comparison to the unthickened products. The quantity of
`acetaminophen dissolved at 30 min was reduced for all three for-
`mulations, with differences caused by addition of thickener of 52,
`86 and 22% for the effervescent tablet, elixir and suspension,
`respectively (Figure 2). The similarity factor f2 was estimated for
`each modified medication with respect to its intact dosage form,
`and in all cases f2 was lower than 50, which confirmed the lack of
`similarity.
`
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`DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
`
`1541
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`Table 2. The percentage dissolution (mean 6 standard error: n ¼ 3) in simulated
`gastric fluid at 30 min for acetaminophen intact liquid dosage forms and with
`thickener added.
`
`Korsmeyer–Peppas
`r2 (SE)
`
`n (SE)
`
`Similarity
`factor f2
`
`% Dissolved
`at 30 min
`Formulation
`96.0 6 2.1%
`Effervescent tablet
`101.0 6 3.1%
`Elixir
`0.55 (0.040) 0.98 (4.81)
`30.0 6 1.3%
`Suspension
`Effervescent tabletþ thickener
`0.34 (0.026) 0.97 (4.63)
`11.7
`50.8 6 2.9%
`Elixir þ thickener
`0.40 (0.013) 0.99 (0.68)
`2.8
`13.6 6 0.7%
`Suspensionþ thickener
`0.58 (0.021) 0.99 (0.74)
`31.6
`12.0 6 4.2%
`Similarity factor (f2) of the thickened liquids with respect to the intact liquids and
`Kosmeyer–Peppas release exponent n (6SE) and r2 (6SE) were calculated.
`
`Effervescent tablet
`Effervescent tablet + thickener
`
`Elixir
`Elixir + thickener
`
`(A)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`100
`
`(B)
`
`80
`
`60
`
`40
`
`20
`
`Paracetamol dissolution (%)
`
`0
`
`100
`
`(C)
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Suspension
`Suspension + thickener
`
`0
`
`50
`
`100
`
`150
`
`200
`
`Figure 3. Flow curves for dosage forms with (filled symbols) and without (open
`symbols) thickener at 37 C using a vane tool. One representative flow curve from
`three replicates is shown. The unthickened effervescent tablet and elixir are not
`shown due to low viscosity (Table 3) that did not change with shear stress.
`
`similar in response to the thickened water alone. As defined by
`Stokes, a weak gel is a substantially diluted system that displays a
`solid-like behavior but is also able to exhibit steady state flow24. As
`these fluids flow above an apparent yield stress, they are referred
`to here as weak gels.
`
`Time (min)
`Figure 2. Dissolution of acetaminophen from (A) effervescent tablet, (B) elixir, (C)
`suspension. 15 mL of medications were delivered straight from the bottle (B, C) or
`dissolved in water (A) (open symbols) or mixed with the quantity of thickener
`required to produce thickened water at level 900 (filled symbols). The data shows
`mean 6 se for three replicates for dissolution tests performed in SGF at 37 C and
`50 rpm. The curves are fits to the Korsmeyer–Peppas model except for unthickened
`formulations in (A) and (B).
`
`high shear stresses. The apparent yield stress, which is the stress
`value at which viscosity decreases by several orders of magnitude
`so flow occurs24, also highlighted the greater resistance to flow of
`the thickened suspension (39 Pa) in comparison to the other thick-
`ened formulations (17-26 Pa) and the unthickened suspension
`(2.7 Pa) (Table 3).
`The thickened formulations were semi-solid in appearance. The
`mechanical spectra were obtained and the results expressed in
`terms of an elastic storage modulus (G’) and viscous loss modulus
`(G’’) (Figure 4). The thickened samples and the unthickened sus-
`pension all behaved as viscoelastic solids with G’ dominating over
`G’’ across a substantial frequency (v) range (cycles/s). Thickened
`effervescent
`tablet and crushed tablet
`in thickener were very
`
`Discussion
`
`The presence of thickened fluid, irrespective of the dosage form or
`the method of preparation, had a substantial
`impact on in vitro
`drug dissolution. The extent of the effect depended upon the
`aggregation state of the drug contained in the dosage form and
`on other components of the dosage form.
`It is well known that
`increasing dissolution media viscosity retards release by increasing
`disintegration and dissolution time25,26 but that was not the reason
`for the delayed dissolution in this case because 15 g of thickened
`fluid does not appreciably increase the viscosity of 900 mL
`of SGF10.
`Method variant 1 with manual mixing was designed to be most
`similar to typical clinical practice, in which thickened fluid is pre-
`pared and then a crushed tablet is added into it and mixed with a
`spatula or spoon. This standard method resulted in acetaminophen
`dissolution being only 36% by 30 min, with a dissimilar release pro-
`file (f2<50) to that of the whole tablet. The amount of drug meas-
`ured in a dissolution test for immediate release tablets should not
`be less than 85% of the labeled amount within 30 min according
`to FDA guidance information for immediate release solid forms27;
`however, acetaminophen dissolution did not reach this level even
`
` KINDERFARMS Ex. 1013
` KINDERFARMS LLC. v. GENEXA INC.
` PGR2023-00051
`
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`Page 6 of 9
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`1542
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`Y. J. MANRIQUE ET AL.
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`Table 3. Rheology of acetaminophen effervescent t