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`TECHNOLOGY CONFERENCE
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`,
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`,, SflmguLngm 7 ,
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`7 W,
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`April 12th - 14th 1994
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`19-SEP-1984 BLDSCBE§§§"7§“
`MRMCEUTICRL TECl-NOLOGY COHERENCE
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` 5
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`3
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`'J
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`Tuesday
`April 1 2th 1994
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`A CHARACTERIZATION OF THREE HPMC SUBSTITUTION GRADES:
`
`RHEOLOGICAL PROPERTIES AND DISSOLUTION BEHAVIOUR
`
`MC. Bonferoni, S. Rossi, R. Sinistri, C. Caramella
`
`Department of Pharmaceutical Chemistry, University of Pavia, V.Ie Taramelli 12,
`
`27100 Pavia, Italy
`
`INTRODUCTION
`
`Hydroxypropylmethylcelluloses (HPMC) represent a wide famin of polymers: each
`
`of the three subtitution types described in the US Pharmacopeia (2906, 2910 and
`
`2208) is available in a wide variety of molecular weights and under different
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`trademarks.
`
`The extensive and successful use of these polymers in pharmaceutical formulation
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`justifies the efforts still recently made to thoroughly characterize them. Both the
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`choice of the most suitable grade and the assessment of brand to brand variability
`
`and lot to lot reproducibility, require in fact the knowledge of the functionally
`
`relevant properties of the polymer.
`
`in particular, in hydrophilic matrix formulation,
`
`the influence of either the substitution type or the viscosity grade of the polymer on
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`the physical properties of the gel layer that is formed around the matrix is worth
`
`investigation (1,2).
`
`Alderman described marked differences in drug release control between the three
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`USP grades of HPMC.
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`In his findings, the 2906 grade (Methocel® F) gave the
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`fastest release, followed by the 2910 grade (Methocel® E) while the 2208 grade
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`(Methocel® K) produced the slowest release. These differences were explained by
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`considering the differing proportions of the hydrophobic methoxyl groups and of the
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`hydrophilic hydroxypropyl groups that characterize the three polymer grades. The
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`rate of polymer hydration was pointed out as a critical property towards controlled
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`drug release (3).
`
`More recently, a few studies dealt with the characterization of the three grades of
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`HPMC, with various results. V.S. Georgiannis et al. (4) compared for example the
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`three grades of HPMC in the formulation of floating matrices. The behaviour
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`observed agreed with the assumption of a K>E>F rank order of hydration rates. On
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`the contrary, Mitchell et al. found that the three grades of HPMC performed similarly
`
`in hydrophilic matrices containing propranoiol hydrochloride. They studied the
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`influence of substitution type of HPMC by using several techniques. Only cloud
`point determination was able to differentiate between the three grades, while no
`evidence of differences could be found when hydration rates were directly
`measured (2, 5).
`
`Besides the rate of hydration or gelation, other polymer properties have been
`considered in the literature as possibly relevant to drug release control. Among
`these are, for example,
`the viscosity and the gel strength of the matrix outer gel
`layer.
`it sounds conceivable that, as already suggested by Alderman (3), the
`viscosity and gel strength of the outer layer affect its resistance to dilution and
`erosion; the effect on drug release will depend, of course, whether erosion is a
`limiting step or not. The relationship between gel strength and erosion has been
`recently studied by Mitchell et al. They used a penetrometer to investigate
`differences in gel strength between the three substitution grades of HPMC. which
`resulted to behave very similarly (2).
`
`Another approach to the characterization of the gelified HPMC is based on
`rheological measurements. Previous studies have pointed out that the simple
`quotation of the viscosity grade of the polymer (which is expressed by the viscosity
`of a 1% or 2% polymer solution) does not provide a sufficient description of its
`rheological properties (6). Rheological characterization should be able to describe
`the interactions that take place between polymer chains in the gel network and that
`are,
`in turn, responsible for disentanglement and erosion processes.
`in order to
`better characterize these interactions, in a recent study viscoelasticity analysis was
`used. The NaCMC behaviour was investigated and a close relationship was found
`between a series of viscoelastlc parameters and sensitivity to erosion of the
`polymer. ln particular, it was found that an increase in resistance of the polymer to
`dilution (from hydrated gel-like solutions) and to erosion (from matrices) was
`accompanied by an increase in creep viscosity and oscillation parameters (storage
`modulus G' and loss modulus G") of the polymer gels (7).
`Aim of the present work was therefore to assess whether this kind of rheological
`analysis allow to reveal differences between three substitution grades of the same
`viscosity grade of HPMC. Creep and oscillatory tests were performed on 5% and
`7% (w/w) polymer solutions. Erosion rate was moreover evaluated from tablets, and
`the dissolution rate from already hydrated polymers (dilution) was measured on 5%
`w/w samples.
`
`in order to assess to what degree the observed differences between the three
`polymers affected drug release, matrices containing 60% of polymer and either a
`very soluble drug (diprophylline) or an insoluble one (acetazolamide) were
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`prepared and tested for drug release. For matrix preparation,
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`the same
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`granulometric fraction of the three HPMC grades was used.
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`EXPERIMENTAL
`
`MATERIALS
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`Three grades of HPMC were tested: Methocel® K4M, Methocel® E4M and
`Methocel® F4M (Colorcon Ltd, Orpington, UK). As model drugs diprophylline
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`(Proter, Milan,
`
`l) and acetazolamide (Sigma Chimica, Milan,
`
`l) were used. Lactose
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`was USP XXII grade.
`
`METHODS
`
`Cloud point measurement
`
`Cloud point measurements were carried out according to Mitchell et al (8) on 2%
`
`w/v solutions in distilled water. Trasmittance % was read at 800 nm by means of a
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`Spectracomp spectrophotometer (Advanced Products, Milan, l).
`
`Rheological studies
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`Polymer solutions at 5% w/w and 7% w/w were prepared in distilled water, taking
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`into account the content in water of the polymers. The samples were stored
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`overnight in refrigerator to allow complete hydration and were analysed within 24 h
`
`from the preparation. Rheological analysis was performed with a Bohlin CS
`
`Rheometer (Bohlin Reologi, W. Pabish, Milan,
`
`I) equipped with a cone and plate
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`system (CP 4/20). All measurements were conducted at 37 :t 2 °C. Dynamic
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`(oscillatory) tests, at frequencies ranging between 0.1 and 4.0 Hz, and constant
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`stress (creep) tests were carried out in the linear viscoelastic response range. From
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`creep curves residual viscosity was calculated; from oscillation tests (3' (storage
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`modulus) and G" (loss modulus) were obtained and tga (G"/G') was calculated.
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`Erosion studies
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`Erosion studies were performed by measuring the amount of HPMC dissolved both
`
`from gel-like solutions (dilution) and from tablets. All the tests were performed at
`37°C.
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`The same 5% w/w solutions characterized for their rheological behaviour were
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`centrifuged to remove entrapped air bubbles, and poured into cylindrical holders
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`(41 mm diameter and 12 mm height). These holders were placed in USP XXII
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`vessels containing 500 ml desaerated water; paddle apparatus (at 2.5 cm above
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`the samples) was used at 25 rpm.
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`300 mg tablets of sieved fractions (105-180 pm) of HPMC were prepared by means
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`of a hydraulic press for KBr discs (Perkin Elmer) equipped with a manometer, at 5
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`tons for 1 minute; a flat punch of 13 mm diameter was used. The tablets were glued
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`at the bottom of rotating discs. 500 ml of desaerated water in USP XXlI vessels
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`were used; rotation speed was 100 rpm. Both in the case of erosion and of dilution
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`tests, 5 ml samples were withdrawn at defined times and replaced with fresh
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`medium. All samples were filtered before analysis. The amount of dissolved
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`polymer was quantified by means of the anthrone method (9).
`
`Anthrone method
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`The reagent was prepared by dissolving 50 mg of anthrone in a mixture of 28 ml
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`water and 72 ml concentrated sulphuric acid. A mixture of 0.5 ml of sample and 2.5
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`ml of
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`reagent was heated 15 minutes in boiling water,
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`refrigerated and
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`spectrophotometrically read at 625 nm. Four standard solutions ranging from 0.1
`
`and 0.4 mg/ml were analysed together the samples and used to calculate a
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`calibration line.
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`Drug release studies
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`Matrices (200 mg total weight) containing either diprophylline or acetazolamide
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`were prepared by direct compression using an hydraulic press at 3 tons for 1 min,
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`with a 10 mm convex punch. Sieved fractions (105-180 pm) of HPMC were used.
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`The matrices contained 60% of polymer and either 40% of acetazolamide or 30% of
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`diprophylline (10% of USP XXll lactose was used in this case as diluent).
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`The release profiles were obtained in USP XXlI basket apparatus at 100 rpm, in
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`desaerated water (1000 ml for diprophylline; 500 ml for acetazolamide). Automatic
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`sampling was performed and absorbence was spectrophotometrically read at 273
`
`nm for diprophylline and at
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`265 nm for acetazolamide (Spectracomp
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`spectrophotometer; Advanced Products, Milan, l).
`
`RESULTS
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`The values of cloud point measured for the three polymers (70 °C for HPMC K4M,
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`57 °C for F4M and 54 °C for E4M) resulted in good agreement with those obtained
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`by Mitchell et al. (2) . They suggests that, for the three batches here examined, the
`K4M grade clearly differentiated from the other two grades, and that the F4M grade
`had slightly higher affinity for the hydration medium than the E4M grade.
`The creep viscosity values obtained from constant stress analysis (creep test) are
`given in Table l: for both concentrations, the K4M grade showed the highest and the
`E4M grade the lowest viscosity, whereas the F4M grade had intermediate viscosity
`values. The same rank order is observed in Table ll, where the results of the
`
`dynamic test at 0.1 Hz frequency are given for the 5% w/w solutions.
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`Table l: Residual viscosity values (from creep test) (Pas) for 5% and 7% w/w
`
`solutions. mean (isd) of 3 replicates
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`5%
`
`7%
`
`K4M
`
`E4M
`
`F4M
`
`314(i104)
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`78 (-106)
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`145 (:275)
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`1200 (i 70 0)
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`307 (a: 28 7)
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`517 (i 38 8)
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`Table ll: G' and G“ values (Pa) for 5% w/w solutions at 1 Hz frequency. mean (isd)
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`of 3 replicates
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`G'
`
`G"
`
`K4M
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`E4M
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`F4M
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`47.7 (i 0.97)
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`16.3 (i 0.14)
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`24.8 (i 1.77)
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`71.7 (:1: 1.70)
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`45.5 (i 0.14)
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`64.9 (i 2.55)
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`The dependence of G' and G“ on frequency is illustrated in Figure 1 for 7% w/w
`solutions. From these profiles it is possible to determine the intersection point of G'
`and G" curves on the frequency axis. When the frequency is lower than the
`
`time enough in each oscillatory cycle for the
`there is
`intersection point,
`rearrangement of the polymer chains, and viscous response can develop and
`prevail over the elastic one. The frequency value at which the elastic response
`overcomes the viscous one can be different depending on the material and is
`
`usually lower for samples with more pronounced elastic character. The results
`given in Figure 1 show that K4M grade had intersection point at lower frequency,
`
`meaning higher elasticity, with respect to F4M and E4M.
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`a G,
`+ G'-
`
`1
`
`2
`
`3
`
`4
`
`frequency (Hz)
`
`G G.
`+ Gll
`
`1
`
`2
`
`3
`
`4
`
`frequency (Hz)
`
`_G_ G,
`+ G"
`
`1
`
`2
`
`a
`
`4
`
`frequency (Hz)
`
`K4M
`
`E4M
`
`HM
`
`1500
`
`1000
`
`500
`
`o
`
`0
`
`1 500
`
`1 000
`
`500
`
`O
`
`0
`
`1500
`
`1000
`
`500
`
`o
`
`o
`
`N
`a.
`
`Gn
`
`.
`
`aa
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`.
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`Figure 1: Dependence of G' and G" on frequency for the three HPMC grades. mean
`(isd) of 3 replicates
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`This result is strictly related to the dependence on frequency of the tangent of the
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`phase angle between stress and strain (thor loss tangent); this is illustrated, for
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`7% w/w solutions of the three polymers, in Figure 2. The loss tangent is the ratio
`
`between loss modulus G" and storage modulus (3': lower values of this parameter
`
`indicate that the elastic component is more pronounced with respect to the viscous
`
`one, The lowest values of tga that can be observed in Figure 2 at each frequency for
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`the K4M grade (followed by F4M and E4M) means once more that the prevalence
`
`of elasticity over viscosity occurs according to the K>F>E order.
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`tga
`
`frequency (Hz)
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`Figure 2: Dependence of loss tangent (tga) on frequency for 7% w/w solutions of the
`
`three HPMC grades. mean (red) of 3 replicates
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`The release profiles of the polymers from 5% w/w hydrated samples (dilution) are
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`shown in Figure 3_ They are in agreement with the rheological characterization: it is
`
`conceivable that
`
`the same forces (weak chemical
`
`interactions and physical
`
`entanglements)
`
`that make the polymer chains to withstand strain during
`
`viscoelasticity tests, also hinder the polymer chains to leave the gel-like sample and
`to dissolve.
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`The erosion profiles (from tablets) are illustrated in figure 4; although very close to
`
`each other, they show that the erosion from tablets follows a different order than
`
`from gel-like solutions. These differences can be attributed to the combined effect of
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`hydration rate of the polymer and of the concentration gradient that is formed
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`around the matrix. The cl0ud point of the K4M grade means in fact that this sample
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`has very high hydration rate; this can overcome the slow release of K4M chains
`
`from the gelified layer. Concerning the concentration of the polymer in the gel layer,
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`as previous studies have pointed out (6.7), the dependence of the viscosity on
`
`concentration can be relevant for erosion phenomena.
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`200
`
`mgdissolved
`
`150
`
`100
`
`50
`
`time (h)
`
`Figure 3: influence of HPMC grade on erosion profiles from 5% w/w gels (dilution).
`
`mean (isd) of 6 replicates
`
`mgdissolved
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`time (h)
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`Figure 4: Influence of HPMC grade on erosion profiles from matrices of polymer
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`alone. mean (:sd)016 replicates
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`Figures 5 and 6 illustrate the release of diprophylline and of acetazolamide
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`respectively. from matrices containing 60% ot HPMC.
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`it
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`is possible to observe that no substantial differences can be seen when the
`
`soluble diprophylline is used as model drug, and diffusion—controlled release is
`involved.
`
`100
`
`80
`
`60
`
`40
`
`20
`
`o
`
`O
`
`G K4M
`4- E4M
`-fl- F4M
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`2
`
`4
`
`6
`
`8
`
`time (h)
`
`3
`U!
`
`m4
`
`’ E
`
`°\o
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`Figure 5: Release profiles of diprophylline from matrices containing 60% of the
`
`three HPMC grades. mean (:sd) of 3 replicates
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`°/oreleased
`
`0
`
`6
`
`12
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`18
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`24
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`Figure 6: Release profiles of acetazolamide from matrices containing 60% of the
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`three HPMC grades. mean (isd) of 3 replicates
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`in the case of the less soluble drug (acetazolamide), when erosion of the matrix is
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`likely to play a more relevant role, differences between the behaviour of the three
`
`HPMC grades become more evident and seem to parallel the erosion behaviour of
`tablets of polymer alone.
`
`CONCLUSIONS
`
`to thouroughly describe the rheological
`Viscoelasticity tests are instrumental
`properties of a sample; they proved here to be sensitive enough to evidence
`differences, although very subtle, between materials having similar structure.
`Good parallelism has been found between the rheological behaviour of a gel and
`its rate of dilution. This confirms that the polymer~polymer and polymer-solvent
`interactions that are responsible for the gel network structure and for its sensitivity to
`erosion can be quite well described by a deep rheological analysis.
`The erosion from tablets resulted however very slow and the differences between
`
`the three grades could not be directly related to the rheological behaviour.
`The use of sieved fractions should have reduced the effect of particle size on
`porosity of the matrix and in turn on water intake. However, it must be taken in mind
`that other factors, such as the hydration rate of the polymer and its gradient of
`concentration along the outer gel layer, can play a role in matrix systems.
`Concerning drug release, the three HPMC grades controlled very similarly the
`release of diprophylline;
`in the case of poorly soluble acetazolamide, where
`erosion is likely to be more important, release rates show the same order as
`
`erosion rates from polymer tablets.
`
`Acknowledgements
`
`The authors wish to thank Dr. J.E. Hogan (Colorcon Ltd, Orpington, UK) for the kind
`gift of the Metl’iocel® samples.
`
`Work partially supported by MURST.
`
`REFERENCES
`
`1) CD. Melia: Hydrophilic matrix sustained release systems based on
`polysaccharide carriers. Crit. Rev. Ther. Drug Carrier Systems 8 (1991), 395-421
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`2) K. Mitchell. J.L. Ford, D.J. Armstrong, P.N.C. Elliott, J.E. Hogan, C. Restron: The
`
`influence of substitution type on the performance of methylcellulose and
`
`hydroxypropylmethylcellulose in gels and matrices. lnt. J. Pharm. 100 (1993), 143-
`154
`
`3) DA. Alderman: A review of cellulose ethers in hydrophilic matrices for oral
`
`controlled release dosage forms. lnt. J. Pharm. Tech and Prod. Mfr, 5 (3) (1984), 1-9
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`4) VS. Georgiannis, D.M. Rekkas, P.P. Dallas and NH. Choulis: Floating and
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`swelling characteristics of various excipients used in controlled release technology.
`
`Proceedings of the 12th Pharmaceutical Technology Conference (1993), 54-73.
`
`5) K. Mitchell, J.L. Ford, D.J. Armstrong, P.N.C. Elliott, C. Rostron, J.E. Hogan: The
`
`influence of concentration on the release of drugs from gels and matrices
`
`containing Methocel®. Int. J. Pharm., 100 (1993), 155-163
`
`6) MC. Bonteroni, C, Caramella, M.E. Sangalli, U. Conte, R.M. Hernandez, J.L.
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`Pedraz: Rheological behaviour of erodible polymers and drug release from
`
`erodible matrices. J. Controlled Rel, 18 (1992), 205-212
`
`7) MC. Bonferoni, S. Rossi, C. Caramella, U. Conte: Rheological properties and
`
`sensitivity to erosion of sodim carboxymethylcellulose. Proceedings of 6th
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`International Conference on Pharmaceutical Technology (1992), 241-249
`
`8) K. Mitchell, J.L. Ford, D.J. Armstrong, P.N.C. Elliott, C. Rostron, J.E. Hogan: The
`
`influence of additives on the cloud point, disintegration and dissolution of
`
`hydroxypropylmethylcellulose gels and matrix tablets.
`233-242
`
`Int. J. Pharm., 66 (1990),
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`9) D.L. Morris: Quantitative determination of carbohydrates with Dreywood's
`
`anthrone reagent. Science, 107 (1948). 254
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`140
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