`
`FLOATING AND SWELLING CHARACTERISTICS OF VARIOUS
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`V.S. Gerogiannis, D.M. Rekkas, P.P. Dallas and N.H.Choulis
`University of Athens, Department of Pharmacy,
`Division of Pharmaceutical Technology,
`Panepistimioupolis 157 71, Athens, Greece
`
`ABSTRACT
`
`During the past few years, great interest was developed in the subject of
`
`floating. In the present study, the floating and swelling characteristics of
`
`several excipients used controlled release technology were examined. The
`
`floating behavior was evaluated with resultant weight measurements, while a
`
`gravimetric method was employed for studying their swelling. The experiments
`
`were carried out in two different media, i.e. deionized water and simulated
`
`meal in order to monitor possible differences. The results indicated that higher
`
`molecular weight polymers and slower rates of polymer hydration are usually
`
`followed by enhanced floating behavior. The floating characteristics of all
`
`evaluated excipients were improved when simulated meal medium was used.
`
`Finally, the combination of resultant weight measurements and swelling
`
`experiments can be used to determine in vitro the buoyancy, weight and
`
`Presented at 11th Pharm. Tech. Conf., April 6-8, 1992, Manchester, U.K.
`
`1061
`
`Copyright © 1993 by Marcel Dekker, Inc.
`
`MYLAN EXHIBIT - 1045
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd. - IPR2022-00722
`
`
`
`1062
`
`GEROGIANNIS ET AL.
`
`volume changes of orally administered dosage forms and to predict floating
`
`behavior.
`
`INTRODUCTION
`
`Gastrointestinal (GI) residence time depends on many factors such as the
`
`density of the dosage form (1, 2, 3), the size of the dosage form (1, 3), meal
`
`intake (4, 5, 6), nature of the meal (4, 7), sleep (8), posture (9), exercise (10),
`
`etc.
`
`Many researchers (11, 12, 2, 13, 14) have suggested that a floating
`
`dosage form may either prolong GI residence time or at least prevent erratic
`
`gastric emptying during the digestive phase (1). Moreover, during the past
`
`few years, several dosage forms, like the Hydrodynamically Balanced System
`
`(I-113S) (11), were designed to prolong GI residence time due to their floating
`
`capabilities. Under that scope, it would be useful to examine the floating and
`
`swelling characteristics of several excipients used in controlled release
`
`technology. To achieve that, resultant weight and water uptake measurements
`
`of several dosage forms, immersed in specific media, were performed, and
`
`volume changes were monitored at various time intervals.
`
`MATERIALS AND METHODS
`
`All excipients were filled volumetrically, by a manual method, into size 2
`
`hard gelatin capsules (Capsugel AG, CH).
`
`
`
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1063
`
`The excipients used were: Hydroxypropyl methylcellulose (HPMC):
`
`Methocel grades K, E and F (Colorcon, U.K.), sodium carboxymethylcellulose:
`
`CMCNa, (Aqualon, U.S.A.), hydroxypropylcellulose: HPC grade H (Nisso,
`
`Japan), Polycarbophil: Noveon AA1 (BF.Goodrich, U.S.A.) ,poly(ethylene)oxide:
`
`Polyox grades WSR N-750 and WSR-303 (Union Carbide, U.S.A.), sodium
`
`alginate: Protanal LF 20/200 and Protanal LF 120M (Protan Biopolymer A/S,
`
`Norway).
`ValreleaseR capsules (Hoffmann-La Roche) were also evaluated.
`
`Test Media
`
`- Air free deionized water (D.W.) (density =0.997gr/ml)
`
`- Simulated meal medium (S.M.M.), prepared by mixing the complete
`
`nutrition product EnsureR
`
`(Abbott Laboratories, Hellas) with the adequate
`
`amount of deionized water (5.0/4.6) (density= 1.033gr/ml).
`
`Floating Measurements
`
`The floating characteristics of the above excipients were evaluated with
`
`resultant weight measurements. Resultant Weight Force (FRW) is a vertical
`
`force and represents the vectorial sum of the buoyancy (F8) and gravity (Fw)
`
`forces which act on an object when it is immersed in a specific medium (15)
`
`(Equation 1).
`
`FRW = FB - Fw = > RW.g = B.g-W.g = > R.W = B-W = df.V-W
`
`(1)
`
`where: g is the acceleration of gravity, df is the fluid density and V, W are the
`
`volume and the weight of the object respectively. RW was measured in vitro.
`
`Each excipient was examined at least three times. The apparatus used, which
`
`
`
`1064
`
`GEROGIANNIS ET AL.
`
`2 1
`
`0
`3
`
`4
`
`5
`
`6
`
`1. Balance
`2. Interface
`3. Water-bath
`4. Test medium
`5. Computer
`6. Printer
`
`Figure 1: The resultant weight measurement
`
`apparatus.
`
`is shown in Figure 1, was based on the one developed recently by
`
`Timmermans and Moes (16,17,18). The most important difference was that
`
`the balance (Mettler AE200) was connected through an RS 232C interface to
`
`a Personal Computer and the recorder was substituted by a printer. Thus, at
`
`any time an exact indication (gr) of the RW value was available. The
`
`
`
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1065
`
`apparatus was validated through comparison of theoretical and experimental
`
`data for spherical objects. The difference between the mean experimental and
`
`the mean theoretical value of RW was not greater than 0.87%. A standard
`
`deviation (SD) of less than 0.0042 was calculated between five subsequent
`
`measurements.
`
`Swelling Measurements
`
`A gravimetric method (19, 20, 21, 22) was considered to be the most
`
`suitable in order to study the swelling behavior of the excipients. The
`
`capsules, containing the excipients, were kept in USP dissolution baskets
`
`without rotation. The wet weight of the swollen dosage form was recorded at
`
`specific time intervals. Swelling characteristics were expressed in terms of
`
`water uptake (WU) (%) (22, 23) according to the equation 2:
`
`(W of swollen form - initial W of the form)
`WU(%) =
`x100
`(2)
`
`initial W of the form
`
`RESULTS AND DISCUSSION
`
`The selected excipients are polymeric materials that can absorb a
`
`significant amount of water (more than 20% of their dry weight), while
`
`maintaining a distinct three-dimmensional structure. As a result, they conform
`
`to the definition of hydrogels provided by Gehrke et al, (24). When a dosage
`
`form is immersed in a specific medium and after the dissolution of the gelatin
`
`capsule, an outer gel layer is formed, accompanied by an increase of its
`
`volume. The process of erosion, due to dissolution of the gel formed or to
`
`
`
`1066
`
`GEROGIANNIS ET AL.
`
`deaggregation (20), and the creation of new gel layers affect both the volume
`
`and the weight of the dosage form.
`
`The RW force which is responsible for floating depends on both the
`
`weight and the buoyancy forces, as shown in equation 1. Water uptake and,
`
`consequently, weight gain should be compensated by adequate swelling in
`
`order to keep the dosage form at buoyant state. RW data for each dosage
`
`form were plotted versus time. Representative graphs are shown in Figures 2
`
`and 3. In all cases RW decreased in a step-like pattern, due to the periodic
`
`release of air bubbles created by the substitution of air, enclosed in pores of
`
`the formulation, by the test medium. Such a phenomenon does not take
`
`place in the case of Valrelease (Figure 2),which maybe due to the
`
`compression of the capsule contents. This observation is in aggreement with
`
`previous findings of Timmermans et al (16,17,18).
`
`In each graph, the
`
`horizontal zero baseline represents the measurement obtained by the
`
`apparatus when no dosage form was immersed. The point where an RW
`
`graph crosses the zero baseline indicates the Maximum Floating Time (MFT),
`
`namely, the time period a dosage form remains at buoyant state, when
`
`immersed in a specific medium. An additional criterion applied in the
`
`evaluation of excipients was the Area Under the Curve (AUC), i.e. the area
`
`between the RW curve and the zero baseline. These data are summarized in
`
`Table 1.
`
`According to Table 1, it can be derived that different viscosity grades of
`
`the same polymer display significant differences both in AUC and MFT values.
`
`
`
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`-4
`
`•
`
`Methocel K 4M
`Valrelease
`
`II
`
`f1111/tfff
`
`0
`
`LT]
`
`280 ;
`260
`17
`
`2224001 11
`200
`TT
`180;
`It
`160
`
`I
`
`201-qIIIT
`18
`100
`± I
`
`60 24'
`40i
`
`—20
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`TIME ( HRS )
`
`Figure 2: Resultant Weight measurements versus time for Methocel K 4M
`size 2 hard gelatin capsules and Valrelease capsules in water.
`Bars indicate SD. Dotted line represents baseline.
`
`
`
`"IV 12 SINNVIDOIIRD
`
`300 .
`280 i: 'T
`I I
`260-i;
`240
`220-] II
`200
`180,!.
`160
`140;
`120
`100-
`80i
`60i
`40i
`201:
`0*
`-20 '
`0
`
`RESULTANT WEIGHT
`
`Deionized Water
`Meal Medium
`
`I
`
`I
`
`A.
`
`T T
`I t
`TIT .
`III
`
`IIT IAIIII.
`'III'
`
`IIIII,
`Iiiiia
`
`0
`,
`1
`
`D
`,
`2
`
`D
`
`,
`3
`
`TI
`AAA.AitiiiiI
`IIlifiiiii
`.. -----------
`
`,
`4
`6
`
` .
`5
`
`.11
` !
`7
`
`8
`
`TIME ( HRS )
`
`Figure 3: Resultant Weight measurements versus time for Methocel K 4M
`size 2 hard gelatin capsules in water and meal medium. Bars
`indicate SD. Dotted line represents baseline.
`
`
`
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1069
`
`Table 1: Area Under the Curve (AUC) and Maximum Floating Time
`
`(MFT) derived from Resultant Weight measurements of
`
`dosage forms. Parentheses indicate SD.
`
`Dosage Form
`
`Medium
`
`AUC (MG HR)
`
`
`
`MFT (HR)
`
`i
`
`Methocel K 4M
`
`D.W.
`
`487.9 (65.8)
`
`5.1 (0.5)
`
`Methocel K 4M
`
`S.M.M.
`
`844.7 ( 6.3)
`
`>8
`
`Methocel K 100M
`
`D.W.
`
`716.2 (52.8)
`
`6.9 (0.2)
`
`Methocel K 100M
`
`S.M.M.
`
`1026.1 (102.0)
`
`>8
`
`Methocel K 100M CR
`
`D.W.
`
`632.1 (44.2)
`
`6.3 (0.9)
`
`Methocel K 100M CR
`
`S.M.M.
`
`620.1 (18.9)
`
`>8
`
`Methocel E 4M
`
`D.W.
`
`624.8 (21.5)
`
`6.1 (0.3)
`
`Methocel E 4M
`
`S.M.M.
`
`739.1 (18.1)
`
`7.2 (0.8)
`
`Methocel E 10M CR
`
`D.W.
`
`992.3 (15.7)
`
`>8
`
`Methocel F.4M
`
`CMC Na
`
`HPC H
`
`Noveon AA1
`
`Polyox 750
`
`Polyox 303
`
`Polyox 303
`
`D.W.
`
`D.W.
`
`D.W.
`
`D.W.
`
`D.W.
`
`D.W.
`
`692.1 (38.7)
`
`7.9 (0.1)
`
`456.8 ( 9.5)
`
`6.1 (0.1)
`
`171.5 ( 9.8)
`
`3.8 (0.2)
`
`35.8 ( 0.5)
`
`0.4 (0 )
`
`115.1 ( 2.2)
`
`1.7 (0.7)
`
`711.7 (36.0)
`
`S.M.M.
`
`1120.2 (64.0)
`
`>8
`
`>8
`
`Protanal LF 20/200
`
`D.W.
`
`247.5 (17.7)
`
`2.1 (0.2)
`
`Protanal LF 120M
`
`D.W.
`
`259.6 ( 2.0)
`
`2.4 (0.5)
`
`Protanal LF 120M
`
`S.M.M.
`
`286.1 ( 6.7)
`
`4.5 (0.3)
`
`Valrelease
`
`D.W.
`
`439.9 (30.0)
`
`7.9 (0.1)
`
`Valrelease
`
`S.M.M.
`
`661.6 (20.2)
`
`>8
`
`D.W. : Deionized Water
`S.M.M.: Simulated Meal Medium
`
`
`
`1070
`
`GEROGIANNIS ET AL.
`
`Particularly, Methocel K 100M displays better floating capabilities compared
`
`to Methocel K 4M (46.7% greater AUC, 34.3% longer MFT). According to the
`
`product's information pamphlet (25), Methocel K 100M has greater Molecular
`
`Weight (MW) than Methocel K 4M. The same was observed in the case of
`
`Polyox polymers (Table 1). Polyox 303 (M.W. 7.000.000) shows 618.3%
`
`greater AUC and more than 479% longer MFT compared to Polyox 750 (M.W.:
`
`300.000). From the above observations, it can be concluded that as the M.W.
`
`of these polymers increases, their floating characteristics are enhanced.
`
`Chemical substitution of Methocel polymers seems to affect the floating
`
`characteristics as well. According to the product's information pamphlet (25)
`
`the differences in chemical substitution result in different rates of hydration.
`
`The lowest percentage of the hydrophobic substituent (methoxyl group) and
`
`the highest amount of hydrophilic (hydroxylpropoxyl) substitution give to
`
`Methocel K series the fastest rate of hydration compared to E and F series.
`
`The findings displayed on Table 1 indicate that there might be some kind of
`
`correlation between the rate of hydration and floating characteristics among
`
`polymers of the same viscosity grade. Methocel K 4M, for instance, which has
`
`the fastest rate of hydration displays 21.9% smaller AUC and 16.4% shorter
`
`MFT compared to Methocel E 4M, which is the next fastest. Methocel K 4M
`
`also shows 29.5% and 35% smaller AUC and MFT values respectively when
`
`compared to F 4M, which has the slowest rate of hydration. It should be
`
`mentioned, however, that the above explanation contradicts with previously
`
`conducted research (26) which indicated that the rates of hydration between
`
`HPMC series are not significantly different.
`
`
`
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1071
`
`From Table 1, it can be concluded that Methocel K 100M (90% passed
`
`through a 40 mesh screen) exhibits more than 13.3% longer MFT and 9.5%
`
`larger AUC compared to Methocel K 100MCR (99% passes through an 100
`
`mesh screen). A similar effect of particle size is also observed in the case of
`
`sodium alginate. Protanal LF 120M (99% passes through 120 mesh screen)
`
`displays 10.1% and 32.3% larger AUC and MFT values respectively (Table 1)
`
`compared to Protanal LF 20/200 (99% passes through a 200 mesh screen).
`
`Although the polymer's particle size seems to have some effect on floating
`
`behavior, the differences were not found significantly different ( t test,
`
`p< 0.01).
`
`The floating behavior of the various dosage forms depends upon the
`
`medium used as well (Table 1).
`
`This has also been suggested by
`
`Timmermans et al (16,17,18). Dosage forms displayed larger ADCs and
`
`longer MFTs when immersed in SMM. The higher density of SMM compared
`
`to DW leads to higher buoyancy values for the same dosage form volume.
`
`Moreover, this effect may be attributed to the presence of fatty substances
`
`which delay water uptake. Excluding Methocel K 100M CR which showed
`
`similar AUC in both DW and SMM, the rest of excipients displayed an at least
`
`10% higher AUC when immersed in SMM compared to DW. All excipients
`
`increased their MFT for at least 18% in SMM. It should also be mentioned that
`
`all members of Methocel K series under evaluation remained buoyant for more
`
`than 8 hours when the test medium was SMM.
`
`Swelling measurements were performed separately in order to collect data
`
`on the weight increase of the various forms over time and also to examine if
`
`
`
`1072
`
`GEROGIANNIS ET AL.
`
`there is any correlation with the previous findings on the floating behavior of
`
`excipients. Water Uptake (%) (Equation 2) data were plotted versus time
`
`(Figures 4, 5). The above graphs express the swelling behavior of a range of
`
`excipients both in DW and SMM. It should be pointed out that such data alone
`
`cannot provide accurate information on floating characteristics, which is
`
`depicted by the fact that dosage forms such as Polyox 303 and Valrelease,
`
`with radically different WU profiles, display both excellent floating behavior.
`
`To investigate further the previous findings Buoyancy (B) has been also
`
`estimated. Based on Equation 1, B can be calculated by adding RW and the
`weight (W) of the dosage form at a specific time point. Both B and W data
`
`were plotted versus the square root of time. Then regression analysis was
`
`performed. In all cases, regression lines for B versus the square root of time
`
`displayed greater intercept and smaller slope values compared to W versus
`
`the square root of time lines. At the point where the regression lines of B and
`
`W cross each other, i.e. when B equals W, the dosage form starts sinking
`
`(Figure 6). Therefore, that point represents Mr-r, and, thus the above
`
`regression equations can be applied effectively in calculating mathematically
`
`MFT. Additionally, the volume (V) of a dosage form can be calculated by
`
`dividing B by the test medium density. Since the volume of orally
`
`administered dosage forms could influence GI residence time (27) the above
`
`measurements can be very useful. The calculated volumes at various time
`
`points of several dosage forms, after immersion in a specific medium, are
`
`shown in Table 2. According to this Table, Polyox 303 acquires after eight
`
`
`
`ri
`x
`n
`1-g
`rri
`Z
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`c4
`C
`ci)
`Cr] c
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`
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`
`O
`r
`r
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`O
`
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`> ci)
`rri
`—3
`rri
`C-)
`X
`Z
`O r
`O
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`-<
`
`T ..... .............:L
`
`......-----.1'.
`
`'
`
`A
`
`1":"."
`
`"I
`
` r
`
`-----------1.--
`
`O
`
`2000
`
`1750 -
`
`1500--
`
`1250--
`
`1000 --
`
`750 -
`
`500 -
`
`250-
`
`WATER UPTAKE ( % )
`
`0
`0
`
`I
`1
`
`I
`2
`
`3
`
`I
`4
`
`I
`5
`
`I
`6
`
`I
`7
`
`I
`8
`
`I
`9
`
`I
`10 11
`
`TIME ( HRS )
`
`Figure 4: Water Uptake ( % ) for a series of excipients, filled in size 2
`hard gelatin capsules, in deionized water. Bars indicate SD.
`•) Methocel K 100M, (a —a)
`(0-0) Methocel K 4M, (•
`•) Polyox 303, (O-O) Valrelease.
`Methocel K 100M cr, (4
`
`
`
`'1V J2 SINNVI9021gD
`
`2000
`
`1750 -
`
`1500--
`
`1250 -
`
`1000 -
`
`750--
`
`500 -
`
`250 -
`o
`0
`
`.......................___-----.I.
`
`.........
`
`I''
`
`1
`
`1.------___T
`I
`
`/ •••
`
`I
`1
`
`I
`2
`
`I
`3
`
`I
`4
`
`I
`5
`
`I
`6
`
`I
`7
`
`I
`8
`
`I
`9
`
`I
`10 11
`
`TIME ( HRS )
`
`Figure 5: Water Uptcke ( % ) for a series of excipients, filled in size 2
`hard gelatin capsules, in meal medium. Bars indicate SD.
`A)
`(0-0) Methocel K 4M, (•—•) Methocel K 100M, (•
`Polyox 303 and (D—o) Valrelease.
`
`
`
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`o Weight
`• Buoyancy
`
`I JOU
`
`1.500-
`
`c
`m 1.250-
`......
`-4-•
`l
`a
`
`
`
`1 .000
`
`--
`
`------
`T ..--•-.
`0.750 7.--------. 1
`
`0.500—
`
`U
`O
`), o
`=
`m 0.250 —
`
`0.000
`0
`
`1
`
`2
`
`3
`
`4
`
`VTIME( HRS )
`
`Figure 6: Buoyancy and Weight versus -Vtirne for Methocel K 4M size 2
`hard gelatin capsules, in water. The continuous and dotted
`lines represent the regression lines for Buoyancy and Weight
`respectively. Bars indicate SD.
`
`
`
`1076
`
`GEROGIANNIS ET AL.
`
`Table 2: Volume of several excipients filled in size 2 hard
`
`gelatin capsules after immersion in a particular
`
`medium. Bars indicate SD.
`
`Volume (ML)
`
`Time (HR)
`
`Dosage Form
`
`Medium
`
`1.0
`
`4.0
`
`8.0
`
`Methocel K 4M
`
`D.W. 0.930 (0.014) 1.275 (0.027) 1.312 (0.055)
`
`Methocel K 4M
`
`S.M.M. 0.959 (0.074) 1.201 (0.025) 1.278 (0.122)
`
`Methocel K 100M
`
`D.W. 0.969 (0.060) 1.404 (0.068) 1.864 (0.175)
`
`Methocel K 100M CR
`
`D.W. 1.170 (0.106) 1.591 (0.059) 1.979 (0.204)
`
`Methocel K 100M CR S.M.M. 1.045 (0.050) 1.333 (0.116) 1.669 (0.064)
`
`Methocel E 4M
`
`D.W. 1.002 (0.099) 1.349 (0.083) 1.521 (0.083)
`
`Methocel E 4M
`
`S.M.M. 1.205 (0.042) 1.575 (0.147) 1.482 (0.122)
`
`Methocel E 10M CR
`
`D.W. 1.083 (0.057) 1.983 (0.197) 2.173 (0.279)
`
`Methocel F 4M
`
`D.W. 1.013 (0.021) 1.298 (0.113) 1.317 (0.103)
`
`Polyox 303
`
`D.W. 1.901 (0.054) 2.812 (0.047) 3.432 (0.084)
`
`Polyox 303
`
`S.M.M. 0.973 (0.070) 1.710 (0.001) 1.789 (0.125)
`
`Valrelease
`
`D.W. 0.733 (0.058) 1.425 (0.013) 1.292 (0.124)
`
`Valrelease
`
`S.M.M. 1.043 (0.077) 1.577 (0.176) 1.477 (0.040)
`
`D.W. : Deionized Water
`S.M.M.: Simulated Meal Medium
`
`
`
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1077
`
`Table 3: Slopes of the regression lines of Weight (Slope W)
`
`and Volume (Slope V) versus the square root of time,
`
`for excipients filled in size 2 hard gelatin capsules.
`
`Parentheses indicate SD.
`
`Dosage Form
`
`Medium
`
`Slope W
`
`Slope V
`
`SlopeW
`
`SlopeV
`
`Methocel K 4M
`
`D.W.
`
`0.406 (0.079) 0.287 (0.088) 1.41
`
`Methocel K 4M
`
`S.M.M. 0.371 (0.080) 0.247 (0.084) 1.50
`
`Methocel K 100M
`
`D.W.
`
`0.591 (0.044) 0.500 (0.707) 1.18
`
`Methocel K 100M CR
`
`D.W.
`
`0.593 (0.042) 0.477 (0.039) 1.24
`
`Methocel K 100M CR S.M.M. 0.523 (0.053) 0.401 (0.052) 1.30
`
`Methocel E 414
`
`D.W.
`
`0.482 (0.033) 0.353 (0.018) 1.36
`
`Methocel E 4M
`
`S.M.M. 0.359 (0.027) 0.221 (0.016) 1.63
`
`Methocel E 10M CR
`
`D.W.
`
`0.706 (0.242) 0.626 (0.243) 1.13
`
`Polyox 303
`
`D.W.
`
`1.016 (0.089) 0.967 (0.093) 1.05
`
`Polyox 303
`
`S.M.M. 0.648 (0.057) 0.547 (0.051) 1.18
`
`D.W. : Deionized Water
`S.M.M.: Simulated Meal Medium
`
`hours of immersion in DW the larger V, 8.7 times greater compared to its initial
`
`V. Moreover, the measurment of V helps identifying which of the two
`
`processes -weight gain or volume expansion- is more important for a particular
`
`excipient. For that purpose, W and V were plotted versus the square root of
`
`time and regression analysis was performed for the first eight hours. The
`
`slopes of these regression lines, for some of the excipients used, are shown
`
`
`
`1078
`
`GEROGIANNIS ET AL.
`
`in Table 3. In all cases, the slopes of W increase versus the square root of
`
`time were larger than those of V increase. The slower rate of V increase
`
`compared to W increase indicates that after a particular time point, V
`
`expansion can not generate a buoyancy force substantial enough to
`
`counteract W increases. It should also be mentioned that the slopes of both
`
`W and V are decreased in SMM compared to DW. In order to investigate
`
`further the above findings, the ratio of the slope of W over the slope of
`
`V(slopeW/slopeV), versus the root of time was calculated. This ratio seems
`
`to correlate with the floating behavior of the excipients. More specifically, the
`
`lower the value of the ratio, the better the floating characteristics. As a
`
`consequence, the floating behavior of an excipient can be predicted by
`
`monitoring W and V over a time period.
`
`CONCLUSION
`
`Resultant Weight measurements of excipients, widely used in controlled
`
`release technology, show that higher molecular weight polymers and slower
`
`rates of polymer hydration are usually followed by enhanced floating behavior.
`
`Therefore, the selection of high molecular weight and less hydrophilic grades
`
`of polymers seem to improve floating characteristics. The floating behavior of
`
`all evaluated excipients was enhanced when simulated meal medium was
`
`used instead of distilled water. The resultant weight measurements combined
`
`with swelling experiments can be used to determine in vitro the buoyancy and
`
`volume changes versus time of various orally administered dosage forms. The
`
`
`
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1079
`
`slopes of weight, volume and buoyancy of dosage forms versus the square
`
`root of time provide important information on their behavior, when immersed
`
`in a specific medium, and can be effectively applied to predict floating
`
`behavior.
`
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`
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`