International Journal of Pharmaceutics 293 (2005) 35–42
`
`Release characterization of dimenhydrinate from an eroding and
`swelling matrix: selection of appropriate dissolution apparatus
`∗
`
`Shahrzad Missaghi, Reza Fassihi
`
`Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140-0000, USA
`
`Received 6 August 2004; received in revised form 9 December 2004; accepted 10 December 2004
`
`Abstract
`
`The objective of this study was to evaluate the effect of various hydrodynamic conditions on drug release from an eroding and
`gel forming matrix. For this purpose, dimenhydrinate was formulated with hydroxypropyl methyl cellulose and polyethylene
`oxide into matrix tablets and the drug release in deionized water was evaluated spectrophotometrically, using multiple dissolution
`methods, namely, compendial USP 27-apparatus I–III, and a modified apparatus II (paddle over mesh). Various hydrodynamic
`conditions were examined at the agitation rates of 50 and 100 rpm for apparatus I and II, and 5 and 8 dpm for apparatus III.
`Similarity and difference factors were calculated using compendial apparatus II release data as reference. Among the methods,
`apparatus I showed the slowest initial release, while the release from apparatus III at 8 dpm was the highest among the methods.
`This was further compared via the dissolution half-times and calculation of the average release rate for each method. Based on
`the analysis of difference and similarity factors (f1 and f2), the study clearly demonstrates the significance of hydrodynamics
`and the choice of a dissolution method and their respective effect on overall release profiles when erodible and swellable matrix
`systems are involved. Full surface exposure with insertion of mesh device in apparatus II may provide more realistic conditions
`especially when release data are to be used in developing IVIVCs.
`© 2005 Elsevier B.V. All rights reserved.
`
`Keywords: Dimenhydrinate; Dissolution apparatus; Swelling and eroding matrix; Hydrodynamic effect; Similarity and difference factors;
`Modified release systems
`
`1. Introduction
`
`Drug release from the dosage form and its subse-
`quent absorption depends upon the physicochemical
`properties of the drug, delivery system, and the phys-
`
`∗
`
`Corresponding author. Tel.: +1 215 707 7670;
`fax: +1 215 707 3678.
`E-mail address: reza.fassihi@temple.edu (R. Fassihi).
`
`0378-5173/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
`doi:10.1016/j.ijpharm.2004.12.024
`
`iologic environment within the gastrointestinal tract.
`Based on the Noyes–Whitney and Nernst–Brunner
`models, several factors may influence the drug dissolu-
`tion kinetics, including, the effective surface area of the
`solid drug, diffusion coefficient of the drug, thickness
`of diffusion layer, the saturation solubility of the drug,
`volume of the dissolution medium, and the amount of
`drug in the solution. It is also known that the perme-
`ability of the gastrointestinal tract to the drug molecule
`
`ENDO - Ex. 2034
`Amneal v. Endo
`IPR2014-00360
`
`

`

`36
`
`S. Missaghi, R. Fassihi / International Journal of Pharmaceutics 293 (2005) 35–42
`
`plays a role in maintaining the sink condition, hence
`influencing both dissolution rate and bioavailability of
`the drug (Dressman et al., 1988; Martin et al., 1993).
`In vitro dissolution testing is a requirement in all
`USP monographs of oral solid dosage forms, where
`drug absorption is essential in order to achieve a thera-
`peutic effect. Drug dissolution study is an integral part
`of quality control (QC), and it also plays an important
`role in pharmaceutical product development to assist
`in selection of a candidate formulation, and in research
`in order to detect the effect of different manufactur-
`ing variables such as granulation procedure, excipi-
`ents type, coating parameters, for comparative studies
`of different formulations, in vitro–in vivo correlations
`(IVIVC), and possibly as a biowaiver under strictly
`defined conditions (Qureshi and McGilveray, 1995;
`Pillay and Fassihi, 1998; D¨urig and Fassihi, 2000; FDA,
`2000) (Fig. 1; Pillay, 2000).
`In the case of swelling and eroding controlled re-
`lease dosage forms, it is paramount to understand the
`interrelationship between physicochemical and hydro-
`dynamic conditions in attaining sensitive and repro-
`ducible dissolution data. Several dissolution methods
`have been described in the USP; however, the selection
`of the appropriate method and data interpretation is not
`easily affordable due to the influence of technologi-
`cal differences and manufacturing process, involved in
`product design, on the dissolution outcome (Pillay and
`Fassihi, 1998; D¨urig and Fassihi, 2000).
`The importance of dissolution testing, its sensitiv-
`ity to various factors, and consequently its impact on
`bioavailability is well recognized during the regulatory
`review. As a result, CDER (Center for Drug Evaluation
`and Research) at the FDA (Food and Drug Adminis-
`tration) has released guidelines such as BCS (Biophar-
`maceutical Classification Scheme) (FDA, 2000), and
`SUPAC (scale up and post approval changes) (FDA,
`1997a) and their applications to dosage from design,
`potential post approval changes and establishment of
`IVIVC (FDA, 1997b). In addition, CDER has recently
`released a draft guidance document in regard with PAT
`(process analytical technology), as a framework for
`innovative pharmaceutical manufacturing, design and
`quality assurance (FDA, 2003).
`The diversity of dosage form designs, the new tech-
`nologies in development of modified release formula-
`tions, the existing problems associated with current dis-
`solution testing procedures and the regulatory concerns
`
`mandate the dissolution studies to be performed with
`scrutiny and under specified conditions. For certain
`non-conventional dosage forms, it may also necessi-
`tate appropriate modification to the current methods or
`potentially the development of new procedures (Pillay
`and Fassihi, 1998; D¨urig and Fassihi, 2000). For in-
`stance, Muzzio et al., using a computational model,
`have recently reported that a possible reason for high
`variations, observed in the dissolution profiles of cer-
`tain delivery systems obtained with USP apparatus II,
`is the relative positioning of tablets in the dissolution
`vessels, hence, the difference in hydrodynamic effects
`and fluid shear forces in each test vessel (Haystead,
`2003; Kukura et al., 2003). Similar results have been
`presented elsewhere as well (Khoury et al., 1988;
`Bocanegra et al., 1990; Kamba et al., 2003). Dosage
`form positioning within the dissolution vessels is espe-
`cially of importance when dealing with low or high den-
`sity delivery systems, where the position of the dosage
`form may vary due to floatation or sticking issues re-
`spectively. This further leads to inconsistent impact of
`hydrodynamics on the dosage form within the vessels
`(Pillay and Fassihi, 1998; D¨urig and Fassihi, 2000).
`Therefore, a more in depth understanding of the role
`of delivery systems, release mechanisms, composition,
`volume, hydrodynamics, and role of potential mechan-
`ical forces on the structure of delivery system within the
`moving dissolution media in some cases necessitates
`the development of alternative dissolution methods in
`order to obtain reliable dissolution data, to be able to
`discriminate among different dissolution methods, and
`to more closely mimic in vivo conditions (Dressman et
`al., 1988; Pillay and Fassihi, 1998).
`The present study has been carried out on dimenhy-
`drinate, an antihistaminic agent possessing antiemetic
`effect, which is commonly used to prevent or relieve
`motion sickness. Chemically, dimenhydrinate is com-
`posed of two active moieties, diphenhydramine and
`8-chlorotheophylline (approximately 1:1; mass ratio
`slightly favors diphenhydramine) (Kraemer, 2001;
`USP, 2004), with the aqueous solubility of approx-
`imately 3 mg/ml (Budavari, 1996). Pharmacokinetic
`studies have shown that dimenhydrinate has a short
`duration of action of about 3–6 h (WholeHealthMD,
`2000);
`therefore,
`it
`is considered as a potential
`candidate for development into a controlled release
`formulation with an initial burst. Considering the popu-
`larity and robustness of hydrophilic matrices as a means
`
`

`

`S. Missaghi, R. Fassihi / International Journal of Pharmaceutics 293 (2005) 35–42
`
`37
`
`Fig. 1. Potential applications of dissolution studies in drug development process (Fassihi and Pillay, unpublished).
`
`of controlled release drug delivery (Genc et al., 1999;
`D¨urig and Fassihi, 2000; Yang and Fassihi, 2003), this
`approach has been adopted in formulating dimenhy-
`drinate tablets (Missaghi and Fassihi, 2002, 2003).
`This study focuses on: (1) evaluation of in vitro
`release characteristics of a controlled release dimen-
`hydrinate tablet formulation with burst components
`under defined hydrodynamic conditions, employing
`compendial methods; USP apparatus I (basket), II
`(paddle), III (reciprocating cylinder), and a non-
`compendial dissolution method, namely, modified
`apparatus II (paddle over mesh), (2) selection of
`appropriate dissolution method by comparison of
`the dissolution profiles obtained from each method
`using similarity and difference factors as a tool for
`interpretation of dissolution data.
`
`2. Materials and methods
`
`2.1. Materials
`
`Dimenhydrinate (Sigma Chemical Company, St.
`Louis, MO), hydroxypropyl methyl cellulose (HPMC)
`
`Table 1
`The formulation used in preparation of dimenhydrinate matrix tablets
`
`Ingredients
`
`Dimenhydrinate
`HPMC
`Maltodextrin
`PEO
`MCC
`Magnesium stearate
`
`Total weight
`
`Amount per tablet (mg)
`
`100
`35
`25
`37
`100
`3
`
`300
`
`(Methocel® K4M, Dow Chemical Company, Midland,
`MI), polyethylene oxide (PEO) (SentryTM PolyoxTM
`WSR N60K-NF, Union Carbide Corp., Danbury, CT),
`maltodextrin (Maltrin® M510, Grain Processing Corp.,
`Muscatine, IA), microcrystalline cellulose (MCC)
`(Avicel® PH 101, FMC Corp., Philadelphia, PA), and
`magnesium stearate NF (Mallinckrodt, St. Louis, MO).
`
`2.2. Methods
`
`2.2.1. Preparation of hydrophilic matrix tablets
`Table 1 displays the formulation used in prepara-
`tion of dimenhydrinate tablets. For this purpose, half of
`the drug was ground and mixed with maltodextrin and
`
`

`

`38
`
`S. Missaghi, R. Fassihi / International Journal of Pharmaceutics 293 (2005) 35–42
`
`two indices or fit factors were determined, as described
`by Moore and Flanner (1996). This approach is model
`independent, and it uses mathematical indices to define
`difference and similarity factors (f1 and f2, respectively)
`for comparison of dissolution profiles:
`• Difference factor, f1:
`n(cid:4)
`|Rt − Tt|
`n(cid:4)
`
`× 100
`
`
`
`t=1
`
`
`
`f1 (%) =
`
`Rt
`t=1
`• Similarity factor, f2:
`f2 = 50 log
`(cid:10)
`n(cid:11)
`1 + 1
`
`
`
`(cid:12)−0.5 × 100
`
`Wt(Rt − Tt)2
`
`n
`
`t=1
`
`
`
`n represents the number of time points, Wt is the op-
`tional weight factor, Rt the dissolution value of the ref-
`erence method at time t, while Tt the dissolution value
`of the test method at time t.
`f1 value indicates the percent difference between two
`profiles at each time point and is a measurement of
`the relative error between them. f2 value, however, is a
`measurement of the similarity between the dissolution
`profiles. In general, to ensure sameness between the
`profiles, f1 should be in the range of 0–10, and f2 in
`the range of 50–100. To calculate the fit factors, the
`mean dissolution values from both profiles at each time
`interval were used, including only one pull point at
`greater than 85% level of drug release in order to avoid
`bias in the similarity assessment (FDA, 1997c; Shah et
`al., 1998).
`
`3. Results and discussion
`
`The rationale for designing the dimenhydrinate con-
`trolled release formulation as described earlier, was to
`achieve a rapid onset of therapeutic activity of the drug
`for the early time period (2.0± 0.5 h), followed by a
`prolonged release pattern to maintain steady plasma
`concentration level of dimenhydrinate up to 12± 2 h.
`Results of the physical testing of the tablets (n = 20)
`demonstrated that the weight variation falls within
`±2.7% of the target weight which is in compliance with
`
`HPMC applying wet granulation method. The gran-
`◦
`ules were vacuum-dried at 40
`C for 15 min. The dried
`granules were then passed through a 40-mesh sieve.
`The other half of dimenhydrinate was dry blended with
`PEO and MCC; the two separate portions were then
`homogeneously mixed together. Prior to compression,
`the formulation blend was lubricated with magnesium
`stearate at 1% level. Tablets were then manufactured on
`a single station Stokes press (Bristol, PA), using a set
`of 11 mm diameter concave punch and die to achieve a
`target tablet weight of 300 mg.
`
`2.2.2. Physical evaluation of tablets
`The compressed tablets were evaluated for weight
`variation, using an analytical balance (A&D Com-
`pany Ltd., Tokyo, Japan), for crushing strength, us-
`ing a Schleuniger hardness tester (Schleuniger and Co.,
`Zurich, Switzerland), and for thickness and diameter,
`using a texture analyzer, TA.XT2i (Texture Technolo-
`gies Corp., Scarsdale, NY), equipped with a 5 kg load
`cell and Texture Expert Exceed software (Version 2.56)
`along with a suitable probe. These tests were carried
`out on 20 tablets.
`Dimenhydrinate tablets were also evaluated for in
`vitro drug release by means of a dissolution tester (VK
`7000, Varian Inc., Cary, NC), using USP 27-apparatus
`I, II, a modification of apparatus II, and USP 27-
`apparatus III (BIO-DIS II system, Vankel Industries,
`Edison, NJ). Apparatus II was modified with the inser-
`tion of a stainless steel mesh device in each vessel as
`described previously (D¨urig and Fassihi, 2000).
`Dissolution studies were conducted in deionized
`water, maintained at 37± 0.5
`◦
`C with the volume of
`250 ml for apparatus III and 900 ml for the other dis-
`solution methods. Various hydrodynamic conditions
`were examined using the agitation rates of 50 and
`100 rpm (revolution per minute) for apparatus I, II and
`modified II, and 5 and 8 dpm (dip per minute) for ap-
`paratus III. Samples were collected periodically from
`each vessel, and the amount of drug released, was quan-
`titatively determined at the wavelength of 277 nm using
`a UV-spectrophotometer (Agilent 8453, Agilent Tech-
`nologies Inc., Wayne, PA) over 24 h. All dissolution
`tests were performed in triplicates.
`
`2.2.3. Comparison of dissolution profiles
`To compare the dissolution profiles of dimenhydri-
`nate tablets under different hydrodynamic conditions,
`
`

`

`S. Missaghi, R. Fassihi / International Journal of Pharmaceutics 293 (2005) 35–42
`
`39
`
`Fig. 2. Comparison of the dissolution profile of standard USP appa-
`ratus II (paddle) at 100 rpm against the reference profile (reference:
`compendial USP-apparatus II, paddle, at 50 rpm). Data points are the
`mean of three tablets (n = 3), and the error bars indicate the standard
`deviation.
`
`the USP 27 (2004). The mean values for tablet thick-
`ness and diameter were 4.1 and 10.89 mm, respectively.
`The average value obtained for crushing strength of the
`tablets was 7.5 kp. After placing the tablets within the
`dissolution media, slight visible surface bursting on the
`periphery of tablets was evident which was then fol-
`lowed by matrix swelling and gradual erosion of the
`swollen mass during the 12± 2 h of dissolution. Ac-
`cordingly, the drug release profiles exhibited an initial
`burst followed by a prolonged release in a near zero
`order manner which was considered desirable in the
`context of this study. The early burst effect was due
`to the presence of drug particles on the matrix surface
`and the hydrophilic property of MCC and high aqueous
`solubility of maltodextrin which tends to rapidly leach
`out and create channels within the hydrating matrix.
`This would further lead to the more gradual diffusion
`and release of the drug molecules from the matrix.
`Dissolution profiles demonstrate a similar pattern
`of drug release under all dissolution conditions, show-
`ing two distinct phases of drug release, the initial burst
`phase followed by a controlled release pattern which
`is associated with the swelling phase. The former in-
`dicates the drug release up to 50%, while the latter
`signifies the release from 50% up to the point where
`100% release is reached (Figs. 2–4). The differences
`among the methods lay in the duration of each phase
`and its respective average release rate, obtained from
`
`Fig. 3. Comparison of the dissolution profile of the modified appara-
`tus II (paddle with mesh) at 50 and 100 rpm with the reference profile
`(reference: compendial USP-apparatus II, paddle, at 50 rpm).
`
`the regression analysis of that segment (Table 2). Given
`the design of the matrix formulation and the graphi-
`cal presentation of the dissolution results, duration of
`the initial phase indicates t50% or dissolution half-time.
`When comparing the release rates, it is apparent that
`the rate for the initial burst is directly related to the
`intensity of hydrodynamics, fluid flow, and apparatus
`type. Higher intensity of the agitation rate in the dis-
`solution medium increased the extent of burst effect
`and consequently decreased the duration of the initial
`phase. On the contrary, the average release rates cal-
`culated for the controlled release phase of the profiles
`show that an increase in the agitation rate is not lead-
`ing to a drastic change in the release rate of this phase.
`
`Fig. 4. Comparison of the dissolution profile of standard USP appa-
`ratus I (basket) at 50 and 100 rpm with the reference profile.
`
`

`

`40
`
`S. Missaghi, R. Fassihi / International Journal of Pharmaceutics 293 (2005) 35–42
`
`Table 2
`Average release rate of the drug at each phase of the dissolution profile obtained for all methods
`
`Dissolution method
`
`Agitation rate
`
`Initial burst phase
`
`Duration (t50%)a (h)
`
`Release rate (%/h)
`
`Paddle
`
`Paddle over mesh
`
`Basket
`
`Oscillating cylinder
`
`50 rpm
`100 rpm
`
`50 rpm
`100 rpm
`
`50 rpm
`100 rpm
`
`5 dpm
`8 dpm
`
`4
`1.5
`
`3.5
`1.7
`
`7
`6
`
`2
`0.3
`
`12.85
`35.71
`
`14.08
`31.80
`
`7.97
`9.33
`
`20.91
`174.80
`
`a t50% indicates time for 50% of the drug to dissolve (dissolution half-time).
`
`Swelling phase
`
`Duration (time to steady
`state− t50%) (h)
`10
`8.5
`
`10.5
`8.3
`
`7
`8
`
`2
`9.7
`
`Release rate (%/h)
`
`4.32
`4.03
`
`4.75
`4.43
`
`5.70
`5.05
`
`5.03
`3.95
`
`This becomes more apparent when the coefficients of
`variation (CV%) are compared for both phases of the
`dissolution profiles at equivalent agitation rates as out-
`lined in Table 3. Overall, the average release rates ob-
`tained for the initial phase at 50 rpm exhibit less vari-
`ation among the methods as compared to the values
`achieved at 100 rpm (CV% of 27.78% versus 55.58%,
`respectively). On the other hand, CV% values for the
`swelling phase seem more comparable at both agitation
`rates (14.34% at 50 rpm versus 11.41% at 100 rpm). It
`may, therefore, be concluded that the average rate of
`the drug release from the matrix at the swelling phase
`is not affected by the hydrodynamics of the system.
`This also indicates that release mechanism during this
`phase is dominated by the diffusion rather than erosion
`process. It should further be noted that the biphasic na-
`ture of drug release was more pronounced when tested
`at lower agitation rates.
`As seen in Table 2, the modified USP method
`demonstrated a slightly faster release compared to
`the standard compendial apparatus II, when tested at
`
`50 rpm (14.08%/h versus 12.85%/h); however, an op-
`posite effect was observed when tested at 100 rpm
`(31.80%/h versus 35.71%/h for modified apparatus II
`and standard apparatus II, respectively). This indicates
`the sensitivity of the swelling and eroding tablets to the
`extent of hydrodynamics intensity within the dissolu-
`tion media as well as the non-discriminatory power of
`these dissolution methods at different rates of agitation.
`As for apparatus III, the overall drug release was
`more rapid among the methods, with complete release
`at about 10 h. Due to the oscillating movement of the
`inner cylinder within the vessel, containing the disso-
`lution media in apparatus III, all surfaces of the tablet
`are intensely exposed to the medium with a potentially
`greater degree of erosion. The higher rate of oscillation
`causes a more vigorous hydrodynamics within the dis-
`solution media, which further intensifies the mechan-
`ical disruption of the tablet periphery and leads to a
`higher release rate of the drug (Fig. 5 and Table 2). Only
`if the agitation intensity was well defined, this type of
`hydrodynamics might resemble the actual environment
`
`Table 3
`Comparison of average release rates among the dissolution methods at equivalent hydrodynamic conditions
`
`Agitation rate
`
`Dissolution phase
`
`Release rate (%/h) for dissolution methods
`
`Paddle
`
`Paddle over mesh
`
`Basket
`
`50
`
`100
`
`Initial burst phase
`Swelling phase
`
`Initial burst phase
`Swelling phase
`
`12.85
`4.32
`
`35.71
`4.03
`
`14.08
`4.75
`
`31.80
`4.43
`
`7.97
`5.70
`
`9.33
`5.05
`
`Mean
`
`11.27
`5.12
`
`25.61
`4.50
`
`Standard deviation
`
`CV (%)
`
`3.85
`1.04
`
`14.24
`0.514
`
`27.78
`14.34
`
`55.58
`11.41
`
`

`

`S. Missaghi, R. Fassihi / International Journal of Pharmaceutics 293 (2005) 35–42
`
`41
`
`Table 4
`Fit factor values, obtained for each dissolution method at different
`hydrodynamic conditions against the reference method (i.e. dissolu-
`tion data from standard USP-apparatus II at 50 rpm)
`
`Dissolution method
`
`Paddle at 100 rpm
`Paddle with mesh at 50 rpm
`Paddle with mesh at 100 rpm
`Basket at 50 rpm
`Basket at 100 rpm
`Apparatus III at 5 dpm
`Apparatus III at 8 dpm
`
`f1 (%)
`42.61
`8.63
`40.12
`36.20
`21.75
`40.58
`73.40
`
`f2
`37.95
`72.56
`39.57
`45.94
`54.75
`39.86
`26.46
`
`method at different hydrodynamic conditions. For this
`purpose, the release data for compendial apparatus II at
`50 rpm was considered as reference, in accordance with
`dimenhydrinate official monograph cited in the USP
`27. Based on the obtained values of f1 and f2, the disso-
`lution profile of the modified apparatus II at 50 rpm was
`considered the “same” as the reference profile. How-
`ever, the profiles obtained from the other dissolution
`methods, were considered “different” compared to the
`reference (Table 4).
`In all figures, data points represent the mean values
`of three tablets (n = 3), and the error bars indicate the
`standard deviation.
`
`4. Conclusions
`
`Although ideally, it is desirable to design delivery
`systems whose performance is independent of the influ-
`ence of external factors, a vast variety of dosage forms
`exhibit sensitivity to such factors. Thus, the present
`study demonstrates the paramount importance of appa-
`ratus selection, shape and size of the apparatus make-
`up, variation of fluid dynamics from one dissolution
`apparatus to another due to the magnitude of the agita-
`tion intensity, and the extent of sensitivity of the eroding
`dosage forms to the hydrodynamics within the system.
`Therefore, the choice of the dissolution method and
`its respective agitation rate significantly influence the
`overall drug release profiles in the case of swelling and
`eroding systems.
`In order to support the significance of in vitro data
`obtained for the dosage forms in this study, In vivo
`experiments have to be carried out for establishing
`and identifying the level of IVIVC. Accordingly, the
`
`Fig. 5. Comparison of the dissolution profile of standard USP appa-
`ratus III (reciprocating cylinder) at 5 and 8 dpm against the reference
`profile.
`
`of the gastrointestinal tract, within which the dosage
`form is exposed to a forceful contraction and peristaltic
`movement as opposed to having a constant position of-
`ten associated with USP apparatus I and II. In this study,
`when comparing the average release rates for dissolu-
`tion profiles from apparatus III at 5 and 8 dpm, with
`data obtained from other methods, it becomes appar-
`ent that performance of the former at 5 dpm is more in
`tune with apparatus I and II at their given conditions
`(Table 2). At 8 dpm, the average release rate for the
`initial phase was calculated as 174.80%/h. Due to the
`relatively high intensity of agitation, these results do
`not seem to provide a realistic situation comparable to
`that of the physiologic environment and further fail to
`be distinctive among the methods.
`The results obtained through comparing the av-
`erage dissolution rates indicate that the overall re-
`lease rate and pattern of release in this study fol-
`lowed the order of: apparatus III at 8 dpm > compendial
`apparatus II at 100 rpm > modified apparatus II at
`100 rpm > apparatus III at 5 dpm > modified appa-
`ratus
`II at 50 rpm > compendial apparatus
`II at
`50 rpm > apparatus I at 100 rpm > apparatus I at 50 rpm.
`Comparison of dissolution half-times yields the same
`rank order (Table 2).
`The order of release described above illustrates large
`differences and complexity of release prediction espe-
`cially when eroding systems are the subject of evalu-
`ation. To further assess the dissolution behavior and
`compare the test results, fit factors were calculated
`for the release profiles obtained for each dissolution
`
`

`

`42
`
`S. Missaghi, R. Fassihi / International Journal of Pharmaceutics 293 (2005) 35–42
`
`appropriate dissolution method and conditions can be
`selected for achieving predictable release data.
`Examination of dissolution data discussed in this
`work may be useful to research scientists who are in-
`volved in formulation development of the swelling and
`eroding matrices and can be used as a “finger-print” in
`apparatus selection and may aid in scientifically sound
`data collection and interpretation.
`
`References
`
`Bocanegra, L.M., Morris, G.J., Jurewicz, J.T., Mauger, J.W., 1990.
`Fluid and particle laser Doppler velocity measurements and
`mass transfer predictions for the USP paddle method dis-
`solution apparatus. Drug Develop. Ind. Pharm. 16, 1441–
`1464.
`Budavari, S., 1996. The Merck Index: An Encyclopedia of Chemi-
`cals, Drugs, and Biologicals, 12th ed. Merck & Co. Inc., White-
`house Station, p. 3250.
`Dressman, J.B., Amidon, G.L., Reppas, C., Shah, V., 1988. Dis-
`solution testing as a prognostic tool for oral drug absorp-
`tion: immediate release dosage forms. Pharm. Res. 15, 11–
`22.
`D¨urig, T., Fassihi, R., 2000. Evaluation of floating and sticking ex-
`tended release delivery systems: an unconventional dissolution
`test. J. Contr. Release 67, 37–44.
`Food and Drug Administration (FDA), Center for Drug Eval-
`uation and Research (CDER), 1997a. Guidance for
`In-
`dustry. SUPAC-MR: Modified Release Solid Oral Dosage
`Forms.
`Food and Drug Administration (FDA), Center for Drug Evaluation
`and Research (CDER), 1997b. Guidance for Industry. Extended
`Release Oral Dosage Forms: Development, Evaluation, and Ap-
`plication of In Vitro/In Vivo Correlations.
`Food and Drug Administration (FDA), Center for Drug Evaluation
`and Research (CDER), 1997c. Guidance for Industry. Dissolution
`Testing of Immediate Release Solid Oral Dosage Forms.
`Food and Drug Administration (FDA), Center for Drug Evaluation
`and Research (CDER), 2000. Guidance for Industry. Waiver of In
`Vivo Bioavailability and Bioequivalence Studies for Immediate-
`release Solid Oral Dosage Forms based on a Biopharmaceutics
`Classification System.
`Food and Drug Administration (FDA), Center for Drug Evaluation
`and Research (CDER), 2003. Draft Guidance. Guidance for In-
`dustry, PAT: A Framework for Innovative Pharmaceutical Man-
`ufacturing And Quality Assurance.
`
`Genc, L., Bilac, H., Guler, E., 1999. Studies on controlled release
`dimenhydrinate from matrix tablet formulations. Pharm. Acta
`Helv. 74, 43–49.
`Haystead, J., 2003. Study highlights flawed dissolution testing pro-
`cedure. Pharm. Technol. 27, 22.
`Kamba, M., Seta, Y., Takeda, N., Hamaura, T., Kusai, A., Nakane,
`H., Nishimura, K., 2003. Measurement of agitation force in dis-
`solution test and mechanical destructive force in disintegration
`test. Int. J. Pharm. 250, 99–109.
`Khoury, N., Mauger, J.W., Stephen, H., 1988. Dissolution rate stud-
`ies from a stationary disk/rotating fluid system. Pharm. Res. 5,
`495–500.
`Kraemer, J., 2001. In vitro dissolution testing of medicated gums.
`AAPSPharmScience 3, 3 (abstract).
`Kukura, J., Arratia, P.E., Sal´ıa, E.S., Muzzio, F.J., 2003. Engineering
`tools for understanding the hydrodynamics of dissolution tests.
`Drug Develop. Ind. Pharm. 29, 231–239.
`Martin, A., Bustamante, P., Chun, A.H.C., 1993. Physical Pharmacy,
`4th ed. Lippincott, Williams & Wilkins, Baltimore.
`Missaghi, S., Fassihi, R., 2002. Design and development of a con-
`trolled release formulation for dimenhydrinate via in-situ inter-
`actions of charged substances and polymers. In: Proceedings of
`the AAPS Annual Meeting and Exposition, Poster Presentation.
`Missaghi, S., Fassihi, R., 2003. Evaluation and comparison of disso-
`lution profiles for a swelling and eroding dimenhydrinate tablet
`using USP apparatus I, II, and III. In: Proceedings of the AAPS
`Annual Meeting and Exposition, Poster Presentation.
`Moore, J.W., Flanner, H.H., 1996. Mathematical comparison of dis-
`solution profiles. Pharm. Technol. 20, 64–69.
`Pillay, V., Fassihi, R., 1998. Evaluation and comparison of dissolution
`data derived from different modified release dosage forms: an
`alternative method. J. Contr. Release 55, 45–55.
`Pillay, V., 2000. Novel formulation approaches in the design strategy,
`development and evaluation of oral controlled release drug de-
`livery systems. Ph.D. Thesis. Temple University School of Phar-
`macy, USA.
`Qureshi, S.A., McGilveray, I.J., 1995. A critical assessment of the
`USP dissolution apparatus suitability test criteria. Drug Develop.
`Ind. Pharm. 21, 905–924.
`Shah, V.P., Tsong, Y., Sathe, P., Lie, J., 1998. In vitro dissolution pro-
`file comparison—statistics and analysis of the similarity factor,
`f2. Pharm. Res. 15, 889–896.
`US Pharmacopeia XXVII, 2004. US Pharmacopeial Convention.
`Rockville, MD, pp. 628–631.
`WholeHealthMD.com,
`WholeHealthMD,
`2000.
`http://www.wholehealthmd.com.
`Yang, L., Fassihi, R., 2003. Accessibility of solid core tablet for
`dissolution in an asymmetric triple-layer matrix system. J. Pharm.
`Pharmacol. 55, 1331–1337.
`
`LLC.
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