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Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug
Journal of Controlled Release 61 (1999) 83–91
Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug Paolo Colombo a , *, Ruggero Bettini a , Nikolaos A. Peppas b b
a Department of Pharmacy, University of Parma, 43100 Parma, Italy Biomaterials and Drug Delivery Laboratories, School of Chemical Engineering, Purdue University, West Lafayette, IN 47907 -1283, USA
Received 18 September 1998; accepted 14 April 1999
Abstract The behavior of gel layer thickness in swellable hydroxypropyl methyl cellulose matrices loaded with increasing amounts of soluble and colored drug and exhibiting swelling, diffusion and erosion fronts, was studied using a colorimetric technique. The effect of the drug loading on the front position in the gel layer, in particular, on the presence of a diffusion front and its movement, was investigated. In addition, the swelling, diffusion and erosion front positions at different releasing times were measured and a theoretical analysis of the overall process was provided. It was found that the diffusion front was visible in systems with more than 30% drug, due to the presence of an undissolved drug layer. The physical analysis of such systems clearly showed the importance of drug solubility and loading in the observation of the diffusion front. 1999 Elsevier Science B.V. All rights reserved. Keywords: Swellable matrices; Drug loading; Diffusion front
1. Introduction Swelling of hydrophilic polymeric matrices has been the subject of significant research in the last few years. In particular, there have been several studies trying to relate molecular characteristics of the swelling process (macromolecular chain extension, solvent accommodation) to macroscopic characteristics [1–6]. Of particular interest are recent experimental *Corresponding author. Tel.: 139-0521-905086; fax: 1390521-905085. E-mail address: [email protected] (P. Colombo)
studies on the swelling and subsequent dissolution of hydroxypropyl methyl cellulose (HPMC) tablets or matrices. For example, Melia et al. [7,8] and RajabiSiahboomi et al. [9] have investigated the swelling process using scanning electron microscopy and NMR spectroscopy. Gao and associates [5,10] presented studies on HPMC swelling using an optical imaging technique. Konrad et al. [11] measured the eroding and swelling front advancement during drug release using ultrasound. In recent years, our group has also examined various aspects of the swelling behavior of such tablets in terms of front positions [3,12–14]. Indeed, during contact between a dry HPMC matrix and a
0168-3659 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 99 )00104-2
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dissolution medium, such as water or a biological fluid, water penetrates the HPMC matrix and swells the macromolecular chains. Molecularly, individual chains, originally found in their unperturbed state [15], absorb water so that their end-to-end distance and radius of gyration expand to the new solvated state. This expansion (swelling) is observed macroscopically by the formation of distinct fronts that separate unswollen and swollen regions. As discussed previously [3], during macroscopic observation of the swelling process, we have identified a ‘swelling front’ that clearly separates the rubbery region (region of swollen HPMC with enough water to have its T g below the experimental temperature) and the glassy region (region where HPMC has a T g above the experimental temperature). A second front is the ‘erosion front’, which separates the matrix from the solvent (water). The gel layer formed on the glassy core of a swellable matrix is considered to be the controlling element of drug release kinetics. The gel layer structure and composition change during matrix swelling, due to the molecular extension of the solvated polymeric chains. The gel layer thickness behavior as a function of time is determined by the relative position of the moving swelling and erosion fronts. In addition, a drug diffusion front located between the swelling and erosion fronts and constituting the boundary separating solid from dissolved drug was identified previously [16]. The diffusion front position in the gel phase during drug release was dependent on the drug’s solubility and loading. In fact, the diffusion front movement was related to the drug’s dissolution rate [3]. Finally, the diffusion and erosion front positions identify the drug’s dissolved gel layer, where the concentration profile relevant to the flux of drug is established. The movement of the swelling and dissolution (erosion) fronts in HPMC matrices containing fluorescein sodium at different drug loadings and polymer viscosities were measured using a nondestructive mode of operating [17]. In this work, the behavior of gel layer thickness in swellable matrices loaded with increasing amounts of soluble and colored drug was studied using a colorimetric technique. The main goal of this work was to determine how the drug loading affected the front position in the gel layer, in particular, the
presence of a diffusion front and its movement. We measured the swelling, diffusion and erosion front positions at different swelling times and provided a theoretical analysis of the overall process.
2. Analysis of swelling behavior
2.1. Swelling process We considered the dynamic swelling behavior of a hydrophilic, glassy, polymeric matrix that can swell (and dissolve) in water. Starting with a slab thickness of 2d0 at time t50; when the slab is placed in water, there is swelling and dissolution, and an erosion and a swelling front appear (E and S, respectively) (Fig. 1).
2.2. Swelling front The water concentration at the glassy–rubbery interface, c*, is established by the glass transition temperature of the polymer, T g and the experimental temperature, T exp [18,19]. Thus, the water concentration at position S, can be calculated as T g 2 T exp c* 5 ]]] b /af
(1)
Here, c* is the threshold concentration, expressed in g of water / g of dry polymer, af is the linear thermal expansion coefficient of the polymer, and b is the contribution of the water to the expansion coefficient of the polymer. In problems of polymer dissolution, it is advantageous to use volume fractions of components, yi , rather than concentrations, c i . This is because of the volume change at any point in a slab. Thus, in order to convert c* to an equivalent volume fraction, the value of c* can also be expressed as a volume of water per volume of polymer as c* rp /rw (cm 3 of water / cm 3 of polymer). At the interface, S, in drug-containing swellable systems, some undissolved drug also exists and is equal to the loading concentration of c d (g of drug / g of polymer), or c d rp /rd (cm 3 of drug / cm 3 of polymer), where rd is the drug density. Then, at the interface, the equivalent threshold
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Fig. 1. Schematic representation of the front positions, water, polymer and drug gradient associated with the dynamic swelling process in a slab-like matrix.
volume fractions of water, y w* , polymer, y p* , and drug, y d* , are as follows (Fig. 1):
rp c*] rw y *w 5 ]]]]] rp rp c*] 1 c d ] 1 1 rw rd 1 y p* 5 ]]]]] rp rp c*] 1 c d ] 1 1 rw rd
(2)
(3)
and
rp c*] rd y *d 5 ]]]]] rp rp c*] 1 c d ] 1 1 rw rd
(4)
Here,
y w* 1 y p* 1 y *d 5 1
(5)
2.3. Erosion front At the erosion front, E, the relevant volume fractions of the components are for pure water, y 1 w, 1 the disentangled macromolecular chains, y p,dis , and 1 the drug, y 1 d . Although y p,dis is known for each 1 1 polymer [4], y w and y d are not known a priori but are dependent on experimental conditions, such as
agitation and the composition of the surrounding fluid (pH and ionic strength). When dynamic swelling / dissolution is established, a volume fraction (concentration) gradient is established in the region between the erosion and swelling fronts, as shown in Fig. 1. This figure shows the shape of the concentration profiles.
2.4. Diffusion front In this section, we consider incorporation of a drug whose solubility in water is c s (g of drug / cm 3 of water). Drug concentration at any point in the gel is obtained by multiplying c s by the corresponding water volume fraction at that point, yw . Then, the drug concentration in the gel (between S and E) is 3 c s yw (g of drug / cm of gel). To further express this value as a local drug volume fraction, yds , we divide by the drug density to obtain: c s yw yds 5 ]] (cm 3 of drug / cm 3 of gel) (6) rd It must be noted that, between S and E, the terms c s and rd are constant (at constant T exp ) and only yw can change as a function of position. As c s has a limiting value, yds will also have a limiting value, i.e., a single local value at which the drug will not be completely dissolved. This value identifies the position of the diffusion front, D. From the diffusion
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front up to the swelling front, the drug concentration should change, as indicated by drug profile in Fig. 1c. Using Eq. (6), it is also possible to calculate the * , that correvalue of the drug volume fraction, y ds sponds to the threshold water volume fraction y w* as: c s y w* y *ds 5 ]] rd
(7)
This parameter is of importance when trying to determine the dissolved and undissolved drug as it will be shown in our experimental studies below. The drug loading below which the diffusion front will not appear can be calculated by making the following assumption. First, we define the value of * , as in Eq. y *d , as in Eq. (4), and we set it equal to y ds (7), to obtain:
rp cd] rd c s y *w * 5 ]] y d* 5 ]]]]] 5 y ds rp rp rd c*] 1 c d ] 1 1 rw rd
(8)
Then, we solve for the value of c d , which becomes
rp rd c*] 1 1 ] rw rp c d 5 ]]]]]] rd ]] 2 1 c s y w*
S
S
DS D D
(9)
In addition, by solving Eq. (8) for y *w , we can obtain: cd rp ] cs y *w 5 ]]]]] rp rp c*] 1 c d ] 1 1 rw rd
to 10 parts HPMC (Methocel K4M, Colorcon, Orpington, UK; particle size, 90%,150 mm). As a binder, four parts of cellulose acetate phthalate dissolved in acetone–ethanol (1:1,v / v) was used. After drying, the granules were lubricated with two parts of magnesium stearate (USP grade) and four parts of talc (USP grade). Finally, the granules were tabletted using a reciprocating tabletting machine (EKO Korsch, Berlin, Germany) equipped with flat face cylindrical punches of 7 mm diameter, in order to prepare matrices weighing 12560.8 mg, having a crushing strength of between 12 and 13 (Monsanto scale) and an initial porosity of 9.260.9%. Swelling studies of these HPMC matrices were performed by clamping each matrix between two transparent Plexiglas disks, thus forming an assembled device that was introduced into the vessel of a USP 23 Apparatus 2 (Esadissolver, Advanced Products, Milan, Italy) containing distilled water at 378C (agitation speed of 200 rpm) [21]. At fixed times during swelling, the device was taken out of the vessel and pictures of the disc matrix base were video-recorded. Using an Image 1.49 program (NIH, Bethesda, MD, USA), the front distance was measured in pixels and these were converted into length units. The densities of drug and polymer were measured using a helium pycnometer (Multivolume Pycnometer 1305, Micromeritics, Norcross, GA, USA).
4. Results and discussion (10)
This equation shows that the threshold fraction of water at the diffusion front is directly related to the ratio of c d /c s , a similar conclusion and relation as that obtained by Lee [20].
3. Experimental Swellable matrices having a disc shape were prepared by granulating 10 to 80 parts of buflomedil pyridoxal phosphate, (BPP, mol. wt. 553.5; solubility in water, c s 50.65 g cm 3 ; Lisapharma S.p.A., Erba, Italy; particle size range, 20–90 mm) mixed with 80
The swellable matrices were prepared using mixtures of BPP and HPMC of different ratios. Drug and polymer constituted 90 wt.% of the formulation, while the rest were adjuvants for tabletting. Matrices were produced by compression under the same conditions. Swelling studies were conducted in a device consisting of two transparent Plexiglas discs clamped onto the bases of the cylindrical matrix. Thus, water penetration and matrix expansion occurred through the lateral side of the matrix [21]. The transparent discs of the device allowed for direct observation of the undergoing swelling and for identification of the positions where polymer transition and drug dissolution took place.
P. Colombo et al. / Journal of Controlled Release 61 (1999) 83 – 91
The drug was light yellow in color in the dry state, whereas in solution, it ranged from yellow to orange as the concentration increased. In fact, the matrix fronts during drug release were visible on the matrix base as concentric circles corresponding to a sharp change in drug color. Fig. 2 shows the three fronts formed during the swelling / dissolution process. From the center to the periphery of the matrix, the swelling front (polymer glassy–rubbery transition boundary), the diffusion front (solid drug–drug solution boundary) and the erosion front (swollen matrix–solvent boundary) could be identified. Clearly, the intensity of the yellow color indicated the dissolved drug concentration. The fronts moved in relation to the phenomena that were active at their respective locations. For example, the erosion front moved outwards due to the swelling of the matrix or inwards due to matrix dissolution, whereas the swelling front moved inwards as a result of water penetration. The gel layer thickness was measured as the
87
Fig. 3. Gel layer thickness as a function of time for matrices containing different percentages of BPP: (s) 10%, (h) 20%, (n) 30%, (d) 40%, (j) 60% and (m) 80%. The bars represent the standard error of the mean (n53).
distance between the erosion and swelling fronts. Fig. 3 shows that the thickness of the gel layer as a function of time was not very different in the systems prepared, despite the varying amounts of
Fig. 2. Image of the matrix containing 60% BPP (w / w) taken after 240 min of swelling.
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drug. It was also found that the individual movement of erosion and swelling fronts (data not shown) was not significantly different in the various systems studied, except for the matrix containing the highest amount of drug (80%), which showed the slowest outward movement of the erosion front and the fastest movement of the swelling front (i.e., high water penetration rate). In this case, the low amount of polymer in the matrix rendered the matrix more sensitive to erosion and, therefore, to water penetration. In the matrices used in this study, the diffusion front moved inwards and was near the swelling front. The distance between the diffusion front and the erosion front represented the thickness of the dissolved drug gel layer [3], that is, the diffusive layer involved in controlling the drug’s release process. Fig. 4 shows the variation in the thickness of the drug-dissolved gel layer versus time. As shown in this figure, samples with 10 and 20% drug exhibited consistently higher dissolved drug gel layer thicknesses than the other samples, due to the absence of the diffusion front. The series of pictures of the matrix base, taken at sequential times, showed a gradient of color in the gel layer due to the dissolved drug. The color gradient in the gel is related to the concentration gradient of dissolved BPP. Typical pictures of the variation of the color in matrices containing increasing amount of drug are shown in Fig. 5 after 120 min
Fig. 4. Dissolved drug gel layer thickness as a function of time for matrices containing different percentages of BPP: (s) 10%, (h) 20%, (n) 30%, (d) 40%, (j) 60% and (m) 80%. The bars represent the standard error of the mean (n53).
of swelling. For example, the color exhibited by the matrix containing 60% of drug ranged from the deep orange color of saturated or highly concentrated drug solutions near the diffusion front to the very light yellow color near the erosion front. The diffusion front was easy to identify because the deep orange saturated drug solution in the gelled portion of the matrix was preceded by a distinct circular yellow layer. This yellow layer became thicker and denser at high loadings (60–80%). It appeared to be uniform in color, and corresponded to the undissolved drug gel layer thickness. Therefore, with an increasing BPP loading, the solid drug tended to persist after the swelling front and gave rise to the diffusion front. The sudden increase in color at the diffusion front is an indication that the local value of the water volume fraction was high enough to dissolve the amount of solid drug present close to the diffusion front. This is also clearly indicated by Eqs. (8) and (9), which indicate that the diffusion front and the associated finite value of c d will appear only when the water volume fraction is at least y w* . A detailed analysis of the threshold volume fractions (concentrations) of water, drug and polymer in the specific HPMC matrices investigated here is shown in Table 1. For these values, the following calculations were performed. First, the threshold concentration, c*, was calculated from Eq. (1), where T exp 5378C, T g 51778C for HPMC, as reported by Doelker [1], the expansion coefficient was af 53.7?10 24 K 21 , as defined by Ferry [18] and the expansion factor b 50.2, as reported by Fujita and Kishimoto [22]. Thus, for our HPMC system, the value of c* was calculated as 0.259 g of water / g of polymer, a value that is close to those reported by Doelker [1], of 0.23, and Hancock and Zografi [23], of 0.20. To determine the threshold volume fractions, we used Eqs. (2–4), with a polymer density of rp 5 1.326 g / cm 3 , a drug density rd 51.394 g / cm 3 , as determined by helium pycnometry, and a water density at 378C equal to rw 50.993 g / cm 3 [24]. Finally, as noted before, the water BPP solubility was c s 50.65 g / cm 3 . As indicated in Table 1, the nominal loading of the studied systems was reported as a percentage of the total tablet weight. These values were recalcu-
P. Colombo et al. / Journal of Controlled Release 61 (1999) 83 – 91
Fig. 5. Images of the matrices containing different percentages of BPP (w / w), taken after 120 min of swelling.
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90
Table 1 Threshold volume fractions for water, drug, polymer and dissolved drug at different nominal loadings of drug, calculated according to Eqs. (2), (3), (4) and (7), respectively Nominal loading (% w / w)
Loading / concentration cd
10 20 30 40 60 80
0.125 0.286 0.500 0.800 2.000 8.000
Threshold volume fractions Water y *w
Drug y *d
Polymer y *p
Dissolved drug y *ds
0.236 0.214 0.190 0.164 0.106 0.038
0.081 0.168 0.260 0.360 0.585 0.849
0.683 0.618 0.549 0.475 0.308 0.112
0.110 0.099 0.088 0.076 0.049 0.018
lated as values of c d required in this work (g of drug / g of polymer) and are shown in the second column of Table 1. The threshold volume fractions were calculated under these conditions and are reported in columns 3, 4 and 5 as y w* , y d* and y p* for water, drug and polymer, respectively. It is evident that the relative volume fractions of each component change according to the system’s nominal drug loading. Most notably, the water threshold volume fraction varies from 0.0328 to 0.236, with the lowest value being observed at the highest loading, where only a small amount of polymer was present. Although we did not take the initial porosity of the matrices (which is of the order of 10%) and the other components used for matrix production (10% w / w) into consideration in these calculations, these values are still deemed reasonable [23]. We were also able to calculate the drug volume * , from Eq. (7) using the corresponding fraction, y ds threshold water volume fraction, y w* . The results are shown in the last column of Table 1 and are quite revealing as they indicate the amount of undissolved drug in the gel layer at the swelling front. For example, for the matrix containing just 10% BPP, the total drug present at the swelling front was 8.1% * 50.110) that could (y d* 50.081), with 11% (y ds dissolve. This is the reason why, in Fig. 5, it was impossible to visibly detect the diffusion front. On the other hand, in the matrix with 80% BPP, the total drug present at the swelling front was 84.9%, with only 1.8% being dissolved. Our results indicate that there was a substantial difference among the matrices that were loaded with different drug concentrations. More specifically, it
was extremely difficult to visually identify the diffusion front position in matrices containing less than 30% drug. According to the theoretical analysis presented here, this was due to the high water solubility of the drug as well as its loading level. In fact, while analyzing all matrices that contained BPP at concentrations ranging from 10 to 80%, we noticed that the diffusion front started to be visible in matrices at above 30% drug, due to the appearance of the thick circular layer with a uniform yellow color, which created a sharp variation in color. In the region beyond the circular yellow layer, the matrix was gel-like and the color changed to an orange color, identifying the boundary separating solid drug from dissolved drug, i.e., the diffusion front. It is interesting to note that, as drug-loading increased, the presence of this yellow layer appeared at earlier swelling times, thus confirming that the observed layer was due to incomplete dissolution of the drug at the swelling front. This situation could be explained by considering that the increase in the amount of drug in the matrix augmented the local drug’s volume fraction, as shown by the data in column 4 of Table 1. Therefore, a higher water volume fraction was required to completely dissolve the drug present at the diffusion front, as shown in Eq. (10).
5. Conclusions From the results obtained in this work, it is concluded that a diffusion front can be observed with BPP-containing HPMC matrices. This front is visible in systems with more than 30% drug, since there is
P. Colombo et al. / Journal of Controlled Release 61 (1999) 83 – 91
an undissolved drug layer in such systems. A new mathematical and physical analysis of such systems shows the importance of drug solubility and loading in the observation of the diffusion front.
[10]
Acknowledgements
[11]
This work was partially supported by a grant from CNR Italy 96.01066.CT03 and from the Showalter Foundation.
[12]
References
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[1] E. Doelker, Cellulose derivatives, in: N.A. Peppas, R.S. Langer (Eds.), Advances in Polymer Science. Biopolymers I, Springer-Verlag, Berlin, 1993, pp. 199–265. [2] N.A. Peppas, R.W. Korsmeyer, Dynamically swelling hydrogels in controlled release applications, in: N.A. Peppas (Ed.), Hydrogels in Medicine and Pharmacy, Properties and Applications, Vol. III, CRC, Boca Raton, FL, 1987, pp. 109–135. [3] P. Colombo, R. Bettini, G. Massimo, P.L. Catellani, P. Santi, N.A. Peppas, Drug diffusion front movement is important in drug release control from swellable matrix tablets, J. Pharm. Sci. 84 (1995) 991–997. [4] B. Narasimhan, N.A. Peppas, Molecular analysis of drug delivery systems controlled by dissolution of the polymer carrier, J. Pharm. Sci. 86 (1997) 297–304. [5] P. Gao, J.W. Skoug, R.P. Nixon, T.R. Ju, N.L. Stemm, K.-C. Sung, Swelling of hydroxypropyl methylcellulose matrix tablets. 2. Mechanistic study of the influence of formulation variables on matrix performance and drug release, J. Pharm. Sci. 85 (1996) 732–740. [6] I.S. Moussa, L.H. Cartilier, Characterisation of moving fronts in cross-linked amylose matrices by image analysis, J. Control. Release 42 (1996) 47–55. [7] C.D. Melia, A.R. Rajabi-Siahboomi, M.C. Davies, The development of structural features in the surface gel layer of hydrating HPMC hydrophilic matrices, Proc. 19th Int. Symp. Control. Rel. Bioact. Mater. 19 (1992) 28–29. [8] C.D. Melia, A.C. Hodsdon, M.C. Davies, J.R. Mitchell, Polymer concentration profiles across the surface gel layer of xanthan, alginate and HPMC matrix systems, Proc. 21st Int. Symp. Control. Rel. Bioact. Mater. 21 (1994) 724–725. [9] A.R. Rajabi-Siahboomi, R.W. Bowtell, P. Mansfield, M.C. Davies, C.D. Melia, Structure and behaviour in hydrophylic matrix sustained release dosage forms: 4. Studies of water
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Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug Paolo Colombo a , *, Ruggero Bettini a , Nikolaos A. Peppas b b
a Department of Pharmacy, University of Parma, 43100 Parma, Italy Biomaterials and Drug Delivery Laboratories, School of Chemical Engineering, Purdue University, West Lafayette, IN 47907 -1283, USA
Received 18 September 1998; accepted 14 April 1999
Abstract The behavior of gel layer thickness in swellable hydroxypropyl methyl cellulose matrices loaded with increasing amounts of soluble and colored drug and exhibiting swelling, diffusion and erosion fronts, was studied using a colorimetric technique. The effect of the drug loading on the front position in the gel layer, in particular, on the presence of a diffusion front and its movement, was investigated. In addition, the swelling, diffusion and erosion front positions at different releasing times were measured and a theoretical analysis of the overall process was provided. It was found that the diffusion front was visible in systems with more than 30% drug, due to the presence of an undissolved drug layer. The physical analysis of such systems clearly showed the importance of drug solubility and loading in the observation of the diffusion front. 1999 Elsevier Science B.V. All rights reserved. Keywords: Swellable matrices; Drug loading; Diffusion front
1. Introduction Swelling of hydrophilic polymeric matrices has been the subject of significant research in the last few years. In particular, there have been several studies trying to relate molecular characteristics of the swelling process (macromolecular chain extension, solvent accommodation) to macroscopic characteristics [1–6]. Of particular interest are recent experimental *Corresponding author. Tel.: 139-0521-905086; fax: 1390521-905085. E-mail address: [email protected] (P. Colombo)
studies on the swelling and subsequent dissolution of hydroxypropyl methyl cellulose (HPMC) tablets or matrices. For example, Melia et al. [7,8] and RajabiSiahboomi et al. [9] have investigated the swelling process using scanning electron microscopy and NMR spectroscopy. Gao and associates [5,10] presented studies on HPMC swelling using an optical imaging technique. Konrad et al. [11] measured the eroding and swelling front advancement during drug release using ultrasound. In recent years, our group has also examined various aspects of the swelling behavior of such tablets in terms of front positions [3,12–14]. Indeed, during contact between a dry HPMC matrix and a
0168-3659 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 99 )00104-2
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P. Colombo et al. / Journal of Controlled Release 61 (1999) 83 – 91
dissolution medium, such as water or a biological fluid, water penetrates the HPMC matrix and swells the macromolecular chains. Molecularly, individual chains, originally found in their unperturbed state [15], absorb water so that their end-to-end distance and radius of gyration expand to the new solvated state. This expansion (swelling) is observed macroscopically by the formation of distinct fronts that separate unswollen and swollen regions. As discussed previously [3], during macroscopic observation of the swelling process, we have identified a ‘swelling front’ that clearly separates the rubbery region (region of swollen HPMC with enough water to have its T g below the experimental temperature) and the glassy region (region where HPMC has a T g above the experimental temperature). A second front is the ‘erosion front’, which separates the matrix from the solvent (water). The gel layer formed on the glassy core of a swellable matrix is considered to be the controlling element of drug release kinetics. The gel layer structure and composition change during matrix swelling, due to the molecular extension of the solvated polymeric chains. The gel layer thickness behavior as a function of time is determined by the relative position of the moving swelling and erosion fronts. In addition, a drug diffusion front located between the swelling and erosion fronts and constituting the boundary separating solid from dissolved drug was identified previously [16]. The diffusion front position in the gel phase during drug release was dependent on the drug’s solubility and loading. In fact, the diffusion front movement was related to the drug’s dissolution rate [3]. Finally, the diffusion and erosion front positions identify the drug’s dissolved gel layer, where the concentration profile relevant to the flux of drug is established. The movement of the swelling and dissolution (erosion) fronts in HPMC matrices containing fluorescein sodium at different drug loadings and polymer viscosities were measured using a nondestructive mode of operating [17]. In this work, the behavior of gel layer thickness in swellable matrices loaded with increasing amounts of soluble and colored drug was studied using a colorimetric technique. The main goal of this work was to determine how the drug loading affected the front position in the gel layer, in particular, the
presence of a diffusion front and its movement. We measured the swelling, diffusion and erosion front positions at different swelling times and provided a theoretical analysis of the overall process.
2. Analysis of swelling behavior
2.1. Swelling process We considered the dynamic swelling behavior of a hydrophilic, glassy, polymeric matrix that can swell (and dissolve) in water. Starting with a slab thickness of 2d0 at time t50; when the slab is placed in water, there is swelling and dissolution, and an erosion and a swelling front appear (E and S, respectively) (Fig. 1).
2.2. Swelling front The water concentration at the glassy–rubbery interface, c*, is established by the glass transition temperature of the polymer, T g and the experimental temperature, T exp [18,19]. Thus, the water concentration at position S, can be calculated as T g 2 T exp c* 5 ]]] b /af
(1)
Here, c* is the threshold concentration, expressed in g of water / g of dry polymer, af is the linear thermal expansion coefficient of the polymer, and b is the contribution of the water to the expansion coefficient of the polymer. In problems of polymer dissolution, it is advantageous to use volume fractions of components, yi , rather than concentrations, c i . This is because of the volume change at any point in a slab. Thus, in order to convert c* to an equivalent volume fraction, the value of c* can also be expressed as a volume of water per volume of polymer as c* rp /rw (cm 3 of water / cm 3 of polymer). At the interface, S, in drug-containing swellable systems, some undissolved drug also exists and is equal to the loading concentration of c d (g of drug / g of polymer), or c d rp /rd (cm 3 of drug / cm 3 of polymer), where rd is the drug density. Then, at the interface, the equivalent threshold
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85
Fig. 1. Schematic representation of the front positions, water, polymer and drug gradient associated with the dynamic swelling process in a slab-like matrix.
volume fractions of water, y w* , polymer, y p* , and drug, y d* , are as follows (Fig. 1):
rp c*] rw y *w 5 ]]]]] rp rp c*] 1 c d ] 1 1 rw rd 1 y p* 5 ]]]]] rp rp c*] 1 c d ] 1 1 rw rd
(2)
(3)
and
rp c*] rd y *d 5 ]]]]] rp rp c*] 1 c d ] 1 1 rw rd
(4)
Here,
y w* 1 y p* 1 y *d 5 1
(5)
2.3. Erosion front At the erosion front, E, the relevant volume fractions of the components are for pure water, y 1 w, 1 the disentangled macromolecular chains, y p,dis , and 1 the drug, y 1 d . Although y p,dis is known for each 1 1 polymer [4], y w and y d are not known a priori but are dependent on experimental conditions, such as
agitation and the composition of the surrounding fluid (pH and ionic strength). When dynamic swelling / dissolution is established, a volume fraction (concentration) gradient is established in the region between the erosion and swelling fronts, as shown in Fig. 1. This figure shows the shape of the concentration profiles.
2.4. Diffusion front In this section, we consider incorporation of a drug whose solubility in water is c s (g of drug / cm 3 of water). Drug concentration at any point in the gel is obtained by multiplying c s by the corresponding water volume fraction at that point, yw . Then, the drug concentration in the gel (between S and E) is 3 c s yw (g of drug / cm of gel). To further express this value as a local drug volume fraction, yds , we divide by the drug density to obtain: c s yw yds 5 ]] (cm 3 of drug / cm 3 of gel) (6) rd It must be noted that, between S and E, the terms c s and rd are constant (at constant T exp ) and only yw can change as a function of position. As c s has a limiting value, yds will also have a limiting value, i.e., a single local value at which the drug will not be completely dissolved. This value identifies the position of the diffusion front, D. From the diffusion
P. Colombo et al. / Journal of Controlled Release 61 (1999) 83 – 91
86
front up to the swelling front, the drug concentration should change, as indicated by drug profile in Fig. 1c. Using Eq. (6), it is also possible to calculate the * , that correvalue of the drug volume fraction, y ds sponds to the threshold water volume fraction y w* as: c s y w* y *ds 5 ]] rd
(7)
This parameter is of importance when trying to determine the dissolved and undissolved drug as it will be shown in our experimental studies below. The drug loading below which the diffusion front will not appear can be calculated by making the following assumption. First, we define the value of * , as in Eq. y *d , as in Eq. (4), and we set it equal to y ds (7), to obtain:
rp cd] rd c s y *w * 5 ]] y d* 5 ]]]]] 5 y ds rp rp rd c*] 1 c d ] 1 1 rw rd
(8)
Then, we solve for the value of c d , which becomes
rp rd c*] 1 1 ] rw rp c d 5 ]]]]]] rd ]] 2 1 c s y w*
S
S
DS D D
(9)
In addition, by solving Eq. (8) for y *w , we can obtain: cd rp ] cs y *w 5 ]]]]] rp rp c*] 1 c d ] 1 1 rw rd
to 10 parts HPMC (Methocel K4M, Colorcon, Orpington, UK; particle size, 90%,150 mm). As a binder, four parts of cellulose acetate phthalate dissolved in acetone–ethanol (1:1,v / v) was used. After drying, the granules were lubricated with two parts of magnesium stearate (USP grade) and four parts of talc (USP grade). Finally, the granules were tabletted using a reciprocating tabletting machine (EKO Korsch, Berlin, Germany) equipped with flat face cylindrical punches of 7 mm diameter, in order to prepare matrices weighing 12560.8 mg, having a crushing strength of between 12 and 13 (Monsanto scale) and an initial porosity of 9.260.9%. Swelling studies of these HPMC matrices were performed by clamping each matrix between two transparent Plexiglas disks, thus forming an assembled device that was introduced into the vessel of a USP 23 Apparatus 2 (Esadissolver, Advanced Products, Milan, Italy) containing distilled water at 378C (agitation speed of 200 rpm) [21]. At fixed times during swelling, the device was taken out of the vessel and pictures of the disc matrix base were video-recorded. Using an Image 1.49 program (NIH, Bethesda, MD, USA), the front distance was measured in pixels and these were converted into length units. The densities of drug and polymer were measured using a helium pycnometer (Multivolume Pycnometer 1305, Micromeritics, Norcross, GA, USA).
4. Results and discussion (10)
This equation shows that the threshold fraction of water at the diffusion front is directly related to the ratio of c d /c s , a similar conclusion and relation as that obtained by Lee [20].
3. Experimental Swellable matrices having a disc shape were prepared by granulating 10 to 80 parts of buflomedil pyridoxal phosphate, (BPP, mol. wt. 553.5; solubility in water, c s 50.65 g cm 3 ; Lisapharma S.p.A., Erba, Italy; particle size range, 20–90 mm) mixed with 80
The swellable matrices were prepared using mixtures of BPP and HPMC of different ratios. Drug and polymer constituted 90 wt.% of the formulation, while the rest were adjuvants for tabletting. Matrices were produced by compression under the same conditions. Swelling studies were conducted in a device consisting of two transparent Plexiglas discs clamped onto the bases of the cylindrical matrix. Thus, water penetration and matrix expansion occurred through the lateral side of the matrix [21]. The transparent discs of the device allowed for direct observation of the undergoing swelling and for identification of the positions where polymer transition and drug dissolution took place.
P. Colombo et al. / Journal of Controlled Release 61 (1999) 83 – 91
The drug was light yellow in color in the dry state, whereas in solution, it ranged from yellow to orange as the concentration increased. In fact, the matrix fronts during drug release were visible on the matrix base as concentric circles corresponding to a sharp change in drug color. Fig. 2 shows the three fronts formed during the swelling / dissolution process. From the center to the periphery of the matrix, the swelling front (polymer glassy–rubbery transition boundary), the diffusion front (solid drug–drug solution boundary) and the erosion front (swollen matrix–solvent boundary) could be identified. Clearly, the intensity of the yellow color indicated the dissolved drug concentration. The fronts moved in relation to the phenomena that were active at their respective locations. For example, the erosion front moved outwards due to the swelling of the matrix or inwards due to matrix dissolution, whereas the swelling front moved inwards as a result of water penetration. The gel layer thickness was measured as the
87
Fig. 3. Gel layer thickness as a function of time for matrices containing different percentages of BPP: (s) 10%, (h) 20%, (n) 30%, (d) 40%, (j) 60% and (m) 80%. The bars represent the standard error of the mean (n53).
distance between the erosion and swelling fronts. Fig. 3 shows that the thickness of the gel layer as a function of time was not very different in the systems prepared, despite the varying amounts of
Fig. 2. Image of the matrix containing 60% BPP (w / w) taken after 240 min of swelling.
88
P. Colombo et al. / Journal of Controlled Release 61 (1999) 83 – 91
drug. It was also found that the individual movement of erosion and swelling fronts (data not shown) was not significantly different in the various systems studied, except for the matrix containing the highest amount of drug (80%), which showed the slowest outward movement of the erosion front and the fastest movement of the swelling front (i.e., high water penetration rate). In this case, the low amount of polymer in the matrix rendered the matrix more sensitive to erosion and, therefore, to water penetration. In the matrices used in this study, the diffusion front moved inwards and was near the swelling front. The distance between the diffusion front and the erosion front represented the thickness of the dissolved drug gel layer [3], that is, the diffusive layer involved in controlling the drug’s release process. Fig. 4 shows the variation in the thickness of the drug-dissolved gel layer versus time. As shown in this figure, samples with 10 and 20% drug exhibited consistently higher dissolved drug gel layer thicknesses than the other samples, due to the absence of the diffusion front. The series of pictures of the matrix base, taken at sequential times, showed a gradient of color in the gel layer due to the dissolved drug. The color gradient in the gel is related to the concentration gradient of dissolved BPP. Typical pictures of the variation of the color in matrices containing increasing amount of drug are shown in Fig. 5 after 120 min
Fig. 4. Dissolved drug gel layer thickness as a function of time for matrices containing different percentages of BPP: (s) 10%, (h) 20%, (n) 30%, (d) 40%, (j) 60% and (m) 80%. The bars represent the standard error of the mean (n53).
of swelling. For example, the color exhibited by the matrix containing 60% of drug ranged from the deep orange color of saturated or highly concentrated drug solutions near the diffusion front to the very light yellow color near the erosion front. The diffusion front was easy to identify because the deep orange saturated drug solution in the gelled portion of the matrix was preceded by a distinct circular yellow layer. This yellow layer became thicker and denser at high loadings (60–80%). It appeared to be uniform in color, and corresponded to the undissolved drug gel layer thickness. Therefore, with an increasing BPP loading, the solid drug tended to persist after the swelling front and gave rise to the diffusion front. The sudden increase in color at the diffusion front is an indication that the local value of the water volume fraction was high enough to dissolve the amount of solid drug present close to the diffusion front. This is also clearly indicated by Eqs. (8) and (9), which indicate that the diffusion front and the associated finite value of c d will appear only when the water volume fraction is at least y w* . A detailed analysis of the threshold volume fractions (concentrations) of water, drug and polymer in the specific HPMC matrices investigated here is shown in Table 1. For these values, the following calculations were performed. First, the threshold concentration, c*, was calculated from Eq. (1), where T exp 5378C, T g 51778C for HPMC, as reported by Doelker [1], the expansion coefficient was af 53.7?10 24 K 21 , as defined by Ferry [18] and the expansion factor b 50.2, as reported by Fujita and Kishimoto [22]. Thus, for our HPMC system, the value of c* was calculated as 0.259 g of water / g of polymer, a value that is close to those reported by Doelker [1], of 0.23, and Hancock and Zografi [23], of 0.20. To determine the threshold volume fractions, we used Eqs. (2–4), with a polymer density of rp 5 1.326 g / cm 3 , a drug density rd 51.394 g / cm 3 , as determined by helium pycnometry, and a water density at 378C equal to rw 50.993 g / cm 3 [24]. Finally, as noted before, the water BPP solubility was c s 50.65 g / cm 3 . As indicated in Table 1, the nominal loading of the studied systems was reported as a percentage of the total tablet weight. These values were recalcu-
P. Colombo et al. / Journal of Controlled Release 61 (1999) 83 – 91
Fig. 5. Images of the matrices containing different percentages of BPP (w / w), taken after 120 min of swelling.
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90
Table 1 Threshold volume fractions for water, drug, polymer and dissolved drug at different nominal loadings of drug, calculated according to Eqs. (2), (3), (4) and (7), respectively Nominal loading (% w / w)
Loading / concentration cd
10 20 30 40 60 80
0.125 0.286 0.500 0.800 2.000 8.000
Threshold volume fractions Water y *w
Drug y *d
Polymer y *p
Dissolved drug y *ds
0.236 0.214 0.190 0.164 0.106 0.038
0.081 0.168 0.260 0.360 0.585 0.849
0.683 0.618 0.549 0.475 0.308 0.112
0.110 0.099 0.088 0.076 0.049 0.018
lated as values of c d required in this work (g of drug / g of polymer) and are shown in the second column of Table 1. The threshold volume fractions were calculated under these conditions and are reported in columns 3, 4 and 5 as y w* , y d* and y p* for water, drug and polymer, respectively. It is evident that the relative volume fractions of each component change according to the system’s nominal drug loading. Most notably, the water threshold volume fraction varies from 0.0328 to 0.236, with the lowest value being observed at the highest loading, where only a small amount of polymer was present. Although we did not take the initial porosity of the matrices (which is of the order of 10%) and the other components used for matrix production (10% w / w) into consideration in these calculations, these values are still deemed reasonable [23]. We were also able to calculate the drug volume * , from Eq. (7) using the corresponding fraction, y ds threshold water volume fraction, y w* . The results are shown in the last column of Table 1 and are quite revealing as they indicate the amount of undissolved drug in the gel layer at the swelling front. For example, for the matrix containing just 10% BPP, the total drug present at the swelling front was 8.1% * 50.110) that could (y d* 50.081), with 11% (y ds dissolve. This is the reason why, in Fig. 5, it was impossible to visibly detect the diffusion front. On the other hand, in the matrix with 80% BPP, the total drug present at the swelling front was 84.9%, with only 1.8% being dissolved. Our results indicate that there was a substantial difference among the matrices that were loaded with different drug concentrations. More specifically, it
was extremely difficult to visually identify the diffusion front position in matrices containing less than 30% drug. According to the theoretical analysis presented here, this was due to the high water solubility of the drug as well as its loading level. In fact, while analyzing all matrices that contained BPP at concentrations ranging from 10 to 80%, we noticed that the diffusion front started to be visible in matrices at above 30% drug, due to the appearance of the thick circular layer with a uniform yellow color, which created a sharp variation in color. In the region beyond the circular yellow layer, the matrix was gel-like and the color changed to an orange color, identifying the boundary separating solid drug from dissolved drug, i.e., the diffusion front. It is interesting to note that, as drug-loading increased, the presence of this yellow layer appeared at earlier swelling times, thus confirming that the observed layer was due to incomplete dissolution of the drug at the swelling front. This situation could be explained by considering that the increase in the amount of drug in the matrix augmented the local drug’s volume fraction, as shown by the data in column 4 of Table 1. Therefore, a higher water volume fraction was required to completely dissolve the drug present at the diffusion front, as shown in Eq. (10).
5. Conclusions From the results obtained in this work, it is concluded that a diffusion front can be observed with BPP-containing HPMC matrices. This front is visible in systems with more than 30% drug, since there is
P. Colombo et al. / Journal of Controlled Release 61 (1999) 83 – 91
an undissolved drug layer in such systems. A new mathematical and physical analysis of such systems shows the importance of drug solubility and loading in the observation of the diffusion front.
[10]
Acknowledgements
[11]
This work was partially supported by a grant from CNR Italy 96.01066.CT03 and from the Showalter Foundation.
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