The Butterfly Effect in Swellable Matrices

The "butterfly effect" was first observed when hypromellose-based matrix compacts partially separated as two "wings" during dissolution studies. Such splitting was pH-independent and the "halves" so generated remained attached to each other. Figure 11.12 illustrates such changes. Such a phenomenon, if reproducible, has potential applications for modifying drug release due to the changed release area consequent to splitting.

Fig. 11.12 Progression of events during disk matrix swelling leading to the manifestation of butterfly effect. (a) Hydration and swelling of the tablet disk matrix upon contact with dissolution medium. (b) Splitting of tablet at the radial side. The tablet edges began to curl outwards. (c) Formation of the butterfly shaped hydrated matrix. The two halves of the tablet remained attached at one end. (d) The two halves of the butterfly shaped tablet detached into two individual swollen matrices

Fig. 11.12 Progression of events during disk matrix swelling leading to the manifestation of butterfly effect. (a) Hydration and swelling of the tablet disk matrix upon contact with dissolution medium. (b) Splitting of tablet at the radial side. The tablet edges began to curl outwards. (c) Formation of the butterfly shaped hydrated matrix. The two halves of the tablet remained attached at one end. (d) The two halves of the butterfly shaped tablet detached into two individual swollen matrices

The phenomenon is ascribable to the following behaviors:

• The dynamics of moving solvent and swelling fronts.

• The anisotropic expansion of materials in solution.

Hydration and swelling begins as the dissolution medium penetrates the compact. A solvent/swelling front is created as polymer swelling progresses. This moving boundary separates the glassy and rubbery states of polymer creating regions of high stress [18]. Stress relaxation occurs when the center of the matrix is plasticized by the penetrating dissolution medium, eliminating the glassy state [19]. In a disk-shaped matrix tablet, the swelling fronts move simultaneously from the axial and radial surfaces toward the center of the tablet. The glassy core tends to restrict the rubbery phase to one-dimensional swelling. Its elimination removes the swelling constraint [20]. This, coupled with the large axial swelling pressure causes sudden relaxation or volume increase of the swellable disk, splitting the tablet into a "butterfly"-shaped matrix.

The axial directional nature of compaction during tablet manufacture generates inherent mechanical anisotropy, resulting in axial and radial stresses and strains [21, 22]. Consequently, penetration of dissolution medium causes nonuniform swelling [23]. It is reported that hypromellose compacts swell predominantly in the axial rather than the radial direction on exposure to aqueous fluids [10]. Such more rapid release of stress in the axial direction would cause the tablet to split on the radial side. Dissolution medium penetrating the core through the fissure could cause greater swelling of the contact area. The outer surfaces, being hydrated much earlier, would have formed a viscous, more flexible layer which would "curl" outwards due to swelling pressure. This could also lead to the "butterfly" configuration.

Tablets exhibiting the "butterfly effect" were relatively thin, characterized by aspect ratios (2 x diameter/thickness) ranging from 12.7 to 14.5. Thicker compacts did not display the effect. Such thicker units may be more likely to accommodate the swelling stresses generated as swelling fronts meet. Disappearance of the glassy core is slower, giving more time for the polymer chains to accommodate the swelling stresses. Moreover, the additional hypromellose possibly allows the matrix to be more strongly hydrated, thus maintaining its structural integrity.

Butterfly Effect Math Fractions
Fig. 11.13 Drug release profiles of matrix formulations containing unsieved hypromellose (Formula C) prepared at different compaction forces

The "butterfly" geometry causes the surface area for drug release to increase. The effect of shape change on release mechanism and kinetics was accordingly evaluated. Hypromellose particle size, applied compaction pressure and proportions of insoluble and soluble excipients were investigated. Findings were as follows:

• Compacts containing sieved (fine or coarse particles) hypromellose fractions did not manifest the "butterfly effect" during dissolution.

• Unsieved hypromellose (almost 70% of material less than 63 mm) contained a mix of coarse and fine particles which was most effective in manifesting the "butterfly effect" in compacts.

• The "butterfly effect" was only manifested when tablets were compacted at a suitable compaction pressure.

The proportions of soluble and insoluble excipients in the formulation affected "butterfly" shape formation and drug release.

Particle size distribution of hypromellose was key to "butterfly" shape formation. Compacts incorporating predominantly fine hypromellose possess larger surface areas, facilitating greater polymer-water interactions. This would help preserve matrix structure by rapidly forming a gel barrier. Coarse hypromellose could have the opposite effect, with compacts disintegrating too rapidly.

Figure 11.13 shows the release profiles of compacts containing unsieved hypromellose prepared at different compaction pressures. There were no significant differences (p > 0.05) between dissolution profiles. However, the "butterfly

Table 11.1 Composition of tablets studied

Formula A

Formula B

Formula C

Materials

mg

%

mg

%

mg

%

Granules

Flurbiprofen

37.50

33.13

37.50

33.13

37.50

33.13

Mannitol

24.01

24.01

24.01

PVP K30

3.37

3.37

3.37

Extragranular

Mannitol

90.82

46.37

67.02

34.22

43.24

22.07

excipients

MCC PH102

-

-

23.80

12.15

47.59

24.30

Hypromellose K4M

39.17

20.00

39.17

20.00

39.17

20.00

Magnesium stearate

0.98

0.50

0.98

0.50

0.98

0.50

Total

195.85

100

195.85

100

195.86

100

0 50 100 150 200

Time (min)

Fig. 11.14 Drug release profiles of matrices (Formula A, B, and C) prepared at compaction force of 10 kN

effect" was only manifested when compaction pressure exceeded 3 kN. At lower compaction pressures, greater compact porosity promoted disintegration due to enhanced penetration of dissolution medium and poorer establishment of swelling fronts. High compaction pressures might have been expected to reduce release rates. However, the "butterfly effect" counteracted this by increasing the surface area for release [11].

Three formulations (Table 11.1) prepared using unsieved hypromellose with different proportions of soluble (mannitol) and insoluble [microcrystalline cellulose (MCC)] excipients were studied.

Figure 11.14 shows release profiles of tablets produced using the different formulations prepared at a compaction pressure of 10 kN. Soluble excipients dissolve and diffuse out of the matrix, increasing porosity, facilitating drug release, and reduce strength of the matrix. The tablet containing the most soluble component

(Formula A) should theoretically display the fastest drug release. However, this was not the case. Release rates were in the following order:

Formula B (12.15% w/w MCC) > Formula A (0% w/w MCC) > Formula C (24.3% w/w MCC).

The "butterfly effect" was manifested in all three formulations. However, it was more extensive with Formula B and provided the fastest drug release. Even in the absence of MCC, Formula A tablets also manifested the "butterfly effect" but shape was quickly lost when the large amount of mannitol dissolved, thereby weakening the matrix. Collectively, these observations suggest that the shape of the "butterfly" disk matrix was influenced mainly by the unsieved hypromellose. MCC, by acting as a physical barrier, helped to promote the "butterfly effect" through an additional disintegrant effect and obstruction to polymer interaction and gelation. It was also noteworthy that Formula B showed the most extensive "butterfly" shape formation, not Formula C, which contained the most MCC. This further emphasizes the importance of formulation for generating the "butterfly effect."

In conclusion, the "butterfly effect" is a promising phenomenon observed in hypromellose matrices. Preliminary studies afforded new mechanistic insights on factors that promote or inhibit the phenomenon. The "butterfly effect" can increase drug release rates by increasing surface area, at a time in the dissolution process when rate may be slowing. However, further studies are required to better understand the phenomenon and utilize this effect in drug release control.

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