Improvement of drug dissolution by solid dispersion approach (III)

As described in Chapter 2.3, there is a growing interest in developing dosage forms, e.g. orally fast disintegrating tablets, which allow a rapidly dissolving drug to absorb directly into the systemic circulation through the oral mucosa. The inherent advantages of the SD approach in enhancing drug dissolution and stability (described in chapter 2.4.3) might mean that even a poorly soluble drug could be administerd in such a formulation.

The model drug used (PPZ) was found to have poor dissolution properties in conditions simulating the buccal cavity (i.e. low liquid volume (3 ml), with pH 6.8). The solubility of PPZ was found to be 149 ± 3 µg/ml and its dissolution rate was poor, i.e. within 4 minutes only 2% of PPZ had dissolved (Figure 5.6 a). Reducing the particle size of PPZ did not markedly change the situation, viz. only 13% of PPZ <15 µm had dissolved within 4 minutes (Figure 5.6 a). Furthermore, even when sink conditions prevailed, only 43 % of PPZ and 88 % of PPZ <15µm had dissolved after 20 minutes (results shown up to 4 min in Figure 5.6 a).

5.3.1.1 Polymer selection by the solubility parameter approach (III)

As described in section 2.4.3.3, two materials are considered to be miscible with each other when Δδ is smaller than 2.0 MPa^1/2 which might lead to the formation of a solid solution. The δ value for PPZ was estimated to be 22.4 MPa^1/2. Evaluation of a wide selection of polymers and their different grades (Hancock et al. 1997, Greenhalgh et al.

1999, Forster et al. 2001, Marsac et al. 2006b) revealed that two hydrophilic polymers, PVP K 30 and PEG 8000, possessed solubility parameter values nearest to that of PPZ, i.e. 22.4 (Δδ = 0) and 21.6 MPa^1/2 (Δδ = 0.8) respectively, and thus they were predicted to provide the most favorable conditions for molecular level mixing with PPZ.

5.3.1.2 Dissolution properties of the solid dispersions (III, IV)

In phase solubility studies, increasing concentrations of PVP and PEG increased linearly the PPZ solubility in pH 6.8 buffer, however PVP was considerably better than PEG (Figure 5.6 b). PPZ solubility was increased over fivefold in 10% (w/v) PVP solution whereas in 10% (w/v) PEG solution, the increase was a mere doubling. Similar behavior has been observed previously for the other model drugs (Sethia and Squillante 2004, Mura et al. 2005, Ruan et al. 2005).

Figure 5.6.Dissolution curves of (a) PPZ (d(0.5) = 30 µm) in supersaturated (_Ÿ) and in sink conditions (¨), and micronized (<15 µm) PPZ) in supersaturated (Ŷ) and in sink conditions (Ƒ); (b) phase solubility diagrams of PPZ in solutions PVP (Ƒ) and PEG (Ŷ) in pH 6.8 buffer solution at room temperature.

The dissolution rates of freeze-dried PPZ and PPZ from prepared PPZ/PVP and PPZ/PEG dispersions were determined in supersaturated conditions due to the small dissolution volume (3 ml), i.e. complete dissolution of PPZ would result in 9-times the equilibrium solubility of crystalline PPZ (Table 5.8). With freeze-dried PPZ, a rapid dissolution at the beginning of the experiment (over 70 % of PPZ dissolved already after 15 seconds) was seen leading to over 7-fold supersaturation of PPZ. The supersaturated

a b

PPZ started to precipitate after one minute and the amount of dissolved PPZ declined down to 60 %.

Instead, in the case of PPZ/polymer SDs, the ability of the polymers to inhibit precipitation of PPZ was seen (Table 5.8). In the case of PPZ/PVP SDs, no precipitation of supersaturated PPZ was observed. After 15 seconds, 20, 35 and 10 % of PPZ had dissolved from 5/1, 1/5 and 1/20 PPZ/PVP, respectively, increasing up to 40, 90 and 40%

after four minutes. In the case of PPZ/PEG SDs, no precipitation of the supersaturated PPZ was observed with 5/1 and 1/5-formulations. However, only 40% of PPZ dissolved from the 5/1 PPZ/PEG after four minutes. The most remarkable improvement in the dissolution rate was seen with 1/5 PPZ/PEG SD which dissolved within one minute without precipitation of the supersaturated PPZ.

Thus, the dissolution rates of PPZ/PVP SDs were not as fast as those of PPZ/PEG SDs, probably due to their surprisingly poor wettability which was observed visually (PPZ/PVP powders remained floating on the liquid surface). On the other hand, at high polymer contents, PVP might form a viscous layer during dissolution, hindering the dissolution of the drug (Craig 2002) or it might act as a binder with some drugs which could cause a decrease in the dissolution rate (Bansal et al. 2007).

The dissolution rates (in 3 ml of pH 6.8 buffer) of freeze-dried PPZ and PPZ/PVP SDs were found to be changed after four weeks of storage at 40°C/silica gel (Table 5.8). In the case of fresh samples, freeze-dried PPZ and 1/5 PPZ/PVP had a faster dissolution, while 5/1 and 1/20 PPZ/PVP dissolved clearly more slowly. In contrast, the best dissolution after storage was found with freeze-dried PPZ (50% of PPZ dissolved in 4 min) and 5/1 PPZ/PVP (60% of PPZ dissolved in 4 min), while the dissolution of 1/5 and 1/20 PPZ/PVP was considerably poorer that encountered with the fresh SDs. In fact, the dissolution rate of PPZ from 1/20 PPZ/PVP had declined back to the level of crystalline PPZ, i.e. 2% PPZ dissolved in four minutes.

In the case of PPZ/PEG SDs, the dissolution profiles were also found to be somewhat different than the profiles of fresh samples (Table 5.8). After storage at 40°C/silica gel, 1/5 PPZ/PEG formulation still had the best dissolution properties (i.e. over 60% of PPZ dissolved in 4 min). The dissolution of 5/1 PPZ/PEG had remained almost unchanged,

but there was a reduction in the dissolution rate of 1/20 PPZ/PEG. After storage at 40°C/75%, the dissolution of PPZ from 1/5 and 1/20 PPZ/PEG had further declined.

Table 5.8. The amount (%) of PPZ dissolved in the freeze-dried PPZ and from the SDs of PPZ before and after four weeks’ storage at 40°C/silica or 40°C/75 % RH (n=3± sd.).

% of perphenazine dissolving at time t (min)

Dispersion Storage t=0.25 t=0.5 t=0.75 t=1 t=2 t=4

freeze-dried