3.6.3. Powder/Formulation Dissolution

A powder dissolution analysis was carried out in two stages: one with the samples physically mixed with lactose monohydrate in a 1:6 *w*/*w* API:excipient ratio to improve the wettability and dispersibility of the drug powders, and another with the samples physically mixed with the same excipients as those in the Sporanox ® formulation. In both dissolution experiments, Sporanox ® capsules, a marketed formulation, was used as the reference. For the purpose of dissolution studies, the pellets were removed from the capsule shells and used without further alteration. While dissolution studies performed on ITR cocrystal particles dominate the literature [14,16], scarce information is available on the behavior during formulation, therefore the inclusion of a range of pharmaceutical excipients in the dissolution studies allows the cocrystal performance to be evaluated better.

In the dissolution experiment where the samples were mixed with lactose, the results showed that Sporanox ® had a superior dissolution profile in comparison to the other samples (Figure 12a). ITR from Sporanox ® had an almost constant dissolution rate until it reached its maximum percent of drug dissolved, %max, of 66.9 ± 2.1% after 40 min. In comparison to ITR, which had a %max of 3.7% ± 0.1%, the concentration of solubilized ITR released from Sporanox ® was greater by 18-fold, highlighting the enhanced dissolution performance of this commercial form.

**Figure 12.** (**a**) Dissolution profile of Sporanox ® and the physical mixtures of ITR and cocrystals with lactose monohydrate in a 1:6 ratio ( *w*/*w*) of the active pharmaceutical ingredient (API) and excipient; (**b**) dissolution profile of Sporanox ® and the ITR, FD IDR, ITR–OXA, ITR–SUC and ITR–TER mixed with excipients present in the Sporanox ® capsule. Tmax—the time to reach the maximum percent (%max) of the dissolved drug, CC—cocrystal.

FD ITR and ITR–SUC had faster initial dissolution rates in comparison to other ITR forms (Figure 12a). The time required to reach the maximum percent of dissolved drug, Tmax, was 20 min for FD ITR and 15 min for ITR–SUC, while for the other samples this time was between 40 and 60 min. This e ffect could be due to the di fferences in solubility between the various forms. Nevertheless, the dissolution profile of FD ITR showed a decrease in the amount of the dissolved material from 18.6 ± 2.8% to 14.6 ± 0.4% after 60 min, which is statistically di fferent (*t*-test, *p*-value = 0.03). This slight "parachute e ffect" might be caused by the crystallization of the dissolved API in order to reduce the chemical potential of the supersaturation generated when the disordered API was dissolved [42]. This was confirmed using PXRD, and it was apparent that the material remaining after the dissolution of FD ITR crystallized to form I of ITR [27].

Among the cocrystals, ITR–SUC had the highest %max, of 7.8% ± 0.8%, while the dissolution profile of ITR–OXA mostly overlapped with that of ITR. The cocrystal had a slightly higher %max, 4.5% ± 0.1%, while ITR had a %max of 3.7% ± 0.1% (Figure 12a). This result contrasts with the IDR study (Figure 11), which showed a faster dissolution rate of ITR–OXA in relation to ITR. In this study, the very small di fference in the percentage of the solubilized drug between ITR and ITR–OXA could be caused by an incongruent dissolution from the cocrystal and the removal of the coformer from its surface. This is due to the very di fferent solubilities of OXA (130–140 mg/mL) in comparison to that of ITR [39,40]. A conversion to crystalline ITR form I was observed by a PXRD analysis of the remaining ITR–OXA. Therefore, the cocrystallisation of an API with a coformer with a very di fferent aqueous solubility might not be able to enhance the dissolution rate of the API [43].

Dissolution studies of the ITR–TER cocrystal showed that the amount of the drug dissolved was increasing until the final measurement at 60 min (Figure 12a), reaching a %max of 5.8% ± 0.4%, which is statistically greater by a *t*-test (*p* = 0.0009) comparison than that of crystalline ITR. The PXRD trace of the undissolved ITR–TER after the dissolution test showed no alteration in the solid-state properties after the test, suggesting that this cocrystal has an enhanced stability in aqueous media in relation to the other samples.

The dissolution analysis using the samples mixed with the same excipients as those present in the Sporanox ® formulation (Figure 12b) yielded di fferent results in comparison to the test using the physical mixtures with lactose (Figure 12a). In this experiment, Sporanox ® also had a superior dissolution profile when compared to the other samples, reaching 86.1% ± 1.0% of dissolved drug. Only 2.4% ± 0.1% dissolved from crystalline ITR. FD ITR had the second highest dissolution profile. This sample continuously released ITR, reaching a %max of 36.0% ± 1.0%. No "parachute" e ffect was observed, in contrast to the previous analysis (Figure 12a). This could be caused by the stabilizer effect of the polymers PEG 6 kDa and HPMC, preventing the crystallization of the solubilized API [44]. The PXRD trace of the undissolved FD ITR recovered after the dissolution test showed no alteration of its solid-state characteristics, suggesting that the FD ITR had an enhanced physical stability in this experiment.

In relation to the cocrystals, ITR–OXA reached the greatest %max of 24.1 ± 0.3% (Figure 12b). The ITR–SUC cocrystal had a %max of 12.1 ± 0.8%, while ITR–TER had the lowest but was nevertheless greater than crystalline ITR, with a drug release of 3.1 ± 0.1%. In comparison to the previous analysis, ITR–OXA and ITR–SUC showed improved dissolution profiles, probably due to the presence of polymers in the dissolution media, as observed for the FD ITR sample. The PXRD analysis of ITR–OXA and ITR–SUC after the dissolution test showed no phase change when compared to the samples before dissolution.
