(T0930-09-52) Biphasic Dissolution Rate and Absorption Study of Adefovir Dipivoxil and Its Cocrystals under Biorelevant Conditions

Purpose: The formulation of pharmaceutical drugs in the form of cocrystals has experienced important advances in the last decade through the discovery of thousands of cocrystals, together with the generation of a huge amount of experimental data. The crystallization of a drug with a suitable coformer to obtain a cocrystal may have different physical properties compared to the drug, such as melting point, moisture sorption, compressibility, solubility, and dissolution rate. The aim of this study is to compare the dissolution rate of Adefovir Dipivoxil (a poorly soluble drug) with its cocrystals, using Resorcinol, Orcinol and Hydroquinone as coformers, at different pH values simulating the transition in the GI-tract and adding a lipid layer to mimic the absorption in the lipid membrane.

Methods: Adefovir dipivoxil (AD) and its co-crystals with the coformers (resorcinol (R), orcinol (O), hydroquinone (H)) were prepared using solvent evaporation or slurry crystallization methods. The obtained cocrystals were characterized by DSC and powder X-ray diffraction (XRPD). For dissolution rate measurements, disks of 3mm diameter containing 8-10 mg of drug or cocrystal were prepared by applying a constant pressure of 0.1 ton. A Sirius GLpKa system equipped with UV fibre-optic spectroscopy probe was used to perform the dissolution rate measurements at the pH values of 1.5, 4.0, 5.5, and 7.4, simulating the different regions of the GI. Pion inForm was used for the biphasic dissolution studies, which a lipid layer (decanol) was added in the second pH sector (after the pH was adjusted to 4.0) to simulate the contact with lipidic membranes. Two UV fibre optic probes allow the quantification of the drug in both layers aqueous and lipid.

Results: Dynamic Dissolution: Aqueous Media - A four-pH sector dissolution study was performed comparing the behaviour of AD with the cocrystals AD-R and AD-O to obtain dynamic information of the dissolution behaviour of the compound along the GIT. Figure 1 shows a fast dissolution for the cocrystals reaching 40% dissolution of the API, where saturation concentration was reached after 5 min. However, AD showed a slowed down dissolution reaching a maximum of 30% dissolved after 30 min. The rapid dissolution at pH 1.5 is due to the basic pK_a of 3.8 of AD, which dissolves rapidly as the sample is completely protonated. However, when the pH values are higher than its pK_a (pH 4.0, 5.5, and 7.4) the percentage of neutral species increases, and the dissolution becomes slower. Biphasic media: The main difference appears once the decanol phase is added (Figure 2), just after adjusting the pH to 4.0. The concentration of AD in the aqueous phase (red-plots) start to decrease as AD partitions into the organic phase (purple-plots). More partitioning is observed when the pH is higher than the pK_a of AD (3.8), (where AD exists in its neutral form), and the maximum concentration in the organic solution is reached at pH 7.4 in all the experiments. All cocrystals dissolved more than AD, except cocrystal AD-H which did not show any difference in dissolution when comparing the dissolution plot of the free base in both layers. Dissolution at single-pH Sector: Aqueous media - Single dissolution experiments were performed at the same pH sectors for 30min. Table 1 shows the percentages of dissolution and dissolution rates of AD and the cocrystals at the different GIT pH values. This table also shows the solid form observed in the tablet surface after the dissolution measurements. In contrast with the dynamic-dissolution the amount of AD decreases considerably from pH 4.0. For instance; at pH 4.0 dynamic-dissolution is 40% for AD-O, but only 14.7% at the single-pH sector for the same pH. This is because whereas in the single-pH sector, determination of the amount of AD in solution is limited by both the dissolution process and the solubility, in the dynamic dissolution, the determination of AD in the solution has already occurred when the change from pH 1.5 to pH 4.0 takes place. At this moment, precipitation of AD would be expected due to the lower solubility at pH 4.0. However, it remains stable in a supersaturated solution. The same occurs for the other pHs.

Conclusion: Dynamic dissolution determinations provide much more realistic information than the single-pH sector experiments. After the first rapid dissolution at pH 1.5, the solution remains supersaturated with AD in the three following pH sectors, and the amount of AD dissolved is more or less constant along entire pH range. This fact may help in the bioavailability of AD along the GIT. The addition of a lipid layer that mimics biological membranes, promoted AD to partition rapidly into the organic phase, especially at high pH values. Hence, both factors, faster dissolution and faster partition into lipid layer, point out that the oral bioavailability of AD should be higher when administered as resorcinol or orcinol cocrystal.

Figure 1: Dissolution profiles of AD (red), AD-R cocrystal Form I (green) and AD-O cocrystal (orange) in a four-pH sectors

Figure 2: Biphasic Dissolution profiles of AD, AD-R, AD-O and AD-H in a four-pH sectors

Table 1: Dissolution results of single-pH study. Final Solid Forms observed in the tablet surface.