A suitable dissolution test as a surrogate for in vivo absorption is highly attractive in the early stage of formulation development. Ideally, changes in dissolution in vivo should be reflected by the corresponding in vitro release. However, conventional dissolution tests have limitations to address this need due to the lack of biorelevance. The purpose of this work was to explore a discriminative dissolution test for manufacturing/ formulation changes within formulations of poorly soluble drugs. 

Evaluation of a discriminative biphasic dissolution test for different cosolvents 

PEG 400 and EtOH increased carbamazepine solubility in a concentration-dependent manner, where PEG 400 had stronger solubilization capacity than EtOH. However, PEG 400 had an inhibiting effect on drug absorption with increasing concentrations, while EtOH had no effect. The biphasic dissolution model discriminated different influences of PEG 400 and EtOH on drug absorption reflected by drug partitioning, which was in good agreement with other studies. The different performances of the two cosolvents could be associated with drug affinity and diffusivity. Therefore, the solubility-permeability interplay should be taken into consideration when designing cosolvent-based formulations. Furthermore, the mixed EtOH-PEG 400 cosolvent system was superior to single EtOH and PEG 400 by enhancing carbamazepine solubility to compensate for low solubilization in EtOH, and by decreasing the inhibiting effect on drug partitioning to compensate for low drug absorption caused by PEG 400. This optimal strategy could be considered in the development of cosolvents formulations. The biphasic dissolution model has the potential to discriminate between cosolvent-based formulations with BCS II drugs.

Evaluation of a discriminative biphasic dissolution test for estimating the bioavailability of carbamazepine polymorphic forms

Three crystal forms (forms I and III, and the dihydrate) of carbamazepine (BCS II) were prepared and characterized. A biphasic dissolution system (phosphate buffer pH 6.8 and octanol) was used to evaluate the dissolution of the three polymorphic forms and to compare it with conventional single phase dissolution tests performed under sink and non-sink conditions. Similar dissolution profiles of the three polymorphic forms were observed in the conventional dissolution test under sink conditions. Although a difference in dissolution was seen in the single phase dissolution test under non-sink conditions as well as in the aqueous phase of the biphasic test, little relevance to in vivo data obtained from the literature was observed. In contrast, the biphasic dissolution system could discriminate between the different polymorphic forms in the octanol phase with a ranking of form III > form I > dihydrate form. This was in agreement with the published in vivo performance. The dissolved drug available for oral absorption, which was dominated by dissolution and solution-mediated phase transformation, could be reflected in the biphasic dissolution test. Moreover, a good correlation was established between in vitro dissolution in the octanol phase of the biphasic test and in vivo pharmacokinetic data (R2 = 0.99). The biphasic dissolution method is a valuable tool to discriminate between different crystal forms in the formulations of poorly soluble drugs. 

Evaluation of a discriminative biphasic dissolution test and correlation with in vivo pharmacokinetic studies for differently formulated racecadotril granules

Three granule formulations of racecadotril (BCS II) were formulated with equivalent composition but prepared with different manufacturing processes (dry granulation, wet granulation with or without binder). In vitro release of the formulations was investigated using a biphasic dissolution system (phosphate buffer pH 6.8 and octanol) and compared to the conventional single phase USP II dissolution test performed under sink and non-sink conditions. The effect of different volume ratios and interfacial areas in the biphasic test was investigated and optimized to establish a discriminative dissolution test and an in vitro-in vivo correlation. In vivo studies with each granule formulation were performed in rats. Interestingly, the granule formulations exhibited pronouncedly different behavior in the various dissolution systems depending on different wetting and dissolution conditions. Similar release profiles between the three granule formulations were observed in the non-discriminating single phase dissolution tests under sink and non-sink conditions. In contrast, biphasic dissolution system showed remarkable discrimination between the granule formulations in the octanol phase with a rank order of release from granules prepared by wet granulation with binder > wet granulation without binder > dry granulation. This release order correlated well with the wettability of these granules. The same rank order as in the biphasic dissolution test was observed with in vivo AUC0-24h values of the three granules, being 4.07 ± 0.22, 3.50 ± 0.22, and 2.85 ± 0.29 µg h/ml (p < 0.05) respectively. An excellent correlation was also established between in vitro release in the octanol phase of the biphasic test and in vivo data (R2 = 0.999). Compared to conventional dissolution methods, the biphasic method is a good tool to discriminate between only minor formulation and process changes within the same dosage form for poorly soluble drugs.

Evaluation of a discriminative biphasic dissolution test for estimating the bioavailability of itraconazole amorphous solid dispersions prepared with different polymers

Three amorphous solid dispersions of itraconazole (BCS II) were prepared with different polymers (Eudragit® EPO, Eudragit® EPO-PVPVA 64, and HPMC). In vitro release of these three solid dispersions was evaluated by a pH-gradient biphasic dissolution test and compared to the conventional single phase dissolution test performed under sink and non-sink conditions. Conventional dissolution tests in 0.1 N HCl under sink and non-sink conditions showed poor prediction of in vivo behavior, while the conventional pH-gradient dissolution test under non-sink conditions exhibited a certain relevance with in vivo performance. In contrast, the pH-gradient biphasic dissolution test discriminated these three solid dispersions with a ranking of HPMC > Eudragit® EPO > Eudragit® EPO-PVPVA 64 in the octanol phase and correlated well with the published in vivo performance. Solid dispersion with HPMC showed the best performance due to its superior supersaturation maintenance and precipitation inhibition induced by interaction between HPMC and itraconazole. An excellent correlation between in vitro release obtained from the organic phase of the biphasic test and reported in vivo data was obtained (R2 ≥ 0.95). This study demonstrates that the pH-gradient biphasic model is a potential tool to discriminate between supersaturation formulations with different polymers during early development of formulations with pH-dependent BCS II drugs.

In conclusion, this entire work indicated that compared to conventional dissolution methods, the biphasic dissolution system provides great potential to discriminate between manufacturing/formulation changes within formulations for BCS II drugs during the early formulation development.

Link to Thesis