Supersaturation

Formulation strategies which can provide the potential for generation of supersaturated solutions relative to the saturation solubility of the most stable solid phase, typically a crystalline phase, can in one sense be very valuable and in another be very problematic. The value in such supersaturated systems comes in that they are one of the few ways that actual driving force, | , can exceed that of the saturated solution of the crystalline compound and provide the potential to enhance absorption of poorly permeable drugs to a meaningful level. The disadvantage of such formulations is that they are highly prone to catastrophic precipitation and the ability to anticipate or predict when or what type of precipitate is poor at best. Therefore, formulations that rely on supersaturation can often show high variability in performance if not appropriately optimized.

The most common ways to initiate supersaturation is through 1) solids of increased free energy, i.e. solid dispersions, amorphous solids, solvates and high energy polymorphs, 2) use of salts which will rapidly dissolve with dissociation from the counter-ion or 3) use of solubilized formulations of the compound which can then result in supersaturated conditions upon dilution into aqueous media, i.e. pH adjusted solutions, cosolvent systems, self-emulsifying or micellarizing systems, or higher order complexes of compounds.

Through the use of a supersaturated cosolvent solution for oral dosing to dogs, it was possible to demonstrate significant absorption enhancement over a micronized suspension of the compound by almost tripling the AUC obtained (Figure 10). While it is difficult to explicitly ascribe the enhanced exposure to supersaturation, a number of other observations certainly indicated that it was likely to be one of the primary reasons for the observation. The use of the supersaturated cosolvent formulation permitted evaluation of the compound at much higher exposure with a near linear dose response (AUC) obtained (Figure 11). While this formulation could be used for proof of concept studies and even limited toxicology studies, it was not possible to take it into the clinical setting, again pointing out the need for optimizing toward a compound that does not require heroic formulation efforts such as these to get exposure.

80% Absolute Bioavailability

Supersaturated Cosolvent Solution

Aqueous Suspension Micronized (crystalline Form I)

Target of 4 ug/mL

80% Absolute Bioavailability

~ 25-35% Absolute ~ 35-45% Relative Bioavailability

Time (hours)

Figure 10. Dog plasma profiles comparing the dosing of a supersaturated cosolvent solution of a lead compound versus an aqueous micronized suspension. Absolute bioavail-ability is in comparison to AUC after IV dosing (not shown). Relative bioavailability of the suspension is to that of supersaturated cosolvent solution.

210 -|

180

E

150

*

120-

O)

90

o

I

60

30

Figure 11. The use of a supersaturated solution of a lead compound gave far superior dose linearity (AUC) for oral exposure relative to the micronized suspension of the same lead compound. (n = 3 dogs at each dose)

Ping Gao and coworkers (2003; 2004) were able to prepare and demonstrate the potential utility of a supersaturable self-emulsifying drug delivery system (S-SEDDS) for oral delivery of Paclitaxel and another poorly water soluble drug. This supersaturation was obtained through the addition of hydroxypropyl methylcel-lulose (HPMC) to the SEDDS formulation as a precipitation inhibitor.

One of the greatest difficulties in obtaining a supersaturated solution resides in obtaining concentrations that are significantly higher than the saturation solubility (> 5-10 fold), but not so high as to induce rapid precipitation. Unless the compound itself has a very high tendency to supersaturate, generally linked to poor propensity to crystallize, it can be very difficult to obtain and maintain levels of supersaturation much beyond that of 10 fold for periods approaching hours, even with precipitation inhibitors. The exponential changes in solubility commonly afforded by pH adjustment of ionizable compounds or cosolvent solubilization of compounds can many times lead to supersaturation levels of 100 or even 1000 times the saturation solubility upon dilution, resulting in very rapid precipitation.

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