Dissolution Method Development for Poorly Soluble Compounds

w h e re, V = Dissolution medium vo l u m e C S = Sat u rated solubility of the co m pound in the medium Sink = Sink condition facto r To increase the maximum dissolvable dose,o n e needs to increase the dissolution media vo l u m e, change the media to increase the sat u ration solub i l i ty of the co m po u n d,or re d u ce the dissolution sink re q u i re m e nt s. Media Vo l u m eTh e re are seve ral ways to increase the dissolution media vo l u m e.Using 4-liter vessels is re l at i ve l y u n co m m o n ,but they are available from ve n d o r s.This offers a po te ntial 4-fold enhance m e nt in maximum dissolvable dose over the standard 1-lite r ve s s e l s.The flow -t h rough apparatus (USP 4) allows flow rates exceeding 50 ml/min (3 L/hr).Although these volumes can provide the theore t i cal ca p a c i ty fo r co m p l e te exte nt of dissolution,for slowly dissolving co m pounds a limiting dissolution rate can be re a c h e d.One then ends up merely diluting the sample co n ce nt ration to a po i nt at which it be comes difficult to dete ct analytica l l y.Us i n g reasonable flow rates and long assay times,t h i s a p p a ratus can provide a significa nt increase in the vo l u m e.Media re p l a ce m e nt is a strate gy used for implant and could theore t i cally be applied to other dosage fo rm s.With this te c h n i q u e,the dosage fo rm is d ro p ped into a limited volume of dissolution media.After given time pe ri od s,the ent i re volume is re p l a ced with fresh media.These tests can occur on the order of days or we e k s,but re q u i re that the dosage fo rm remains int a ct so that when the media is re p l a ce d,one does not lose undissolved dru g p a rt i c l e s. Sat u ration So l u b i l i tyThe standard way to affe ct the sat u ration solub i l i ty of drug in the dissolution media is to change the media,ty p i cally by adjusting the pH,adding a s u rf a ct a nt,or in ra re ca s e s,using non-aqueous s o l ve nt s.