Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility

Abstract

The inclusion of certain polymers within solid dispersion or lipid-based formulations can maintain drug supersaturation after dispersion and/or digestion of the vehicle, leading to improvements in bioavailability and variability in exposure. This review presents an overview of the fundamental principles that underpin drug precipitation mechanisms, describes the mechanisms by which precipitation may be inhibited, discusses the methods that can be used to identify polymeric precipitation inhibitors (PPIs), and summarizes current literature evidence of the most effective PPIs. Preliminary data from our laboratory is also presented, which describes the precipitation inhibition behavior of 53 polymeric materials using supersaturated solutions of danazol as a model, poorly water-soluble drug. These studies identify a group of PPIs with superior precipitation inhibition qualities, the majority of which are cellulose-based. These new results in combination with previous published data indicate that PPIs represent an appealing new technology with the potential to improve drug absorption for poorly water-soluble drugs. The molecular determinants of polymer utility, however, remain relatively poorly understood, although the cellulose derivates appear, in general, to provide the most benefit. More detailed studies are therefore required to define the parameters that most effectively predict and quantify the drug-polymer relationships that control precipitation inhibition.

Insight into Flufenamic Acid Cocrystal Dissolution in the Presence of a Polymer in Solution: from Single Crystal to Powder Dissolution

“…5,6 In order to maximise the potential of cocrystals, it is critical to include inhibitors in a formulation to prevent or delay the precipitation of the parent drug during dissolution. [7][8][9][10][11][12][13] Although polymeric crystallization inhibitors have been extensively studied in many other systems, in particular amorphous solid dispersions, 14,15 such studies are still rare for cocrystal based formulations. In a recent study, we have found that the competition of intermolecular hydrogen bonding among drug/coformer, drug/polymer, and coformer/polymer was a key factor responsible for maintaining the supersaturation through nucleation inhibition and crystal growth modification in a supersaturated cocrystal solution with a pre-dissolved polymer.…”

Role of polymers in solution and tablet-based carbamazepine cocrystal formulations

“…Three chemi ca l l y di vers e pol ymers i ncl udi ng hydroxypropyl emthyl cel l ul os e a ceta te s ucci na te (HPMCAS), pol yvi nyl pyrrol i done (PVP) a nd pol yethyl ene gl ycol (PEG) were s elected i n the s tudy beca us e they ha ve been wi del y us ed a s preci pitation i nhi bi tors i n other s upers a tura ti ng drug del i very s ys tems a nd a pproved orally commercial products [12][13][14]22 . In order to eva l uate the effectiveness of these pol ymers on i nhi bi ti ng the pha se tra nsformation of cocrys tals, the s tudy was ca rri ed out wi th pol ymers i n both pre -di s s ol ved s ol uti on a nd ta bl et ba s ed formul ations.…”

“…Thi s coul d be a chi eved through i ncl us i on of pha rma ceuti ca l exci pi ents a s preci pi ta ti on ( or crys ta l lisation) inhibi tors i n the formul a ti on. A l a rge number of exci pi ents ha ve been expl ored a s preci pi ta ti on i nhi bi tors to ma i ntain drugs i n other s upersaturating drug delivery s ystems s uch a s s olid di s pers i ons a nd l i pi d -ba s ed formul a ti ons [12][13][14] . Thes e exci pients i ncluding polymers, s urfa cta nts a nd cycl odextri ns ca n i nterfere wi th drug nucl ea ti on a nd/or crys ta l growth to i nhi bi t a nd/or retard the drug precipitation from sol uti on.…”

Hot-melt extrusion of polyvinyl alcohol for oral immediate release applications

“…In contrast, CEL release from the commercially available formulation (Celebrex ® ) was much slower in the medium and was equivalent to the maximum solubility of CEL in 0.1N HCl (3 mg/L). PVOH has already been reported as a precipitation inhibitor, able to stabilize supersaturation of drugs (caffeine (Gift et al, 2008), danazol (Warren et al, 2010), estradiol (Megrab et al, 1995) and tacrolimus (Overhoff et al, 2008)) via drug/polymer interactions. In addition to the lower extrusion temperature of this formulation during HME, this could be an important feature to improve the bioavailability of solubility-limited drugs (BSC class II).…”