Formulation of a Danazol Cocrystal with Controlled Supersaturation Plays an Essential Role in Improving Bioavailability

Abstract

Cocrystals have become an established and adopted approach for creating crystalline solids with improved physical properties, but incorporating cocrystals into enabling pre-clinical formulations suitable for animal dosing has received limited attention. The dominant approach to in vivo evaluation of cocrystals has focused on deliberately excluding additional formulation in favor of "neat" aqueous suspensions of cocrystals or loading neat cocrystal material into capsules. However, this study demonstrates that, in order to take advantage of the improved solubility of a 1:1 danazol:vanillin cocrystal, a suitable formulation was required. The neat aqueous suspension of the danazol:vanillin cocrystal had a modest in vivo improvement of 1.7 times higher area under the curve compared to the poorly soluble crystal form of danazol dosed under identical conditions, but the formulated aqueous suspension containing 1% vitamin E-TPGS (TPGS) and 2% Klucel LF Pharm hydroxypropylcellulose improved the bioavailability of the cocrystal by over 10 times compared to the poorly soluble danazol polymorph. In vitro powder dissolution data obtained under non-sink biorelevant conditions correlate with in vivo data in rats following 20 mg/kg doses of danazol. In the case of the danazol:vanillin cocrystal, using a combination of cocrystal, solubilizer, and precipitation inhibitor in a designed supersaturating drug delivery system resulted in a dramatic improvement in the bioavailability. When suspensions of neat cocrystal material fail to return the anticipated bioavailability increase, a supersaturating formulation may be able to create the conditions required for the increased cocrystal solubility to be translated into improved in vivo absorption at levels competitive with existing formulation approaches used to overcome solubility limited bioavailability.

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

“…Therefore, the i mpl i ca ti on of thes e observations i s of s ignificance because it demons tra tes tha t cocrys ta ls ca n be ea s i l y formul a ted through a s i mpl e s ol uti on formul ation or powder formul a ti on to genera te s upers a tura ted concentrations a nd fa s ter di s s ol uti on ra tes to overcome thos e drugs with solubility a nd/or dissolution limited bioavailabi l i ty. Thi s concl usion has been supported by a similar work which has recently been done for devel opment of a n ena bl i ng da na zol -va ni l l i n cocrys ta l formulation, although a relatively compli ca ted a pproa ch ha s been used contai ni ng both a s urfa cta nt a nd pol ymer i n the formul ation 16 . Therefore the cocrys tal a pproa ch s houl d ha ve the s a me priority to be considered for formul a ti ng drug compounds wi th s olubility a nd/or dissolution limited bi oa va i l a bi l i ty a s ma ny other s uccessfully supersaturating drug delivery a pproa ches , s uch a s s olubilized formulations, s olid dispersi ons , na nopa rti cl es , a nd crys ta l l i ne s a l t forms a nd pa rti cl e s i ze reducti on 13 .…”

“…Th e drug preci pi ta ti on proces s ca n occur s i mul ta neous l y wi th the di ssolution of cocrystals, showing that the apparent drug s ol ubi l i ty of cocrys ta ls has not been improved i n comparison with that of the s ta bl e form of the pa rent drug. Study on ma i nta i ni ng the a dva nta ges of cocrys ta l s i s of i mporta nce 11,[15][16][17][18][19] .…”

“…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. However, very l i mited research has been carried out to s tudy a s upers a tura ti ng cocrys ta l s ystem i n order to ca pture the s olubility a dva nta ges 11,[15][16][17][18][19] . In a n earlier s tudy, i t has been found tha t th e combi na ti ons of cel ecoxib-nicotinamide (Cel-N SDS a nd PVP ca n have up to 4-fold more bioavailable than marketed Cel -III in contrast with the neat Cel-Nic cocrys tal formulation whi ch di ssolves more s lowly than commercial Cel-III i nto 1% SDS s ol uti on 17 .…”

“…In a n earlier s tudy, i t has been found tha t th e combi na ti ons of cel ecoxib-nicotinamide (Cel-N SDS a nd PVP ca n have up to 4-fold more bioavailable than marketed Cel -III in contrast with the neat Cel-Nic cocrys tal formulation whi ch di ssolves more s lowly than commercial Cel-III i nto 1% SDS s ol uti on 17 . In a nother study, i t has been demonstrated that the a dva nta ge of the i mproved solubility of a 1:1 danazole -va ni l l i n cocrys ta l ca n onl y be captured by a s uitable formulation containing 1% vi tamin E-TPGS a nd 2% Kl ucel LF Pha rm hydroxypropyl cel l ul os e 16 . In the mea ntime, several previous s tudies have revealed that inclusions of the exci pients of polymers and surfactants i n formulations have not s hown the effecti venes s to ca pture the enha nced s ol ubi l i ty a dva nta ge of the cocrys ta l s of i ndometha ci n -s a ccha ri n a nd ca rba mazepine-nicotinamide 15,18 .…”

Cocrystallization of Etodolac: Prediction of Cocrystallization, Synthesis, Solid State Characterization And In Vitro Drug Release

“…application of the fundamental concepts presented in this paper explains to examine the ability of hansen solubility parameter to predict the formation of cocrystals systems and pharmaceutical properties of cocrystals, in particular solubility, dissolution, and stability (3). Several research reports of cocrystals show their ability to improve physicochemical including solubility, dissolution, stability, tabletability and pharmacokinetic characteristics especially bioavailability of active pharmaceutical ingredients (4)(5)(6)(7)(8). Cocrystal synthesis can work as green technique becoming avenue for pharmaceutical industry (9).…”