Like Dissolves Like? A Comprehensive Evaluation of Partial Solubility Parameters to Predict Polymer–Drug Compatibility in Ultrahigh Drug-Loaded Polymer Micelles

Abstract

Despite decades of research, our understanding of the molecular interactions between drugs and polymers in drug loaded polymer micelles does not extend much beyond concepts such as "likedissolves-like" or hydrophilic/hydrophobic. However, polymer-drug compatibility strongly affects formulation properties and therefore the translation of a formulation into the clinics. Specific interactions such as hydrogen-bonding, π-π stacking or coordination interactions can be utilized to increase drug-loading. This is commonly based on trial-and-error and eventually leads to an optimized drug carrier. Unfortunately, due to the unique characteristics of each drug, the deduction of advanced general concepts remains challenging. Furthermore, the introduction of complex moieties or specifically modified polymers hampers systematic investigations regarding polymer drug-compatibility as well as clinical translation. In this study, we reduced the complexity in order to isolate crucial factors determining drug-loading. Therefore, the compatibility of 18 different amphiphilic polymers for 5 different hydrophobic drugs was determined empirically. Subsequently, the obtained specificities were compared to theoretical compatibilities derived from either the Flory-Huggins interaction parameter or Hansen solubility parameters. In general, Flory-Huggins interaction parameters were less suited to correctly estimate the experimental drug solubilization compared to the Hansen solubility parameters. The latter were able to correctly predict some trend regarding good and poor solubilizers, yet the overall predicitive strength of Hansen Solubility parameters is clearly unsatisfactory. Materials and Methods Reagents and Solvents All substances for the preparation of the polymers were purchased from Sigma-Aldrich (Steinheim, Germany) or Acros (Geel, Belgium) and were used as received unless otherwise stated. Soluplus® (polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol graft copolymer) and Resomer® (polyethyleneglycol-poly(L-lactide); 35 wt.% PEG) were a generous gift by BASF SE (Ludwigshafen, Germany) and Evonik Industries AG (Essen, Germany), respectively. Curcumin powder from Curcuma longa (turmeric) was purchased from Sigma-Aldrich and analyzed in-house (curcumin = 79%; demethoxycurcumin = 17%, bisdemethoxycurcumin = 4%; determined by HPLC analysis; Figure S22). Paclitaxel (> 99%, HPLC) was purchased from LC Laboratories (Woburn, MA, USA). Efavirenz (> 98%, HPLC) and dexamethasone (> 99%, HPLC) were purchased from TCI (Eschborn, Germany). Tanshinone IIA (> 98%, HPLC) was purchased from Shanghai Yuanye BioTechnology (Shanghai, China). Deuterated chloroform (CDCl 3) for NMR analysis was obtained from Deutero GmbH (Kastellaun, Germany). The monomers 2-iso-propyl-2-oxazoline (iPrOx), 2-iso-propyl-2-oxazine (iPrOzi), 2-n-propyl-2oxazoline (nPrOx), 2-n-propyl-2-oxazine (nPrOzi), 2-cyclo-2-propyl-2-oxazoline (cPrOx), 2-cyclo-2propyl-2-oxazine (cPrOzi), 2-(cyclo-propyl-methylene)-2-oxazoline (cPrMeOx), 2-(cyclo-propylmethylene)-2-oxazine (cPrM...

In Vitro Blood-Brain-Barrier Permeability and Cytotoxicity of Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

“…ATV solubilization As reported recently, poly(2-oxazoline) (POx) and poly(2-oxazine) (POzi) based ABA triblock copolymers, all comprising the same hydrophilic poly(2-methyl-2-oxazoline) (PMeOx) shell A and structurally very similar, hydrophobic cores B exhibit different loading capacities for various hydrophobic drugs [50,[53][54][55][56][57] as well as varying drug/polymer interactions in dependence of the drug-loading [58,59] . Whereas the triblock copolymer with a barely hydrophobic poly(2-n-butyl-2-oxazoline) (pBuOx, = A-pBuOx-A) core enabled moderately high loadings of 24 wt.% of the hydrophobic compound curcumin (CUR), its structural isomer with a poly(2-n-propyl-2-oxazine) (pPrOzi; = A-pPrOzi-A) core was able to yield exceptionally high loadings up to 54 wt.%.…”

14N–1H HMQC solid-state NMR as a powerful tool to study amorphous formulations – an exemplary study of paclitaxel loaded polymer micelles

“…18 Moreover, additional difficulties arise from overlap between PTX and POL resonances as can be seen from comparison with the 13 C CP MAS spectrum of the neat polymer (red spectrum). Note, that for better comparability, the neat polymer was heated above its glass transition temperature Tg (Tg(POL)=56°C) 37 prior to the measurement to account for similar conditions during the preparation of the formulations. Consequently, the analysis of the carbon spectra and extraction of reliable structural information is difficult and requires complementary tools such as quantum chemical calculations, which will be explored in detail in a separate work.…”

Predicting the Loading Capability of mPEG‐PDLLA to Hydrophobic Drugs Using Solubility Parameters†

“…The Flory–Huggins interaction parameter ( χ ) was often used to predict the compatibility of polymers and small molecules . The Flory–Huggins χ DP of drug and mPEG 5k ‐PDLLA 5k was given by Hansen (Equation 8): …”