Development of Poly(2-oxazoline)s and poly(2-oxazine)s based formulation library and estimation of polymer/drug compatibility.

Abstract

The main objective of this study is to formulate a library of difficult to solubilize drugs with four slightly different poly(2-oxazoline)s (POx) and poly(2-oxazine)s (POzi) based amphiphilic triblock copolymers and to elucidate whether the drug-polymer compatibility, as estimated by solubility parameters (SPs) might be used as tool to guide formulation development. The theoretical and experimental SPs of different homo-/triblock copolymers and 21 different hydrophobic drugs were calculated by two group contribution methods (i.e. Hoftyzer Van-Krevelen and Yamamoto molecular break method) and determined experimentally by solubility testing in list of selective solvents (for polymers only). The obtained SPs were further utilized to calculate the distance between polymers and drugs (Ra) in 3 dimensional Hansen space. Out of 21 structurally diverse drugs, the loading capacity (LC) was found to be higher than 40, 30, 20 and 10 wt.% for 4, 4, 3 and 5 drugs, respectively. In the remaining of 5 drugs the maximum achievable LC was found below 10 wt.%. The experimental results obtained by formulation development were not in accordance with the results predicted by Ra calculation. In contrast to several reports found in the literature, the determination of SPs and concurrent compatibility estimation appeared not to be a suitable tool to predict polymer-drug compatibility in the present system. As the predictive power of SPs is based on simple mathematical calculations, limiting the precise prediction of overall polarity, hydrogen bonding ability of molecules and interplay between the hydrophilic and hydrophobic domains resulting in differing deviations than predicted interactions thus might compromise the predictive power of HSPs.

Unravel the Tangle: Atomistic Insight into Ultrahigh Curcumin‐Loaded Polymer Micelles

“…Micelle LC has been investigated experimentally in great detail for a variety of drugs and pOx/pOzi variants, and a strong dependence on the B block monomer type has been found. [3,12] For example, poly(2-methyl-2-oxazoline) 35 -b-poly(2-propyl-2oxazine) 20 -b-poly(2-methyl-2-oxazoline) 35 -N-Boc-piperazine (A-pPrOzi-A) has been shown to provide drastically superior drug loading for curcumin (CUR), with a LC of 11.9 g L −1 given a polymer feed of 10 g L −1 , in comparison to poly(2-methyl-2-oxazoline) 35 -b-poly(2-butyl-2-oxazoline) 20 -b-poly(2-methyl-2oxazoline) 35 -piperidine (A-pBuOx-A) comprising a constitutional isomer as B block repeat units (LC: 3.2 g L −1 ). [10] The underlying reason for this difference remained unknown until now.…”

POxload: Machine Learning Estimates Drug Loadings of Polymeric Micelles

“…51 Assessing polymer-drug compatibility through solubility parameters obtained by group contribution methods has repeatedly provided only very limited predictability. 49,50 Furthermore, for the case of coformulations containing multiple drugs, synergistic and antagonistic effects have been reported. 52 While dissecting the driving polymer−drug interactions for explaining mechanistically the observed differences in LC and LE remains subject to future studies, a recent chemoinformaticsdriven study by Alves et al 35 demonstrated the potential of applying QSPR modeling techniques to predict micelle drug loading.…”

Highly Porous and Drug-Loaded Amorphous Solid Dispersion Microfiber Scaffolds of Indomethacin Prepared by Melt Electrowriting

“…13 The selection of an excipient is not only based on the processability using a given method and the possibility of designing a controlled release from the amorphous formulation, but also the miscibility and possible interactions between the drug and polymer play an important role. 14 Previously, poly(2-oxazoline)/poly(2-oxazine) triblock copolymers have been employed very successfully in high drug loading formulations 15,16 with up to and more than 50 wt% of the drug for a variety of drugs. 17−19 In addition, diblock, random, and gradient copolymers from poly(2-oxazoline)s/ poly(2-oxazine)s have been investigated as potential excipients 20−22 and some systems also allowed high drug loadings.…”

“…Previously, poly­(2-oxazoline)/poly­(2-oxazine) triblock copolymers have been employed very successfully in high drug loading formulations , with up to and more than 50 wt% of the drug for a variety of drugs. − In addition, diblock, random, and gradient copolymers from poly­(2-oxazoline)­s/poly­(2-oxazine)­s have been investigated as potential excipients − and some systems also allowed high drug loadings. − …”