Polymer structure and property effects on solid dispersions with haloperidol: Poly(N-vinyl pyrrolidone) and poly(2-oxazolines) studies

Abstract

Poly(2-methyl-2-oxazoline) (PMOZ), poly(2-propyl-2-oxazoline) (PnPOZ) and poly(2-isopropyl-2-oxazoline) (PiPOZ) were synthesized by hydrolysis of 50 kDa poly(2-ethyl-2-oxazoline) (PEOZ) and subsequent reaction of the resulting poly(ethylene imine) with acetic, butyric and isobutyric anhydrides, respectively. These polymers were characterized by proton nuclear magnetic resonance, FTIR spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The poly(2-oxazolines) as well as poly(N-vinyl pyrrolidone) (PVP) were used to prepare solid dispersions with haloperidol, a model poorly soluble drug. Dispersions were investigated by powder X-ray diffractometry, differential scanning calorimetry and FTIR spectroscopy. Increasing the number of hydrophobic groups (-CH 2 -and -CH 3 ) in the polymer resulted in greater inhibition of crystallinity of haloperidol in the order: PVP > PnPOZ=PEOZ > PMOZ. Interestingly, drug crystallization inhibition by PiPOZ was lower than with its isomeric PnPOZ because of the semi-crystalline nature of the former polymer. Crystallization inhibition was consistent with drug dissolution studies using these solid dispersions, with exception of PnPOZ, which exhibited lower critical solution temperature that affected the release of haloperidol.

Mutual Effects of Hydrogen Bonding and Polymer Hydrophobicity on Ibuprofen Crystal Inhibition in Solid Dispersions with Poly(N-vinyl pyrrolidone) and Poly(2-oxazolines)

“…Its solubility parameter difference to ibuprofen (Δδ) was 7.6 MPa 1/2 , and thus beyond the notional value of 7 for miscibility but close to the borderline value 6.9 MPa 1/2 calculated for PVP, which has the greatest tendency to disorder the drug. An alternative explanation is that the hydrophobic–hydrophilic balance (HHB) value for PMOZ (3.95) demonstrates that it is highly hydrophilic, and so the hydrophobic IB molecules will be less likely to molecularly disperse into the hydrophilic domains of PMOZ, consistent with our earlier findings on the non-hydrogen bonding dispersions with haloperidol where, again, PMOZ showed reduced interactions compared with the more hydrophobic carriers [ 29 ]. The importance of polymer hydrophobicity for crystal growth inhibitors has previously been reported [ 16 ].…”

“…For various groups, the values of F di , F pi , E hi , and V (molar volume) are given in the literature [ 43 , 45 ]. The solubility parameters of these five polymers were taken from our previous study [ 29 ] and the solubility parameters calculated for IB and PVP are in good agreement with the literature [ 46 ].…”

“…This peak apparently moves towards ~1629 cm −1 as the polymer content increases, but in fact is due to the increased contribution of the “excess” (or “free”) PMOZ carbonyl peak intensity, which overlaps and obscured the carbonyl group of PMOZ that interacts with IB. The weaker interaction of PMOZ with IB compared with that in other polyoxazoline dispersions can be attributed to PMOZ’s relatively high hydrophilicity, which inhibits its ability to disorder the hydrophobic drug molecules [ 29 ].…”

“…Poly(2-ethyl-2-oxazoline) (PEOZ), 50 kDa (polydispersity index, PDI 3-4); poly( N -vinyl pyrrolidone) (PVP), 55 kDa (K-value 30); and buffer tablets, pH 6.8 were from Sigma-Aldrich (Gillingham, UK). Poly(2-methyl-2-oxazoline) (PMOZ), poly(2-n-propyl-2-oxazoline) (PnPOZ), and poly(2-isopropyl-2-oxazoline) (PiPOZ) were synthesized according to our previously reported procedure [ 29 ]. Ibuprofen (IB) was from Tokyo Chemistry Industry (Japan).…”

“…In our previous work [ 29 ], PVP and a series of water-soluble poly(2-oxazolines) including PMOZ, PEOZ, PnPOZ, and PiPOZ were used to prepare solid dispersions with haloperidol. The effects of polymer hydrophobicity and their semi-crystalline nature on drug crystallinity were demonstrated.…”