Solid State Solubility of Miconazole in Poly[(ethylene glycol)-g-vinyl alcohol] Using Hot-Melt Extrusion

Abstract

The use of hot-melt extrusion for preparing homogeneous API-excipient mixtures is studied for miconazole-PEG-g-PVA [poly(ethylene glycol)-poly(vinyl alcohol) graft copolymer] solid dispersions with a 5 cm(3) table-top, twin-screw corotating microcompounder (DSM Xplore). Phase behavior of PEG-g-PVA, miscibility of miconazole in PEG-g-PVA and the partitioning of miconazole between PEG and PVA amorphous phases are characterized using a combination of modulated DSC, XRPD, and solid-state (1)H and (13)C NMR methods. The (1)H NMR transverse magnetization relaxation (T(2) relaxation) method is used to analyze the phase composition and molecular mobility of the copolymer. The T(2) relaxation decay of pure PEG-g-PVA can be described by four T(2) relaxation components in the temperature range studied. PVA crystallinity is not largely affected by hot-melt extrusion and the presence of the drug. Miconazole preferably resides in the PEG amorphous phase, and its molecules are well dispersed in the PEG-g-PVA matrix using hot-melt extrusion mixing. Miconazole forms amorphous nanoclusters whose average size equals approximately 1.6 nm, indicating solid solution formation (molecular level dispersion) of the drug in the polymer.

Interactions between drugs and polymers influencing hot melt extrusion

“…However, the phase behaviour of solid dispersion can be extremely complicated. Drug and polymer may be miscible, partially miscible or immiscible …”

Water‐Induced Transitions from Ellipsoidal Micelles to Chain‐Like Nanostructures Self‐Assembled by the Coil‐Rod‐Coil Block Copolymer Based on Hydrogen‐Bonding Urea Groups

“…The obtained triblock copolymer was dried under vacuum at 80 °C for 12 h. The triblock polymer was characterized by 13 C‐NMR spectrum (Figure S1, Supporting Information), 1 H‐NMR spectrum (Figure S2, Supporting Information), FT‐IR spectrum (Figure S3, Supporting Information), and MALDI‐TOF MS spectra (Figure S4a,b, Supporting Information), respectively. 13 C‐NMR (500 MHz, solid): δ = 162.7 ppm (HN( C O)NH), 74 ppm (O C H 2 C H 2 O), 20–60 ppm (aliphatic carbons of IPDI and IPDA); 1 H‐NMR (500 MHz, solid): δ = 7.0–8.0 ppm (O(CO)N H CH), 5.0–6.0 ppm (N H (CO)N H ),2.0–5.0 ppm (OC H 2 C H 2 O,C H of the IPDI and IPDA); FT‐IR (KBr): ν = 1645 cm −1 (CO of the urea), 3370 cm −1 (NH of the urea), 1558 cm −1 (NH of amide II band), 1244 cm −1 (amide III band), 650 cm −1 (amide IV band), and 771 cm −1 (amide V band), 2954 cm −1 and 2918 cm −1 (CH 2 ‐, CH 3 ‐ of IPDI, IPDA, and MPEG).…”

Structural and Dynamic Properties of Amorphous Solid Dispersions: The Role of Solid-State Nuclear Magnetic Resonance Spectroscopy and Relaxometry

“…As it is practically challenging to prepare ASD with known phase dimension and calculate its D S , the value of D S is generally taken from literature: typical values are 0.5 × 10 −7 mm 2 /s for a mobile system and 8 × 10 −7 mm 2 /s for a rigid system . Alternatively, the measurement of transverse spin relaxation enables to estimate the value of D S as the ratio of the squared average of 1 H‐to‐ 1 H distance to 1 H T 2 or by using some empirical relation with 1 H T 2 . Obviously, in addition to D S , [ L ] depends on the values of 1 H T 1ρ and T 1 , in turn depending on the system investigated.…”

“…Static proton NMR spectra showed that crystallization led to the appearance of sharp spikes over the broad signal of the amorphous fraction. Moreover, Litvinov et al have demonstrated a promising application of variable temperature SS‐NMR relaxometry to access crystallinity in complex amorphous formulations prepared by HME that contains amorphous miconazole dispersed within a semicrystalline copolymer, poly[(ethyleneglycol)‐g‐poly(vinyl alcohol)] (PEG‐g‐PVA). Both PEG and PVA portions present as different mobile amorphous fractions with varying T 2 values and a rigid crystalline fraction with the slowest mobility.…”