Influence of Particle Size and Drug Load on Amorphous Solid Dispersions Containing pH-Dependent Soluble Polymers and the Weak Base Ketoconazole

Abstract

Among the great number of poorly soluble drugs in pharmaceutical development, most of them are weak bases. Typically, they readily dissolve in an acidic environment but are prone to precipitation at elevated pH. This was aimed to be counteracted by the preparation of amorphous solid dispersions (ASDs) using the pH-dependent soluble polymers methacrylic acid ethylacrylate copolymer (Eudragit L100–55) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) via hot-melt extrusion. The hot-melt extruded ASDs were of amorphous nature and single phased with the presence of specific interactions between drug and polymer as revealed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). The ASDs were milled and classified into six particle size fractions. We investigated the influence of particle size, drug load, and polymer type on the dissolution performance. The best dissolution performance was achieved for the ASD made from Eudragit L100–55 at a drug load of 10%, whereby the dissolution rate was inversely proportional to the particle size. Within a pH-shift dissolution experiment (from pH 1 to pH 6.8), amorphous-amorphous phase separation occurred as a result of exposure to acidic medium which caused markedly reduced dissolution rates at subsequent higher pH values. Phase separation could be prevented by using enteric capsules (Vcaps Enteric®), which provided optimal dissolution profiles for the Eudragit L100–55 ASD at a drug load of 10%.

Eudragit®: A Versatile Family of Polymers for Hot Melt Extrusion and 3D Printing Processes in Pharmaceutics

“…EL100-55 is a good candidate for this purpose due to its pH-dependent solubility (soluble at pH > 5.5). This approach was used by Monschke (2019Monschke ( , 2021 in two sequential studies, in which nevirapine and ketoconazole were used as models of weak bases. In both cases, EL100-55 was combined with a plasticizer to improve its extrudability and was able to form an ASD, increasing the aqueous solubility of both drugs and avoiding their release in the gastric medium [73,75].…”

Boost of solubility and supersaturation of celecoxib via synergistic interactions of methacrylic acid-ethyl acrylate copolymer (1:1) and hydroxypropyl cellulose in ternary amorphous solid dispersions

“…As EL 100–55 exhibits a high melt viscosity ( Monschke et al, 2021 ; Parikh et al, 2014 ), it is a challenging polymer for processing through HME. However, we confirmed our assumption of using HPC SSL as solid state plasticizer, as extrusion of the polymer extrudate P2, and of the ternary ASD F5 was conducted without using an additional plasticizer.…”

“…The aim of this study was to investigate ternary ASDs using HPC SSL, methacrylic acid-ethyl acrylate copolymer (1:1) (EL 100–55) as alternative pH-dependent soluble polymer, and celecoxib (CXB) as BCS class II model drug, (solubility at pH 6.8: 1.5 μg/ml ( Xie and Taylor, 2016 )) processed by vacuum compressing molding (VCM) and hot melt extrusion (HME). Since EL 100–55 exhibits high melt viscosity ( Parikh et al, 2014 ), it is a challenging polymer for processing via HME, thus the addition of a solid state plasticizer is required to reduce the torque during processing and to avoid a motor overload of the extruder ( Monschke et al, 2021 ). Zecevic et al detected the potential of HPC SSL serving as solid state plasticizer in HPMCAS ASDs due to its low molecular weight (40,000 g/mol) and low glass transition temperature (T g ) ( Zecevic et al, 2014 ).…”

Polyelectrolyte Matrices in the Modulation of Intermolecular Electrostatic Interactions for Amorphous Solid Dispersions: A Comprehensive Review

“…Except for the different Eudragit grades, anionic polymers HPMCAS, and HPMCP of various types have been reported as suitable matrices for stable ASDs produced by HME [ 76 , 79 , 101 ]. Their pH-dependent solubility has formed the basis of advanced ASD formulations in order to enhance the low bioavailability of mainly weakly ionic drugs due to the gastric pH variability [ 67 , 75 , 78 ]. This approach has been recently reported for amorphous extrudates of the weakly basic model drug nevirapine with the anionic pH-dependent soluble polymers HPMCAS, HPMCP (HP-55, HP-50), and Eudragit L 100-55, which were developed via a twin-screw extruder.…”

“…However, the dissolution rate at elevated pH values was noticeably decreased compared to the static dissolution experiment at pH 6.8. This was due to phase separation, which arose during the contact of ASDs with the acidic medium, an obstacle that was circumvented with the use of enteric capsules [ 78 ].…”