ABSTRACT
In this work, etonogestrel implants were manufactured using coextrusion. The purpose of the study was to correlate changes in microstructure and transport properties that occurred in etonogestrel implants to drug release mechanisms. The implants consisted of an EVA 28 (28% vinyl acetate) core containing dispersed and dissolved etonogestrel, and an EVA 15 (15% vinyl acetate) skin. The drug release was determined to be via diffusion at a controlled rate and governed by implant dimensions. In-vitro release revealed evidence of supersaturation in the implant core and skin, likely from the intense mechanical energy input during the twin-screw manufacturing process. Subsequently during storage under ambient conditions, supersaturation resulted in recrystallization of drug crystals, preferentially in the implant core. Etonogestrel solubility and diffusivity in EVA were determined by permeation experiments and used for release modeling. Drug release from the EVA skin layer deviated from the predicted values due to 1) formation of a drug depletion zone in the core and 2) presence of a stagnant media layer adjacent to the skin. Drug release from implant ends was significantly faster than predicted. Air-filled pores were observed in the implant core using microCT which likely contributed to the faster release from implant ends.
ABSTRACT
This study investigates the effects of supercritical CO2 as a foaming agent on structure and physical properties of hot melt extruded hydroxypropyl methylcellulose acetate succinate (HPMCAS)-itraconazole (ITZ) amorphous solid dispersions (ASDs) with the aim of improving the milling efficiency and tabletability of these ASDs. Two different grades of AFFINISOLTM HPMCAS, the standard grade (Std) and the High Productivity grade (HP) were used. The HP-grade has a lower molecular weight, melt viscosity and wider processing temperature range. Extrudates with different ITZ concentrations (0%, 20% and 40%) and CO2 injection pressure of 100 and 200 bar were prepared. The cellular microstructure of the foams showed that HP-grade HPMCAS had better affinity with the CO2 resulting in better distribution of CO2. The results of DSC and X-ray diffraction analysis revealed that the supercritical CO2 did not affect the amorphous state of the API in the extrudates. Milling efficiency of the ASDs was significantly improved up to around 90% increase in the mass recovery. The tabletability of the milled extrudates showed a considerable increase in tablet tensile strength. In addition, foaming considerably improved the supersaturation of HP-grade ASD while showing minimal improvement in dissolution behavior of the Std-grade material.
Subject(s)
Carbon Dioxide , Itraconazole , Cellulose/analogs & derivatives , Drug Compounding , Methylcellulose/analogs & derivatives , Solubility , SuccinatesABSTRACT
The effect of thermal binders on the physicochemical properties of gabapentin, a thermally labile drug, in granules prepared using twin-screw melt granulation was investigated in this study. Hydroxypropyl cellulose (HPC), a thermoplastic high molecular-weight binder, was compared against conventional low molecular-weight semi-crystalline thermal binders PEG 8000 and Compritol. Both the chemical degradation and polymorph form change of gabapentin were analyzed. The effects of particle size and molecular weight of HPC on the properties of granules were also studied. To overcome the high melt viscosity of HPC, higher barrel temperatures and higher specific mechanical energy were required to attain suitable granules. As a result, higher levels of gabapentin degradant were observed in HPC-based formulations. However, gabapentin form change was not observed in all formulations. Smaller particle size and lower molecular weight of HPC led to faster granule growth. The tabletability of granules was insensitive to the variations in particle size and molecular weight of HPC. Gabapentin crystal size reduction, HPC size reduction, and HPC enrichment on granule surface were observed for HPC-based granules.
Subject(s)
Gabapentin/chemistry , Tablets/chemistry , Bone Screws , Cellulose/analogs & derivatives , Cellulose/chemistry , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Excipients/chemistry , Molecular Weight , Particle Size , Powders/chemistry , Technology, Pharmaceutical/methods , Tensile Strength/drug effects , Viscosity/drug effectsABSTRACT
Poorly water-soluble drug substances that exhibit high melting points are difficult to process by melt extrusion due to chemical instability at high temperatures required for processing. The purpose of this study was to extrude meloxicam (melting point 255°C) by optimizing processing parameters and formulation composition. Five extrusion studies were performed: 1) design space, 2) impact of moisture, 3) impact of melt residence time, 4) specific energy optimization, and 5) altered microenvironment pH. Powder X-ray diffraction and polarized light microscopy were used to confirm amorphous conversion. Liquid chromatography-mass spectrometry was used to characterize the extrusion degradation pathway. The formulation consisted of 10% meloxicam and 90% copovidone. When processed above 140°C, significant chemical degradation was observed. The minimum energy input to convert meloxicam was 1.8kWh/kg. Degradation of meloxicam during extrusion was identified as hydrolysis. Barrel configuration and screw design were designed to drive-off moisture and reduce melt residence time. With optimized parameters, the purity of the extrudate was 96.7%. To further enhance chemical stability, meglumine was added to provide a stabilizing basic microenvironment resulting in 100% purity. By process parameter optimization and formulation modification, we successfully extruded a meloxicam amorphous solid dispersion.
Subject(s)
Chemistry, Pharmaceutical , Drug Stability , Hot Temperature , Solubility , X-Ray DiffractionABSTRACT
Our hypothesis is that melt extrusion is a more suitable processing method than spray drying to prepare amorphous solid dispersions of drugs with a high crystallization tendency. Naproxen-povidone K25 was used as the model system in this study. Naproxen-povidone K25 solid dispersions at 30% and 60% drug loadings were characterized by modulated DSC, powder X-ray diffraction, FT-IR, and solid-state 13C NMR to identify phase separation and drug recrystallization during processing and storage. At 30% drug loading, hydrogen bond (H-bond) sites of povidone K25 were not saturated and the glass transition (Tg) temperature of the formulation was higher. As a result, both melt-extruded and spray-dried materials were amorphous initially and remained so after storage at 40°C. At 60% drug loading, H-bond sites were saturated, and Tg was low. We were not able to prepare amorphous materials. The initial crystallinity of the formulations was 0.4%±0.2% and 5.6%±0.6%, and increased to 2.7%±0.3% and 21.6%±1.0% for melt-extruded and spray-dried materials, respectively. Spray-dried material was more susceptible to re-crystallization during processing, due to the high diffusivity of naproxen molecules in the formulation matrix and lack of kinetic stabilization from polymer solution. A larger number of crystalline nucleation sites and high surface area made the spray-dried material more susceptible to recrystallization during storage. This study demonstrated the unique advantages of melt extrusion over spray drying for the preparation of amorphous solid dispersions of naproxen at high drug level.