Holistic QbD approach for hot-melt extrusion process design space evaluation: Linking materials science, experimentation and process modeling.

The aim of this work was to investigate the relationship between formulation material properties, process parameters and process performance for the manufacturing of amorphous solid dispersions via hot-melt extrusion (HME) using experimentation coupled with process modeling. Specifically, we evaluated the impact of the matrix copovidone melt rheology with and without the addition of a plasticizing surfactant, polysorbate 80, while also varying the process parameters, barrel temperature and screw speed, and keeping fill volume constant. To correlate the process performance to a critical quality attribute, we used telmisartan as an indicator substance by processing at temperatures below its solubility temperature in the polymeric matrix.

Micro-scale solubility assessments and prediction models for active pharmaceutical ingredients in polymeric matrices.

The number of models for assessing the solubility of active pharmaceutical ingredients (APIs) in polymeric matrices on the one hand and the extent of available associated data on the other hand has been rising steadily in the past few years. However, according to our knowledge an overview on the methods used for prediction and the respective experimental data is missing. Therefore, we compiled experimental data, the techniques used for their determination and the models used for estimating the solubility.

Validation of Model-Based Melt Viscosity in Hot-Melt Extrusion Numerical Simulation.

A validation for the use of model-based melt viscosity in hot-melt extrusion numerical simulations was presented. Here, the melt viscosity of an amorphous solid dispersion (ASD) was calculated by using its glass transition temperature () and the rheological flow profile of the pure polymeric matrix. All further required physical properties were taken from the pure polymer.

Numerical simulation of hot-melt extrusion processes for amorphous solid dispersions using model-based melt viscosity.

Simulation of HME processes is a valuable tool for increased process understanding and ease of scale-up. However, the experimental determination of all required input parameters is tedious, namely the melt rheology of the amorphous solid dispersion (ASD) in question. Hence, a procedure to simplify the application of hot-melt extrusion (HME) simulation for forming amorphous solid dispersions (ASD) is presented.

Predicting melt rheology for hot-melt extrusion by means of a simple T-measurement.

The feasibility of predicting melt rheology by using the glass transition temperature (T) of a desired amorphous solid dispersion (ASD) for hot-melt extrusion (HME) and other melt based processes is presented. Three groups of three different active pharmaceutical ingredients (APIs) or plasticizer/copovidone mixtures, with identical glass transition in rheological testing, were used. Their rheological behavior as a function of temperature and frequency were analyzed by means of small amplitude oscillatory shear (SAOS) on an oscillatory rheometer.

Micro-scale prediction method for API-solubility in polymeric matrices and process model for forming amorphous solid dispersion by hot-melt extrusion.

A new predictive micro-scale solubility and process model for amorphous solid dispersions (ASDs) by hot-melt extrusion (HME) is presented. It is based on DSC measurements consisting of an annealing step and a subsequent analysis of the glass transition temperature (Tg). The application of a complex mathematical model (BCKV-equation) to describe the dependency of Tg on the active pharmaceutical ingredient (API)/polymer ratio, enables the prediction of API solubility at ambient conditions (25°C).

Hot melt extrusion as an approach to improve solubility, permeability and oral absorption of a psychoactive natural product, piperine.

Objective: The aims of the current research project were to investigate the efficiency of various polymers to enhance the solubility and increase the systemic absorption of piperine using hot melt extrusion technology.

Methods: Piperine 10-40% w/w and Eudragit(®) EPO/Kollidon(®) VA 64 or Soluplus(®) were mixed, and the resulting blends were extruded using a twin-screw extruder (Process 11, Thermo Fisher Scientific). Drug release profiles and piperine solubility studies of the extrudates were evaluated.

Optimization of hot melt extrusion parameters for sphericity and hardness of polymeric face-cut pellets.

The aim of this study was to formulate face-cut, melt-extruded pellets, and to optimize hot melt process parameters to obtain maximized sphericity and hardness by utilizing Soluplus(®) as a polymeric carrier and carbamazepine (CBZ) as a model drug. Thermal gravimetric analysis (TGA) was used to detect thermal stability of CBZ. The Box-Behnken design for response surface methodology was developed using three factors, processing temperature ( °C), feeding rate (%), and screw speed (rpm), which resulted in 17 experimental runs.

Influence of Molecular Weight of Carriers and Processing Parameters on the Extrudability, Drug Release, and Stability of Fenofibrate Formulations Processed by Hot-Melt Extrusion.

The objective of this study was to investigate the extrudability, drug release, and stability of fenofibrate (FF) formulations utilizing various hot-melt extrusion processing parameters and polyvinylpyrrolidone (PVP) polymers of various molecular weights. The different PVP grades selected for this study were Kollidon 12 PF (K12), Kollidon 30 (K30), and Kollidon 90 F (K90). FF was extruded with these polymers at three drug loadings (15%, 25%, and 35% w/w).

Solid-state characterization of Felodipine-Soluplus amorphous solid dispersions.

The aim of the current study is to develop amorphous solid dispersion (SD) via hot melt extrusion technology to improve the solubility of a water-insoluble compound, felodipine (FEL). The solubility was dramatically increased by preparation of amorphous SDs via hot-melt extrusion with an amphiphilic polymer, Soluplus® (SOL). FEL was found to be miscible with SOL by calculating the solubility parameters.

Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions.

Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary.

Stability-enhanced hot-melt extruded amorphous solid dispersions via combinations of Soluplus® and HPMCAS-HF.

The aim of this study was to evaluate a novel combination of Soluplus® and hypromellose acetate succinate (HPMCAS-HF) polymers for solubility enhancement as well as enhanced physicochemical stability of the produced amorphous solid dispersions. This was accomplished by converting the poorly water-soluble crystalline form of carbamazepine into a more soluble amorphous form within the polymeric blends. Carbamazepine (CBZ), a Biopharmaceutics Classification System class II active pharmaceutical ingredient (API) with multiple polymorphs, was utilized as a model drug.

Investigation of phase diagrams and physical stability of drug-polymer solid dispersions.

Solid dispersion technology has been widely explored to improve the solubility and bioavailability of poorly water-soluble compounds. One of the critical drawbacks associated with this technology is the lack of physical stability, i.e.

Compositional analysis of low quantities of phase separation in hot-melt-extruded solid dispersions: a combined atomic force microscopy, photothermal fourier-transform infrared microspectroscopy, and localised thermal analysis approach.

Purpose: To characterise phase separations in aged hot-melt-extruded solid dispersions at a micron to submicron scale.

Methods: Hot-melt-extruded felodipine and Eudragit® E PO systems at a range of compositions were studied after a standard period of aging to allow phase separation to occur. The samples were characterised using combined nano-thermal analysis, photothermal FTIR microspectroscopy coupled with pulsed force mode AFM as a novel characterisation approach.

Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion.

In the current study Ibuprofen was embedded in a methacrylate copolymer (Eudragit® EPO) matrix to produce solid dispersions by hot-melt extrusion (HME) processing. The obtained granules were incorporated in orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and crosslinked polyvinylpyrrolidone grades while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness.

Development and evaluation of cetirizine HCl taste-masked oral disintegrating tablets.

The purpose of the current study was to mask the taste of cetirizine HCl and to incorporate the granules produced in oral disintegrating tablets (ODT). The bitter, active substance was coated by fluidized bed coating using Eudragit® RL30-D at levels between 15% and 40% w/w. The ODTs were developed by varying the ratio of superdisintegrants such as sodium croscarmellose, crospovidone grades and low substituted hydroxypropyl cellulose (L-HPC).

Characterisation of solid dispersions of paracetamol and EUDRAGIT E prepared by hot-melt extrusion using thermal, microthermal and spectroscopic analysis.

Hot-melt extrusion has attracted considerable interest within the pharmaceutical industry. However, there remains some uncertainty as to how to characterise the physical structure of the extruded systems, particularly in terms of identifying the nature of the drug dispersion within the polymer. The aim of the study was to develop a combined thermal, imaging and spectroscopic approach for the identification and characterisation of the drug and polymer structure.