Pharmaceutical Hot Melt Research Articles

Progress on the process analysis technology for the pharmaceutical hot melt extrusion

Progress on the process analysis technology for the pharmaceutical hot melt extrusion

System-agnostic prediction of pharmaceutical excipient miscibility via computing-as-a-service and experimental validation

We applied computing-as-a-service to the unattended system-agnostic miscibility prediction of the pharmaceutical surfactants, Vitamin E TPGS and Tween 80, with Copovidone VA64 polymer at temperature relevant for the pharmaceutical hot melt extrusion process. The computations were performed in lieu of running exhaustive hot melt extrusion experiments to identify surfactant-polymer miscibility limits. The computing scheme involved a massively parallelized architecture for molecular dynamics and free energy perturbation from which binodal, spinodal, and mechanical mixture critical points were detected on molar Gibbs free energy profiles at 180 °C. We established tight agreement between the computed stability (miscibility) limits of 9.0 and 10.0 wt% vs. the experimental 7 and 9 wt% for the Vitamin E TPGS and Tween 80 systems, respectively, and identified different destabilizing mechanisms applicable to each system. This paradigm supports that computational stability prediction may serve as a physically meaningful, resource-efficient, and operationally sensible digital twin to experimental screening tests of pharmaceutical systems. This approach is also relevant to amorphous solid dispersion drug delivery systems, as it can identify critical stability points of active pharmaceutical ingredient/excipient mixtures.

Predicting Residence Time and Melt Temperature in Pharmaceutical Hot Melt Extrusion.

Hot-melt extrusion is increasingly applied in the pharmaceutical area as a continuous processing technology, used to design custom products by co-processing drugs together with functional excipients. In this context, the residence time and processing temperature during extrusion are critical process parameters for ensuring the highest product qualities, particularly of thermosensitive materials. Within this study, a novel strategy is proposed to predict the residence time distribution and melt temperature during pharmaceutical hot-melt extrusion processes based on experimental data. To do this, an autogenic extrusion mode without external heating and cooling was applied to process three polymers (Plasdone S-630, Soluplus and Eudragit EPO) at different specific feed loads, which were set by the screw speed and the throughput. The residence time distributions were modeled based on a two-compartment approach that couples the behavior of a pipe and a stirred tank. The throughput showed a substantial effect on the residence time, whereas the influence of the screw speed was minor. On the other hand, the melt temperatures during extrusion were mainly affected by the screw speed compared to the influence of the throughput. Finally, the compilation of model parameters for the residence time and the melt temperature within design spaces serve as the basis for an optimized prediction of pharmaceutical hot-melt extrusion processes.

Pharmaceutical hot melt extrusion process development using QbD and digital twins

Pharmaceutical product development guided by Quality by Design (QbD) is based on a complete understanding of the critical process parameters (CPPs) that are important for achieving the desired product critical quality attributes (CQAs). The effect of process settings, such as the screw speed, the throughput, the barrel temperature, and the screw configuration, is a well-known factor in the setup of pharmaceutical hot melt extrusion (HME) processes. A CPP that has not yet been extensively researched is the type of cross-section geometry of the screw elements. Typically, pharmaceutical extruders have double-flighted screw cross-sections, with some elements having a single- or triple-flighted element section. The exception is a NANO16 extruder from Leistritz, with all screw elements having a triple-flighted screw geometry. We investigated the process setup and scale-up to a double-flighted extruder experimentally and in silico via a digital twin. Two formulations were processed on a NANO16 extruder and virtually transferred to a ZSE18 double-flighted co-rotating twin-screw extruder. Detailed smoothed particle hydrodynamics simulations of all screw elements available from both extruders were performed, and their efficiency in conveying, pressure build-up, and power consumption were studied. Reduced-order 1D HME simulations, which were carried out to investigate the process space and scalability of both extruders, were experimentally validated.

Predicting Throughput and Melt Temperature in Pharmaceutical Hot Melt Extrusion.

Even though hot melt extrusion (HME) is a commonly applied process in the pharmaceutical area, determination of the optimal process parameters is demanding. The goal of this study was to find a rational approach for predetermining suitable extrusion parameters, with a focus on material temperature and throughput. A two-step optimization procedure, called scale-independent optimization strategy (SIOS), was applied and developed further, including the use of an autogenic extrusion mode. Three different polymers (Plasdone S-630, Soluplus, and Eudragit EPO) were considered, and different optimal process parameters were assessed. The maximum barrel load was dependent on the polymers’ bulk density and the extruder size. The melt temperature was influenced by the screw speed and the rheological behavior of the polymer. The melt viscosity depended mainly on the screw speed and was self-adjusted in the autogenic extrusion. A new approach, called SIOS 2.0, was suggested for calculating the extrusion process parameters (screw speed, melt temperature and throughput) based on the material data and a few extrusion experiments.

Improving Pellet Quality in a Pharmaceutical Hot Melt Extrusion Process via PID Control and LOLIMOT-Based MPC

PurposeThe aim of this paper is the development of a process control concept for a hot melt extrusion (HME) and pelletization process. The new concept should improve the particle size distribution of the pellets produced.MethodsProduction of pellets containing an active pharmaceutical ingredient (API) can be achieved by means of HME, followed by a pelletization process step. The quality of pellets produced depends on the strand temperature at the pelletizer’s inlet and the pelletizer’s intake speed. This paper presents a strategy for the strand diameter and temperature control based on adjusting the cooling intensity on the cooling track between the HME and the pelletization step and altering the pelletizer’s intake speed. Two concepts are presented and compared to the open-loop operation of the system: the first one is model predictive control (MPC) in combination with a model based on the local linear model tree (LOLIMOT) algorithm, and the second one is PID control. The quality of the pellets produced was analyzed in terms of particle size distribution (PSD).ResultsBy implementation of the two control concepts, strand temperature and diameter could be kept close to the desired set points. Consequently, the presented concepts yielded pellets with a narrower particle size distribution than the open-loop operation of the plant.ConclusionsThe application of the presented control strategies can improve the quality of the pellets produced by an HME and pelletization system in terms of their particle size distribution.

Characterization of the Solid Physical State of API and Its Distribution in Pharmaceutical Hot Melt Extrudates Using Terahertz Raman Imaging.

In this study, a method employing THz Raman imaging to characterize the solid state of acetaminophen within a solid dispersion prepared by hot melt extrusion was reported. The peak at 89cm-1 originating from the crystalline lattice vibrations provides unambiguous discrimination between crystalline and amorphous N-acetyl-para-aminophenol (APAP; acetaminophen) contents in the hot melt extrusion (HME) extrudates. Extrudates from four different HME processes (two different temperatures and two levels of screw speeds) were analyzed and compared. The results show that both high process temperature and high screw speed favor the formation of amorphous APAP solid dispersions. Finally, the high spatial resolution (~ 1μm) Raman images of the extrudates prepared at 170°C and 200rpm show a near-complete amorphous APAP dispersion in an HPMC matrix, confirming an efficient HME process. The study demonstrates that THz Raman imaging is ideally suited for the identification of different solid physical states of the APIs in a polymer matrix, and provides direct visualization of their distribution in HME extrudates.

Modified Polymer Matrix in Pharmaceutical Hot Melt Extrusion by Molecular Interactions with a Carboxylic Coformer.

Hot melt extrusion (HME) has become an essential technology to cope with an increasing number of poorly soluble drug candidates. However, there is only a limited choice of pharmaceutical polymers for obtaining suitable amorphous solid dispersions (ASD). Considerations of miscibility, stability, and biopharmaceutical performance narrow the selection of excipients, and further technical constraints arise from needed pharmaceutical processing. The present work introduces the concept of molecularly targeted interactions of a coformer with a polymer to design a new matrix for HME. Model systems of dimethylaminoethyl methacrylate copolymer, Eudragit E (EE), and bicarboxylic acids were studied, and pronounced molecular interactions were demonstrated by 1H, 13C NMR, FTIR spectroscopy, as well as by different techniques of microscopic imaging. A difference was shown between new formulations exploiting specifically the targeted molecular interactions and a common drug-polymer formulation. More specifically, a modified matrix with malic acid exhibited a technical extrusion advantage over polymer alone, and there was a benefit of improved physical stability revealed for the drug fenofibrate. This model compound displayed greatly enhanced dissolution kinetics from the ASD formulations. It can be concluded that harnessing molecularly designed polymer modifications by coformers has much potential in solid dispersion technology and in particular regarding HME processing.

Rheological Characterization of Molten Polymer-Drug Dispersions as a Predictive Tool for Pharmaceutical Hot-Melt Extrusion Processability.

The aim of this study was to investigate (i) the influence of drug solid-state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests. Poly (ethylene oxide) (PEO) (100.000g/mol) and physical mixtures (PM) containing 10-20-30-40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized. Rheological tests were performed (frequency and temperature sweeps in oscillatory shear as well as shear-induced crystallization experiments) to obtain a thorough understanding of the flow behaviour and crystallization of PEO-drug dispersions. Theophylline did not dissolve in PEO as the complex viscosity (η*) of the drug-polymer mixture increased as compared to that of neat PEO. In contrast, ketoprofen dissolved in PEO and acted as a plasticizer, decreasing η*. Acting as a nucleating agent, theophylline induced the crystallization of PEO upon cooling from the melt. On the other hand, ketoprofen inhibited crystallization upon cooling. Moreover, higher concentrations of ketoprofen in the drug-polymer mixture increasingly inhibited polymer crystallization. However, shear-induced crystallization was observed for all tested mixtures containing ketoprofen. The obtained rheological results are relevant for understanding and predicting HME processability (e.g., barrel temperature selection) and downstream processing such as injection moulding (e.g., mold temperature selection).

Mechanistic modeling of modular co-rotating twin-screw extruders

In this study, we present a one-dimensional (1D) model of the metering zone of a modular, co-rotating twin-screw extruder for pharmaceutical hot melt extrusion (HME). The model accounts for filling ratio, pressure, melt temperature in screw channels and gaps, driving power, torque and the residence time distribution (RTD). It requires two empirical parameters for each screw element to be determined experimentally or numerically using computational fluid dynamics (CFD). The required Nusselt correlation for the heat transfer to the barrel was determined from experimental data. We present results for a fluid with a constant viscosity in comparison to literature data obtained from CFD simulations. Moreover, we show how to incorporate the rheology of a typical, non-Newtonian polymer melt, and present results in comparison to measurements. For both cases, we achieved excellent agreement. Furthermore, we present results for the RTD, based on experimental data from the literature, and found good agreement with simulations, in which the entire HME process was approximated with the metering model, assuming a constant viscosity for the polymer melt.

Monitoring the Output of Pharmaceutical Hot Melt Extruders with near Infrared Spectroscopy

Monitoring the Output of Pharmaceutical Hot Melt Extruders with near Infrared Spectroscopy

Inline monitoring and a PAT strategy for pharmaceutical hot melt extrusion

Implementation of continuous manufacturing in the pharmaceutical industry requires tight process control. This study focuses on a PAT strategy for hot melt extrusion of vegetable calcium stearate (CaSt) as matrix carrier and paracetamol as active pharmaceutical ingredient (API). The extrusion was monitored using in-line near-infrared (NIR) spectroscopy. A NIR probe was located in the section between the extrusion screws and the die, using a novel design of the die channel. A chemometric model was developed based on premixes at defined concentrations and was implemented in SIPAT for real time API concentration monitoring. Subsequently, step experiments were performed for different API concentrations, screw speeds and screw designs. The predicted API concentration was in good agreement with the pre-set concentrations. The transition from one API plateau to another was a smooth curve due to the mixing behaviour of the extruder. The accuracy of the model was confirmed via offline HPLC analysis. The screw design was determined as the main influential factor on content uniformity (CU). Additionally the influence of multiple feeders had a significant impact on CU. The results demonstrate that in-line NIR measurements is a powerful tool for process development (e.g., mixing characterization), monitoring and further control strategies.

Experimental characterization and modeling of twin‐screw extruder elements for pharmaceutical hot melt extrusion

In this study we characterized various screw elements of a co‐rotating twin‐screw extruder used for pharmaceutical hot melt extrusion (HME) and measured the pressure characteristic, i.e., the correlation between the axial pressure gradient and the material throughput in a completely filled screw section at different screw speeds. A typical HME matrix material, Soluplus, was used for the experiments and its required rheological properties were determined. A three‐parameter model based on a dimensionless formulation of the measured quantities was used. These parameters could not be determined uniquely by fitting to experimental data. Therefore we developed an approach to approximate one empirical parameter based on the mechanistic consideration of a pressure‐driven channel flow. The model was extended to account for the variable melt temperature. The results confirmed the expected tendencies and established an essential input parameter set for one‐dimensional simulations of co‐rotating twin‐screw extruders. © 2013 American Institute of Chemical Engineers AIChE J, 59: 4440–4450, 2013