Impact of surfactant raw material variability on extrudate clarity appearance (transparency) in HME continuous manufacturing.

The appearance of an extrudate formulation was monitored during hot-melt extrusion (HME) continuous manufacturing over three days. The formulation matrix consisted of a polymeric component, copovidone, and a low molecular weight surfactant, polysorbate 80. Based on studies prior to the continuous manufacturing, the desired appearance of the target extrudate is translucent. Although process parameters such as feed rate and screw speed were fixed during the continuous manufacturing, the extrudate appearance changed over time from turbid to translucent. For root-cause investigation, the extrudates were analyzed offline by differential scanning calorimetry (DSC) and advanced polymer chromatography (APC™). Although the polysorbate 80 content of both turbid and translucent extrudates was within target, the glass transition temperature of the turbid extrudate was 2 °C above expected value. The observed turbidity was traced to lot-to-lot variability of the polysorbate 80 used in the continuous manufacturing, where APC™ analysis revealed that the relative content of the low molecular weight component varied from 23% to 27% in correlation with the evolution from turbid to translucent extrudates. This work stresses the importance of taking feeding material variability into account during continuous manufacturing.

Thermodynamic Modeling of the Amorphous Solid Dispersion-Water Interfacial Layer and Its Impact on the Release Mechanism.

During the dissolution of amorphous solid dispersion (ASD) formulations, the gel layer that forms at the ASD/water interface strongly dictates the release of the active pharmaceutical ingredient (API) and, hence, the dissolution performance. Several studies have demonstrated that the switch of the gel layer from eroding to non-eroding behavior is API-specific and drug-load (DL)-dependent. This study systematically classifies the ASD release mechanisms and relates them to the phenomenon of the loss of release (LoR). The latter is thermodynamically explained and predicted via a modeled ternary phase diagram of API, polymer, and water, and is then used to describe the ASD/water interfacial layers (below and above the glass transition). To this end, the ternary phase behavior of the APIs, naproxen, and venetoclax with the polymer poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) and water was modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT). The glass transition was modeled using the Gordon-Taylor equation. The DL-dependent LoR was found to be caused by API crystallization or liquid-liquid phase separation (LLPS) at the ASD/water interface. If crystallization occurs, it was found that API and polymer release was impeded above a threshold DL at which the APIs crystallized directly at the ASD interface. If LLPS occurs, an API-rich phase and a polymer-rich phase are formed. Above a threshold DL, the less mobile and hydrophobic API-rich phase accumulates at the interface which prevents API release. LLPS is further influenced by the composition and glass transition temperature of the evolving phases and was investigated at 37 °C and 50 °C regarding impact of temperature of. The modeling results and LoR predictions were experimentally validated by means of dissolution experiments, microscopy, Raman spectroscopy, and size exclusion chromatography. The experimental results were found to be in very good agreement with the predicted release mechanisms deduced from the phase diagrams. Thus, this thermodynamic modeling approach represents a powerful mechanistic tool that can be applied to classify and quantitatively predict the DL-dependent LoR release mechanism of PVPVA64-based ASDs in water.

Assessment of the amorphous solid dispersion erosion behavior following a novel small-scale predictive approach.

In general, the erosion rate of copovidone-based amorphous solid dispersions (ASDs) in contact with water diminishes with increasing drug load, causing poor drug release from the final drug product. A new easy-to-use tool with low material- and time-consumption, the microscopic erosion time test (METT), was established to allow prediction of the API-specific drug load threshold between an eroding and a non-eroding ASD. This API-specific drug load value is further described as the drug load dispersibility limit (DDL) and is the highest drug load at which an eroding ASD was still observed. A minor increase of 2.5% in drug load above the DDL already led to a non-eroding ASD and it was subsequently connected to the drug load-associated drop in API in vitro dissolution of ASD tablets and an impeded tablet disintegration. In total, 19 APIs in copovidone-based ASDs were characterized via the METT while a subset of these was investigated in more detail, namely indomethacin, celecoxib, dipyridamole, fenofibrate, naproxen and ritonavir. Furthermore, indomethacin- and celecoxib-containing ASDs with various drug loads were prepared and characterized to link the METT outcome with ASD tablet in vitro dissolution and disintegration performance.

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. Our focus was on polymers commonly used in spray drying and hot-melt extrusion to form amorphous solid dispersions (ASDs), namely polyvinylpyrrolidone grades (PVP), polyvinyl acetate (PVAc), vinylpyrrolidone-vinyl acetate copolymer (copovidone, COP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft polymer (Soluplus®, SOL), different types of methacrylate copolymers (PMMA), polyethylene glycol grades (PEG) and hydroxypropyl-methylcellulose grades (HPMC). The literature data were further supplemented by our own results. The final data set included 37 APIs and two sugar derivatives. The majority of the prediction models was constituted by the melting point depression method, dissolution endpoint measurements, indirect solubility determination by Tg and the use of low molecular weight analogues. We observed that the API solubility depended more on the working group which conducted the experiments than on the measuring technique used. Furthermore, this compilation should assist researchers in choosing a prediction method suited for their investigations. Furthermore, a statistical assessment using recursive feature elimination was performed to identify descriptors of molecules, which are connected to the API solubility in polymeric matrices. It is capable of predicting the criterium 20% API soluble at 100 °C (Yes/No) for an unknown compound with a balanced accuracy of 71%. The identified 8 descriptors to be connected to API solubility in polymeric matrices were the number of hydrogen bonding donors, three descriptors related to the hydrophobicity of the molecule, glass transition temperature, fractional negative polar van der Waals surface area, out-of-plane potential energy and the fraction of rotatable bonds. Finally, in addition to our own model, the data set should help researchers in training their own solubility prediction models.

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. We observed a broader design space of HME processes for the plasticized formulation with respect to screw speed than for the copovidone-only matrix formulation. This observation was determined by the range of observed melt temperatures in the extruder, both measured and simulated. The reason was not primarily linked to a reduced shear-thinning behavior, characterized by the power law index, n, but instead more to an overall reduced melt viscosity during extrusion and zero-shear rate viscosity, η0, accordingly. We also found that the amount of residual crystallinity of telmisartan correlated with the simulated maximum melt temperature in the extruder barrel. This finding confirmed the applicability of the temperature-dependent API-matrix solubility phase diagram for HME to process development. Given the complex inter-dependent relationships between material properties, process and performance, process modeling combined with reduced laboratory experimentation was established as a holistic approach for the evaluation of Quality-by-Design-based HME process design spaces.

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 (Tg) and the rheological flow profile of the pure polymeric matrix. All further required physical properties were taken from the pure polymer. For forming the ASDs, four active pharmaceutical ingredients (APIs), that had not been considered in first place to establish the correlation between Tg and melt viscosity were examined. The ASDs were characterized in terms of density, specific heat capacity, melt rheology, API solubility in the polymeric matrix, and deviation from the Couchman⁻Karasz fit to, identify the influencing factors of the accuracy of the simulation using model-based melt viscosity. Furthermore, the energy consumption of the hot-melt extrusion (HME) experiments, conventional simulation, and simulation using model-based melt viscosity were compared. It was shown, with few exceptions, that the use of model-based melt viscosity in terms of the HME simulation did not reduce the accuracy of the computation outcome. The commercial one-dimensional (1D) simulation software Ludovic® was used to conduct all of the numerical computation. As model excipients, vinylpyrrolidone-vinyl acetate copolymer (COP) in combination with four APIs (celecoxib, loratadine, naproxen, and praziquantel) were investigated to form the ASDs.

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. The commercial 1D simulation software Ludovic® was used to conduct (i) simulations using a full experimental data set of all input variables including melt rheology and (ii) simulations using model-based melt viscosity data based on the ASDs glass transition and the physical properties of polymeric matrix only. Both types of HME computation were further compared to experimental HME results. Variation in physical properties (e.g. heat capacity, density) and several process characteristics of HME (residence time distribution, energy consumption) among the simulations and experiments were evaluated. The model-based melt viscosity was calculated by using the glass transition temperature (Tg) of the investigated blend and the melt viscosity of the polymeric matrix by means of a Tg-viscosity correlation. The results of measured melt viscosity and model-based melt viscosity were similar with only few exceptions, leading to similar HME simulation outcomes. At the end, the experimental effort prior to HME simulation could be minimized and the procedure enables a good starting point for rational development of ASDs by means of HME. As model excipients, Vinylpyrrolidone-vinyl acetate copolymer (COP) in combination with various APIs (carbamazepine, dipyridamole, indomethacin, and ibuprofen) or polyethylene glycol (PEG 1500) as plasticizer were used to form the ASDs.

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

The feasibility of predicting melt rheology by using the glass transition temperature (Tg) 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. The zero-shear viscosity (η0) identified at 150°C was compared to Tg, measured by differential scanning calorimetry (DSC) and SAOS. A strong correlation between η0 and Tg was identified, independent of the API or plasticizer used to achieve Tg of the mixture. To evaluate and rate the discrepancy in η0 of the different mixtures at same Tg, hot-melt extrusion trials were conducted to measure torque and mean residence time. In this paper, carbamazepine, dipyridamole, indomethacin, ibuprofen, polyethylene glycol (PEG 1500) in vinylpyrrolidone-vinyl acetate copolymer (copovidone) as matrix polymer were used.

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). Furthermore, estimation of the minimal processing temperature for forming ASDs during HME trials could be defined and was additionally confirmed by X-ray powder diffraction data. The suitability of the DSC method was confirmed with melt rheological trials (small amplitude oscillatory system). As an example, ball milled physical mixtures of dipyridamole, indomethacin, itraconazole and nifedipine in poly(vinylpyrrolidone-co-vinylacetate) (copovidone) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) were used.