Integrated Continuous Wet Granulation and Drying: Process Evaluation and Comparison with Batch Processing.

The pharmaceutical industry is in the midst of a transition from traditional batch processes to continuous manufacturing. However, the challenges in making this transition vary depending on the selected manufacturing process. Compared with other oral solid dosage processes, wet granulation has been challenging to move towards continuous processing since traditional equipment has been predominantly strictly batch, instead of readily adapted to material flow such as dry granulation or tablet compression, and there have been few equipment options for continuous granule drying. Recently, pilot and commercial scale equipment combining a twin-screw wet granulator and a novel horizontal vibratory fluid-bed dryer have been developed. This study describes the process space of that equipment and compares the granules produced with batch high-shear and fluid-bed wet granulation processes. The results of this evaluation demonstrate that the equipment works across a range of formulations, effectively granulates and dries, and produces granules of similar or improved quality to batch wet granulation and drying.

Continuous Twin-Screw wet granulation process with In-Barrel drying and NIR setup for Real-Time Moisture Monitoring.

The purpose of this study was to evaluate if wet granule formation and drying could take place in a single operation by utilizing in-barrel drying. The drying kinetics of the formulation were studied in order to select appropriate processing parameters and assess feasibility with short residence times in the extruder. The 18-mm extruder was operated in a 40:1 L:D ratio with 8 zones. The first two zones were used for material feeding and wet granule formation and the remaining zones were used for drying at elevated temperature. The impact of screw configuration as well as screw speed, feed rate, and residence time were all studied to optimize the drying process. Due to limitations of temperature and residence time, vacuum was added to enable sufficient drying. In-line NIR spectroscopy was incorporated into the twin-screw wet granulation (TSWG) process to monitor the moisture content of wet granules in real-time. The set-up was optimized and a predictive model was developed for future experiments. This study demonstrated the success of this technique on a pilot-scale (18-mm) extruder for the first time. Granules were formed and dried to a target loss on drying (LOD) of less than 2 % at moderate temperatures (100 °C - 110 °C) with one single operation. Streamlining wet granulation and drying into one unit operation can have a profound impact on pharmaceutical manufacturing reducing time, footprint, and environmental exposure due to reduced product transfers.

Scale-Up and In-line Monitoring During Continuous Melt Extrusion of an Amorphous Solid Dispersion.

Chemical degradation of drug substances remains a major drawback of extrusion. Larger-scale extrusion equipment has advantages over smaller equipment due to deeper flight elements and added flexibility in terms of screw design, unit operations, and residence time. In a previous study, we extruded a meloxicam-copovidone amorphous solid dispersion (ASD) on a Nano-16 extruder and achieved 96.7% purity. The purpose of this study is to introduce a strategy for scaling the process to an extruder with dissimilar geometry and to investigate the impact on the purity of the ASD. The formulation previously optimized on the Nano-16, 10:90 meloxicam and copovidone, was used for scale-up. Our approach to scale-up to the ZSE-18, utilized specific mechanical energy input and degree of fill from the Nano-16. Vacuum was added to prevent hydrolysis of meloxicam. Downstream feeding and micronization of meloxicam were introduced to reduce the residence time. In-line monitoring of the solubilization of meloxicam was monitored with a UV probe positioned at the die. We were able to achieve the same purity of meloxicam with the Micro-18 as we achieved with Nano-16. When process conditions alone were not sufficient, meglumine was added to further stabilize meloxicam. In addition to the chemical stability advantage that meglumine provided, we also observed solubility enhancement which allowed for an increase in drug loading to 20% while maintaining 100% purity.

Evaluation of Accuracy of Amorphous Solubility Advantage Calculation by Comparison with Experimental Solubility Measurement in Buffer and Biorelevant Media.

The accuracy of amorphous solubility advantage calculation was evaluated by experimental solubility measurement. Ten structurally diverse compounds were studied to test the generlity of the theoretical calculation. Three reported methods of calculating Gibbs free energy difference between amorphous and crystalline solids were evaluated. Experimental solubility advantage was measured by direct dissolution of amorphous solid in buffer. When necessary, hydroxypropyl methylcellulose acetate succinate (HPMCAS) was predissolved in buffer to inhibit desupersaturation. By direct dissolution, the effect of different preparation methods on amorphous solubility was also studied. Finally, solubility measurement was performed in fasted state simulated intestinal fluid (FaSSIF) to assess the effect of bile salt on the concentration-based amorphous solubility advantage. The results showed that the assumption of constant heat capacity differences between crystal and supercooled liquid or amorphous solid is sufficient for accurate theoretical calculation, which is attributed to the fact that the heat capacity of crystal is nearly parallel to that of supercooled liquid or amorphous solid. Different preparation methods do not have significant impact on amorphous solubility advantage. Experimental measurement agrees with the theoretical calculation within a factor of 0.7 to 1.8. The concentration-based amorphous solubility advantage in FaSSIF agrees well with theoretical calculation. This work demonstrates that theoretical calculation of amorphous solubility advantage is robust and can be applied in early drug development for assessing the utility of the amorphous phase.

In Situ Salt Formation during Melt Extrusion for Improved Chemical Stability and Dissolution Performance of a Meloxicam-Copovidone Amorphous Solid Dispersion.

As the pipeline for poorly soluble compounds continues to grow, drug degradation during melt extrusion must be addressed. We present a novel method for stabilizing a thermally labile drug substance while preserving its physical stability and even improving its dissolution performance. In a previous study, we found that incorporating meglumine during extrusion of meloxicam results in chemical stabilization that cannot be achieved using process optimization alone. The purpose of this study is to understand the mechanism behind this stabilization and its impact on the performance of a meloxicam-Kollidon VA64 amorphous solid dispersion. The meloxicam concentration was maintained at 10% (w/w) for blends with and without meglumine. The optimal meglumine blend contained an equimolar amount of meloxicam to meglumine with the remainder consisting of Kollidon VA64. Both formulations were processed with optimized extrusion conditions and analyzed by HPLC for purity. Meglumine at a 1:1 molar ratio with meloxicam results in 100% purity of meloxicam after melt extrusion. Solid-state NMR revealed a proton transfer between the meloxicam and meglumine indicating an in situ salt formation. During non-sink dissolution, the meglumine ASD enables meloxicam to maintain supersaturatation (≅50 times more than meloxicam free acid) for >7.25 h. The ASD without meglumine began precipitating 2.25 h following the pH shift. The ASDs were placed at 40 °C/75% RH for 6 months, and their stability was assessed. No significant chemical degradation, recrystallization, or significant moisture uptake was observed after six months' storage at 40 °C/75% RH.

New Strategies for Improving the Development and Performance of Amorphous Solid Dispersions.

The understanding of amorphous solid dispersions has grown significantly in the past decade. This is evident from the number of approved commercial amorphous solid dispersion products. While amorphous formulation is considered an enabling technology, it has become the norm for formulating poorly soluble compounds. Despite this success, improvements can still be made that enable early development formulation decisions, to develop a rationale for selecting a manufacturing process, to overcome degradation and phase separation during processing, to help achieve physical stability during storage, and to optimize dissolution behavior. The purpose of this literature review is to present recently reported strategies for improving the development and performance of ASDs. The benefits and limitations of each strategy as well as recent relevant case studies will be presented in this review. The strategies are presented from three different aspects: (a) prediction techniques that enable formulation decisions, (b) manufacturing considerations that help produce physically and chemically stable ASDs, and

An approach for chemical stability during melt extrusion of a drug substance with a high melting point.

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.

Melt extrusion vs. spray drying: The effect of processing methods on crystalline content of naproxen-povidone formulations.

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.