A Novel PBM for Nanomilling of Drugs in a Recirculating Wet Stirred Media Mill: Impacts of Batch Size, Flow Rate, and Back-Mixing.

We examined the evolution of fenofibrate (FNB, drug) particle size distribution (PSD) during the production of nanosuspensions via wet stirred media milling (WSMM) with a cell-based population balance model (PBM). Our objective was to elucidate the potential impacts of batch size, suspension volumetric flow rate, and imperfect mixing in a recirculating WSMM. Various specific breakage rate functions were fitted to experimental PSD data at baseline conditions assuming perfect mixing. Then, the best function was used to simulate the PSD evolution at various batch sizes and flow rates to validate the model. A novel function, which is a product of power-law and logistic functions, fitted the evolution the best, signifying the existence of a transition particle size commensurate with a grinding limit. Although larger batches yielded coarser and wider PSDs, the suspensions had identical PSDs when milled for the same effective milling time. The flow rate had an insignificant influence on the PSD. Furthermore, the imperfect mixing in the mill chamber was simulated by considering more than one cell and different back-mixing flow ratios. The effects were weak and restricted to the first few turnovers. These insights contribute to our understanding of recirculating WSMM, providing valuable guidance for process development.

Development of a Semi-Mechanistic Modeling Framework for Wet Bead Milling of Pharmaceutical Nanosuspensions.

This study aimed to develop a practical semi-mechanistic modeling framework to predict particle size evolution during wet bead milling of pharmaceutical nanosuspensions over a wide range of process conditions and milling scales. The model incorporates process parameters, formulation parameters, and equipment-specific parameters such as rotor speed, bead type, bead size, bead loading, active pharmaceutical ingredient (API) mass, temperature, API loading, maximum bead volume, blade diameter, distance between blade and wall, and an efficiency parameter. The characteristic particle size quantiles, i.e., x10, x50, and x90, were transformed to obtain a linear relationship with time, while the general functional form of the apparent breakage rate constant of this relationship was derived based on three models with different complexity levels. Model A, the most complex and general model, was derived directly from microhydrodynamics. Model B is a simpler model based on a power-law function of process parameters. Model C is the simplest model, which is the pre-calibrated version of Model B based on data collected from different mills across scales, formulations, and drug products. Being simple and computationally convenient, Model C is expected to reduce the amount of experimentation needed to develop and optimize the wet bead milling process and streamline scale-up and/or scale-out.

Preparation and Characterization of Spray-Dried Hybrid Nanocrystal-Amorphous Solid Dispersions (HyNASDs) for Supersaturation Enhancement of a Slowly Crystallizing Drug.

We prepared hybrid nanocrystal-amorphous solid dispersions (HyNASDs) to examine their supersaturation capability in the release of a poorly soluble drug, itraconazole (ITZ), a slow crystallizer during dissolution. The HyNASD formulations included a polymer (HPC: hydroxypropyl cellulose, Sol: Soluplus, or VA64: Kollidon-VA64) and a surfactant (SDS: sodium dodecyl sulfate). Additionally, the dissolution performance of the HyNASDs and ASDs was compared. To this end, wet-milled aqueous nanosuspensions containing a 1:5 ITZ:polymer mass ratio with/without SDS as well as solutions of the same ratio without SDS in dichloromethane were spray-dried. XRPD-DSC confirmed that ASDs were formed upon spray drying the solution-based feeds, whereas HyNASDs (~5-30% amorphous) were formed with the nanosuspension-based feeds. SDS aided to stabilize the ITZ nanosuspensions and increase the amorphous content in the spray-dried powders. During dissolution, up to 850% and 790% relative supersaturation values were attained by HyNASDs with and without SDS, respectively. Due to the stronger molecular interaction between ITZ-Sol than ITZ-HPC/VA64 and micellar solubilization by Sol, Sol-based HyNASDs outperformed HPC/VA64-based HyNASDs. While the ASD formulations generated greater supersaturation values (≤1670%) than HyNASDs (≤790%), this extent of supersaturation from a largely nanocrystalline formulation (HyNASD) has not been achieved before. Overall, HyNASDs could boost drug release from nanoparticle-based formulations and may render them competitive to ASDs.

Do Mixtures of Beads with Different Sizes Improve Wet Stirred Media Milling of Drug Suspensions?

The impacts of bead sizes and bead mixtures on breakage kinetics, the number of milling cycles applied to prevent overheating, and power consumption during the nanomilling of drug (griseofulvin) suspensions were investigated from both an experimental and theoretical perspective. Narrowly sized zirconia beads with nominal sizes of 100, 200, and 400 µm and their half-and-half binary mixtures were used at 3000 and 4000 rpm with two bead loadings of 0.35 and 0.50. Particle size evolution was measured during the 3 h milling experiments using laser diffraction. An nth-order breakage model was fitted to the experimental median particle size evolution, and various microhydrodynamic parameters were calculated. In general, the beads and their mixtures with smaller median sizes achieved faster breakage. While the microhydrodynamic model explained the impacts of process parameters, it was limited in describing bead mixtures. For additional test runs performed, the kinetics model augmented with a decision tree model using process parameters outperformed that augmented with an elastic-net regression model using the microhydrodynamic parameters. The evaluation of the process merit scores suggests that the use of bead mixtures did not lead to notable process improvement; 100 µm beads generally outperformed bead mixtures and coarser beads in terms of fast breakage, low power consumption and heat generation, and low intermittent milling cycles.

Nanoseeded Desupersaturation and Dissolution Tests for Elucidating Supersaturation Maintenance in Amorphous Solid Dispersions.

The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on the solution-mediated precipitation from griseofulvin ASDs. Nanoparticle crystals (nanoseeds) were used as a more realistic surrogate for residual crystals compared with conventional micron-sized seeds. ASDs of griseofulvin with Soluplus (Sol), Kollidon VA64 (VA64), and hydroxypropyl methyl cellulose (HPMC) were prepared by spray-drying. Nanoseeds produced by wet media milling were used in the dissolution and desupersaturation experiments. DLS, SEM, XRPD, and DSC were used for characterization. The results from the solvent-shift tests suggest that the drug nanoseeds led to a faster and higher extent of desupersaturation than the as-received micron-sized crystals and that the higher seed loading facilitated desupersaturation. Sol was the only effective nucleation inhibitor; the overall precipitation inhibition capability was ranked: Sol > HPMC > VA64. In the dissolution tests, only the Sol-based ASDs generated significant supersaturation, which decreased upon an increase in the nanoseed loading. This study has demonstrated the importance of using drug nanocrystals in lieu of conventional coarse crystals in desupersaturation and dissolution tests in ASD development.

Predicting the Temperature Evolution during Nanomilling of Drug Suspensions via a Semi-Theoretical Lumped-Parameter Model.

Although temperature can significantly affect the stability and degradation of drug nanosuspensions, temperature evolution during the production of drug nanoparticles via wet stirred media milling, also known as nanomilling, has not been studied extensively. This study aims to establish both descriptive and predictive capabilities of a semi-theoretical lumped parameter model (LPM) for temperature evolution. In the experiments, the mill was operated at various stirrer speeds, bead loadings, and bead sizes, while the temperature evolution at the mill outlet was recorded. The LPM was formulated and fitted to the experimental temperature profiles in the training runs, and its parameters, i.e., the apparent heat generation rate Qgen and the apparent overall heat transfer coefficient times surface area UA, were estimated. For the test runs, these parameters were predicted as a function of the process parameters via a power law (PL) model and machine learning (ML) model. The LPM augmented with the PL and ML models was used to predict the temperature evolution in the test runs. The LPM predictions were also compared with those of an enthalpy balance model (EBM) developed recently. The LPM had a fitting capability with a root-mean-squared error (RMSE) lower than 0.9 °C, and a prediction capability, when augmented with the PL and ML models, with an RMSE lower than 4.1 and 2.1 °C, respectively. Overall, the LPM augmented with the PL model had both good descriptive and predictive capability, whereas the one with the ML model had a comparable predictive capability. Despite being simple, with two parameters and obviating the need for sophisticated numerical techniques for its solution, the semi-theoretical LPM generally predicts the temperature evolution similarly or slightly better than the EBM. Hence, this study has provided a validated, simple model for pharmaceutical engineers to simulate the temperature evolution during the nanomilling process, which will help to set proper process controls for thermally labile drugs.

An Enthalpy-Balance Model for Timewise Evolution of Temperature during Wet Stirred Media Milling of Drug Suspensions.

PURPOSE: Nanosuspensions have been used for enhancing the bioavailability of poorly soluble drugs. This study explores the temperature evolution during their preparation in a wet stirred media mill using a coupled experimental-enthalpy balance approach. METHODS: Milling was performed at three levels of stirrer speed, bead loading, and bead sizes. Temperatures were recorded over time, then simulated using an enthalpy balance model by fitting the fraction of power converted to heat ξ. Moreover, initial and final power, ξ, and temperature profiles at 5 different test runs were predicted by power-law (PL) and machine learning (ML) approaches. RESULTS: Heat generation was higher at the higher stirrer speed and bead loading/size, which was explained by the higher power consumption. Despite its simplicity with a single fitting parameter ξ, the enthalpy balance model fitted the temperature evolution well with root mean squared error (RMSE) of 0.40-2.34°C. PL and ML approaches provided decent predictions of the temperature profiles in the test runs, with RMSE of 0.93-4.17 and 1.00-2.17°C, respectively. CONCLUSIONS: We established the impact of milling parameters on heat generation-power and demonstrated the simulation-prediction capability of an enthalpy balance model when coupled to the PL-ML approaches.

Analysis of heat generation during the production of drug nanosuspensions in a wet stirred media mill.

Although heat is generated during the wet stirred media milling of drug suspensions, leading to notable temperature rise, a comprehensive analysis of heat generation does not exist. Hence, we investigated the impact of stirrer speed, bead loading, and bead size at three levels on the evolution of suspension temperature at the mill outlet during the milling of fenofibrate. The particle sizes and viscosities of the milled suspensions and power were measured. Our results suggest that stirrer speed had the most significant impact on the temperature increase, followed by bead loading and bead size. Both the time when the temperature reached 22 °C and the temperature at 5 min of milling were strongly correlated with the power. Assessing the impacts of the process parameters on the temperature rise, cycle time, power, and median particle size holistically, an optimal milling process was identified: 3000 rpm with 50% loading of 200 or 400 µm beads. A power number correlation was established to calculate power at any milling condition which determines the heat generation rate. Overall, this study indicated the importance of developing a good understanding of heat generation during nanomilling for development of a robust milling process especially for thermally labile drugs.

Impact of Matrix Surface Area on Griseofulvin Release from Extrudates Prepared via Nanoextrusion.

We aimed to examine the impact of milling of extrudates prepared via nanoextrusion and the resulting matrix surface area of the particles on griseofulvin (GF, a model poorly soluble drug) release during in vitro dissolution. Wet-milled GF nanosuspensions containing a polymer (Sol: Soluplus®, Kol: Kolliphor® P407, or HPC: Hydroxypropyl cellulose) and sodium dodecyl sulfate were mixed with additional polymer and dried in an extruder. The extrudates with 2% and 10% GF loading were milled-sieved into three size fractions. XRPD-SEM results show that nanoextrusion produced GF nanocomposites with Kol/HPC and an amorphous solid dispersion (ASD) with Sol. For 8.9 mg GF dose (non-supersaturating condition), the dissolution rate parameter was higher for extrudates with higher external specific surface area and those with 10% drug loading. It exhibited a monotonic increase with surface area of the ASD, whereas its increase tended to saturate above ~30 × 10-3 m2/cm3 for the nanocomposites. In general, the nanocomposites released GF faster than the ASD due to greater wettability and faster erosion imparted by Kol/HPC than by Sol. For 100 mg GF dose, the ASD outperformed the nanocomposites due to supersaturation and only 10% GF ASD with 190 × 10-3 m2/cm3 surface area achieved immediate release (80% release within 30 min). Hence, this study suggests that ASD extrudates entail fine milling yielding > ~200 × 10-3 m2/cm3 for rapid drug release, whereas only a coarse milling yielding ~30 × 10-3 m2/cm3 may enable nanocomposites to release low-dose drugs rapidly.

Kinetic and Microhydrodynamic Modeling of Fenofibrate Nanosuspension Production in a Wet Stirred Media Mill.

This study examined the impact of stirrer speed and bead material loading on fenofibrate particle breakage during wet stirred media milling (WSMM) via three kinetic models and a microhydrodynamic model. Evolution of median particle size was tracked via laser diffraction during WSMM operating at 3000-4000 rpm with 35-50% (v/v) concentration of polystyrene or zirconia beads. Additional experiments were performed at the center points of the above conditions, as well as outside the range of these conditions, in order to test the predictive capability of the models. First-order, nth-order, and warped-time kinetic models were fitted to the data. Main effects plots helped to visualize the influence of the milling variables on the breakage kinetics and microhydrodynamic parameters. A subset selection algorithm was used along with a multiple linear regression model (MLRM) to delineate how the breakage rate constant k was affected by the microhydrodynamic parameters. As a comparison, a purely empirical correlation for k was also developed in terms of the process/bead parameters. The nth-order model was found to be the best model to describe the temporal evolution; nearly second-order kinetics (n ≅ 2) was observed. When the process was operated at a higher stirrer speed and/or higher loading with zirconia beads as opposed to polystyrene beads, the breakage occurred faster. A statistically significant (p-value ≤ 0.01) MLRM of three microhydrodynamic parameters explained the variation in the breakage rate constant best (R2 ≥ 0.99). Not only do the models and the nth-order kinetic-microhydrodynamic correlation enable deeper process understanding toward developing a WSMM process with reduced cycle time, but they also provide good predictive capability, while outperforming the purely empirical correlation.

Impact of altered hydrophobicity and reduced agglomeration on dissolution of micronized poorly water-soluble drug powders after dry coating.

The impact of dry coating with hydrophobic or hydrophilic nano-silica at 25-100% surface area coverage on dissolution of micronized poorly water-soluble drugs was investigated by examining their agglomeration and surface hydrophobicity. Ibuprofen (20 µm and 10 µm) and griseofulvin (10 µm) were selected having differing solubility, hydrophobicity, and surface morphology. Characterization involved particle agglomeration via two dry dispersion methods, drug dissolution using the USP IV method, cohesion reduction through shear testing, and powder wettability via the modified Washburn method. Dry coating dramatically reduced the cohesion hence agglomerate size of both the coated ibuprofen particles, but less for griseofulvin, attributed to its surface morphology. For hydrophobic silica, agglomerate size reduction outweighed the adverse impact of increased surface hydrophobicity for ibuprofen. For griseofulvin, the agglomerate reduction was much lower, not able to overcome the effect of increased drug particle hydrophobicity with hydrophobic silica coating. Hydrophilic silica coating reduced hydrophobicity for all three drug powders, leading to the synergistic improvement in the dissolution along with agglomerate size reduction. Overall, the combined effect of the drug particle surface hydrophobicity and agglomerate size, represented by specific surface area, could explain the dissolution behavior of these poorly water-soluble drugs.

Use of Bead Mixtures as a Novel Process Optimization Approach to Nanomilling of Drug Suspensions.

PURPOSE: We aimed to evaluate the feasibility of cross-linked polystyrene (CPS)-yttrium-stabilized zirconia (YSZ) bead mixtures as a novel optimization approach for fast, effective production of drug nanosuspensions during wet stirred media milling (WSMM). METHODS: Aqueous suspensions of 10% fenofibrate (FNB, drug), 7.5% HPC-L, and 0.05% SDS were wet-milled at 3000-4000 rpm and 35%-50% volumetric loading of CPS:YSZ bead mixtures (CPS:YSZ 0:1-1:0 v:v). Laser diffraction, SEM, viscometry, DSC, and XRPD were used for characterization. An nth-order model described the breakage kinetics, while a microhydrodynamic model allowed us to gain insights into the impact of bead materials. RESULTS: CPS beads achieved the lowest specific power consumption, whereas YSZ beads led to the fastest breakage. Breakage followed second-order kinetics. Optimum conditions were identified as 3000 rpm and 50% loading of 0.5:0.5 v/v CPS:YSZ mixture from energy-cycle time-heat dissipation perspectives. The microhydrodynamic model suggests that YSZ beads experienced more energetic/forceful collisions with smaller contact area as compared with CPS beads owing to the higher density-elastic modulus of the former. CONCLUSIONS: We demonstrated the feasibility of CPS-YSZ bead mixtures and rationalized its optimal use in WSMM through their modulation of breakage kinetics, energy utilization, and heat dissipation.

Electro-Hydrodynamic Drop-on-Demand Printing of Aqueous Suspensions of Drug Nanoparticles.

We demonstrate the ability to fabricate dosage forms of a poorly water-soluble drug by using wet stirred media milling of a drug powder to produce an aqueous suspension of nanoparticles and then print it onto a porous biocompatible film. Contrary to conventional printing technologies, a deposited material is pulled out from the nozzle. This feature enables printing highly viscous materials with a precise control over the printed volume. Drug (griseofulvin) nanosuspensions prepared by wet media milling were printed onto porous hydroxypropyl methylcellulose films prepared by freeze-drying. The drug particles retained crystallinity and polymorphic form in the course of milling and printing. The versatility of this technique was demonstrated by printing the same amount of nanoparticles onto a film with droplets of different sizes. The mean drug content (0.19-3.80 mg) in the printed films was predicted by the number of droplets (5-100) and droplet volume (0.2-1.0 µL) (R2 = 0.9994, p-value < 10-4). Our results also suggest that for any targeted drug content, the number-volume of droplets could be modulated to achieve acceptable drug content uniformity. Analysis of the model-independent difference and similarity factors showed consistency of drug release profiles from films with a printed suspension. Zero-order kinetics described the griseofulvin release rate from 1.8% up to 82%. Overall, this study has successfully demonstrated that the electro-hydrodynamic drop-on-demand printing of an aqueous drug nanosuspension enables accurate and controllable drug dosing in porous polymer films, which exhibited acceptable content uniformity and reproducible drug release.

Impact of media material and process parameters on breakage kinetics-energy consumption during wet media milling of drugs.

While crosslinked polystyrene (CPS) beads and yttrium-stabilized zirconia (YSZ) beads have been commonly used as media for wet milling of poorly soluble drugs and their dissolution enhancement, no first-principle rationale exists for selecting the bead material. The aim of this study is to investigate the impact of stirrer speed (2000-4000 rpm) and CPS bead loading (~20-60%) on the breakage kinetics-energy consumption during milling of griseofulvin, a model poorly soluble drug, and compare the performance of CPS vs. YSZ at the highest bead loading. Laser diffraction, SEM, rheological analysis, and XRPD were used for characterization. The milling was most effective at the highest bead loading-stirrer speed. A microhydrodynamic model suggests that an increase in stirrer speed led to faster breakage due to more frequent and forceful CPS bead-bead collisions. Despite causing slight decrease in maximum contact pressure, an increase in CPS bead loading caused a dramatic increase in average frequency of drug particle compressions, which dominated the faster breakage observed. While YSZ generally required higher specific energy consumption than CPS, it achieved the same product fineness faster than CPS. The microhydrodynamic model rationalized the favorable use of YSZ over CPS beads within the experimental domain studied.

Synergistic and antagonistic effects of various amphiphilic polymer combinations in enhancing griseofulvin release from ternary amorphous solid dispersions.

We aimed to elucidate the impact of various amphiphilic polymers on drug wettability and recrystallization inhibition and in turn drug release from binary and ternary amorphous solid dispersions (ASDs). Griseofulvin (GF) was selected as a challenging, fast-crystallizing poorly soluble drug. GF solutions with hydroxypropyl cellulose (HPC), Kollidon VA64 (VA64), and Soluplus® (Sol) were spray-dried to prepare various binary and ternary GF ASDs. XRPD, DSC, and Raman spectroscopy confirmed the formation of ASDs and suggested that HPC appears to have lower miscibility and weaker interactions with GF than Sol/VA64 with GF. In dissolution tests, the Sol-based ASD generated supersaturation very slowly and achieved 170% GF supersaturation in 210 min (230% after 6 h). The HPC-based ASD exhibited fast recrystallization in the matrix due to its low glass transition temperature and poor miscibility of HPC with GF; whereas VA64-based ASD exhibited 220% supersaturation in 10 min followed by rapid GF recrystallization. The modified Washburn experiments revealed significant wettability enhancement of GF by HPC/VA64 and inadequate enhancement by Sol, which explains the initial rapid release from VA64-based ASD and slow supersaturation build-up in Sol-based ASD. Poor GF recrystallization inhibition ability of the HPC/VA64 was confirmed by desupersaturation tests and polarized light microscope imaging. Addition of HPC to Sol and VA64 deteriorated the GF release from the ASDs with either Sol or VA64 alone. In most cases, combination of Sol with HPC/VA64 led to a trade-off between high supersaturation and rapid drug release. A strong synergistic effect emerged for the ASD with 5:1 Sol:VA64: ~220% supersaturation within 30 min was generated and maintained over three hours, whereas an antagonistic effect was observed for 1:5 Sol:VA64 with 70% supersaturation. The combination of an amphiphilic polymer that provides effective drug wettability enhancement (VA64) as a minor component along with an amphiphilic crystallization inhibiting polymer as a major component (Sol), which also provides micellar solubilization of the drug, in a ternary ASD exhibited synergistic rapid drug release with prolonged supersaturation.

A semi-theoretical model for simulating the temporal evolution of moisture-temperature during industrial fluidized bed granulation.

Moisture plays a major role in determining the attributes of granules prepared by fluidized bed granulation (FBG). Here, a semi-theoretical droplet-based evaporation rate model was developed and incorporated into moisture mass-enthalpy balances to simulate the temporal evolution of bed moisture-temperature. Experimental data from a GPCG30 unit were used to fit the model parameters. With only two fitting parameters, the model demonstrated excellent capability to describe the moisture-temperature evolution for a wide range of operating conditions. Then, in a global process model (GPM) approach, the evaporation parameters were fitted to multi-linear functions of inlet air temperature, binder concentration, and spray rate. The GPM was validated successfully by simulating a different data set which was not used in its calibration. As the GPM demonstrated a good predictive capability, it was further used to investigate the impacts of process parameters. Numerical simulations suggest that the proposed GPM predicts the experimentally well-established trends of moisture-temperature profiles in previously published data, proving the applicability of the GPM approach. This study has demonstrated the capabilities of simple process models as a practical approach to predict time-wise evolution of bed moisture-temperature profiles in industrial FBG modeling, while also pointing out their limitations.

Spray-Dried Amorphous Solid Dispersions of Griseofulvin in HPC/Soluplus/SDS: Elucidating the Multifaceted Impact of SDS as a Minor Component.

This study aimed to elucidate the impact of a common anionic surfactant, sodium dodecyl sulfate (SDS), along with hydroxypropyl cellulose (HPC) and Soluplus (Sol) on the release of griseofulvin (GF), a poorly soluble drug, from amorphous solid dispersions (ASDs). Solutions of 2.5% GF and 2.5%-12.5% HPC/Sol with 0.125% SDS/without SDS were prepared in acetone-water and spray-dried. The solid-state characterization of the ASDs suggests that GF-Sol had better miscibility and stronger interactions than GF-HPC and formed XRPD-amorphous GF, whereas HPC-based ASDs, especially the ones with a lower HPC loading, had crystalline GF. The dissolution tests show that without SDS, ASDs provided limited GF supersaturation (max. 250%) due to poor wettability of Sol-based ASDs and extensive GF recrystallization in HPC-based ASDs (max. 50%). Sol-based ASDs with SDS exhibited a dramatic increase in supersaturation (max. 570%), especially at a higher Sol loading, whereas HPC-based ASDs with SDS did not. SDS did not interfere with Sol's ability to inhibit GF recrystallization, as confirmed by the precipitation from the supersaturated state and PLM imaging. The favorable use of SDS in a ternary ASD was attributed to both the wettability enhancement and its inability to promote GF recrystallization when used as a minor component along with Sol.

Hybrid nanocrystal-amorphous solid dispersions (HyNASDs) as alternative to ASDs for enhanced release of BCS Class II drugs.

A major shortcoming of drug nanocomposites as compared with amorphous solid dispersions (ASDs) is their limited supersaturation capability in dissolution media. Here, we prepared drug hybrid nanocrystal-amorphous solid dispersions (HyNASDs) and compare their performance to ASDs. A wet-milled griseofulvin (GF, BCS II drug) nanosuspension and a GF solution, both containing the same dissolved polymer-surfactant (SDS: sodium dodecyl sulfate) with 1:1 and 1:3 GF:polymer mass ratios, were spray-dried. Hydroxypropyl cellulose (HPC) and Soluplus (Sol) were used as matrix-forming polymers. XRPD, DSC, and Raman spectroscopy reveal that ASDs were formed upon spray-drying the solution-based feed, whereas nanocomposites and nanocomposites with >10% amorphous content, HyNASDs, were formed with the nanosuspension-based feed. Sol provided higher GF relative supersaturation, up to 180% and 360% for HyNASDs and ASDs, respectively, in the dissolution tests than HPC (up to 50% for both) owing to Sol's stronger intermolecular interactions and miscibility with GF and its recrystallization inhibition. Besides the higher kinetic solubility of GF in Sol, presence of GF nanoparticles vs. micron-sized particles in the nanocomposites enabled fast supersaturation. This study demonstrates successful preparation of fast supersaturating (190% within 20 min) HyNASDs, which renders nanoparticle formulations competitive to ASDs in bioavailability enhancement of poorly soluble drugs.

A predictive transport model for convective drying of polymer strip films loaded with a BCS Class II drug.

Drying is an important unit operation in the manufacturing of polymer strip films as it affects various film quality attributes. Optimal design and control of convective drying process require models that capture the impact of critical process parameters such as air temperature and velocity on the temporal evolution of film thickness and moisture. Here, a detailed transport model was presented to capture moisture diffusion, heat transfer and moving boundary in convective drying of polymer strip films loaded with griseofulvin (GF), a poorly water-soluble drug. It incorporates a solvent diffusivity model based on free-volume theory. Experimentally, film precursor suspensions were prepared by mixing silica-coated and micronized GF powder with an aqueous solution of hydroxypropyl methylcellulose (HPMC)-glycerin. Films were cast and moisture-time variation during drying was measured. The transport model, whose diffusivity parameters were estimated using drying data at a reference condition, was validated at different drying conditions and wet film thicknesses. It delineates underlying mechanisms of drying kinetics and demarcates a smooth transition from constant-rate to falling-rate period. Overall, our results suggest that the transport model is capable of predicting the temporal evolution of moisture and final film thickness at different drying air velocities and temperatures with reasonable accuracy.

Scale-up of pharmaceutical spray drying using scale-up rules: A review.

Spray drying is one of the widely used manufacturing processes in pharmaceutical industry. While there are voluminous experimental studies pertaining to the impact of various process-formulation parameters on the quality attributes of spray dried powders such as particle size, morphology, density, and crystallinity, there is scant information available in the literature regarding process scale-up. Here, we first analyze salient features of scale-up attempts in literature. Then, spray drying process is analyzed considering the fundamental physical transformations involved, i.e., atomization, drying, and gas-solid separation. Each transformation is scrutinized from a scale-up perspective with non-dimensional parameters & multi-scale analysis, and comprehensively discussed in engineering context. Successful scale-up entails similar key response variables from each transformation across various scales. These variables are identified as droplet size distribution, outlet temperature, relative humidity, separator pressure loss coefficient, and collection efficiency. Instead of trial-and-error-based approaches, this review paper advocates the use of mechanistic models and scale-up rules for establishing design spaces for the process variables involved in each transformation of spray drying. While presenting a roadmap for process development and scale-up, the paper demonstrates how to bridge the current gap in spray drying scale-up via a rational understanding of the fundamental transformations.