Comparative Analysis of Polystyrene versus Zirconia Beads on Breakage Kinetics, Heat Generation, and Amorphous Formation during Wet Bead Milling.

This study determined process conditions under which polystyrene (CPS) and zirconia (YSZ) beads cause similar breakage kinetics and temperature rise during manufacturing of drug nanosuspensions via wet bead milling and explored relative advantages of CPS beads, particularly for stress-sensitive compounds. Besides temperature and particle size measurements, a microhydrodynamic-based kinetic model simulated the conditions for CPS to achieve breakage rates equivalent to those of YSZ. A power law correlation was applied to find conditions conducive to temperature equivalency.

15th Anniversary of Pharmaceutics-Advances in Process and Formulation Modeling.

The modeling of processes and formulations significantly enhances product development in the pharmaceutical industry [...

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.

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.

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.

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.

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.

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.

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.

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.

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% (/) 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation⁻Processing Aspects and Challenges.

Drug nanoparticles embedded in a dispersant matrix as a secondary phase, i.e., drug-laden nanocomposites, offer a versatile delivery platform for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs.

A comparative assessment of nanocomposites vs. amorphous solid dispersions prepared via nanoextrusion for drug dissolution enhancement.

Nanoextrusion was used to produce extrudates of griseofulvin, a poorly water-soluble drug, with the objective of examining the impact of drug particle size and polymeric matrix type-size of the extrudates on drug dissolution enhancement. Hydroxypropyl cellulose (HPC) and Soluplus® were used to stabilize wet-milled drug suspensions and form matrices of the extrudates. The wet-milled suspensions along with additional polymer (HPC/Soluplus®) were fed to a co-rotating twin-screw extruder, which dried the suspensions and formed various extrudates.

A microhydrodynamic rationale for selection of bead size in preparation of drug nanosuspensions via wet stirred media milling.

Although wet stirred media milling has proven to be a robust process for producing nanoparticle suspensions of poorly water-soluble drugs and thereby enhancing their bioavailability, selection of bead size has been largely empirical, lacking fundamental rationale. This study aims to establish such rationale by investigating the impact of bead size at various stirrer speeds on the drug breakage kinetics via a microhydrodynamic model. To this end, stable suspensions of griseofulvin, a model BCS Class II drug, were prepared using hydroxypropyl cellulose and sodium dodecyl sulfate.