This study investigates the compatibility of excipients with the model system SDI-X and their role in the induced crystallization of the amorphous compound-X in tablet formulations. We aimed to establish a straightforward and practical screening approach for evaluating excipient-induced crystallization of SDI in tablet matrices. Three methodologies—binary powder mixture, binary compact, and bilayer tablets—were employed to qualitatively and quantitatively evaluate the recrystallization of SDI-X with various excipients under accelerated storage conditions. The results demonstrated that binary compacts, providing direct physical contact between SDI-X and excipients, are superior in reflecting realistic drug-excipient contact within pharmaceutical tablets, enabling a more accurate assessment of excipient-induced crystallization for SDI-X. In contrast, the broadly used conventional binary blends can significantly underestimate this risk due to insufficient proximity. In addition, the bilayer tablets further confirmed that crystallization initiates at the contact surface between SDI-X and the excipients. The study highlighted that not only hygroscopicity but also the type of excipient and its physical contact with SDI-X significantly influence the recrystallization extent and rate of SDI-X. Interestingly, less hygroscopic diluents such as mannitol and lactose induced much higher levels of crystallization of SDIs, contrary to expectations based on moisture content alone. This suggests that the excipient type and contact surface are more critical in inducing recrystallization than just the level of moisture. The findings emphasize the need for careful excipient selection, study design, and sample preparation to enable appropriate assessments of SDI-excipient compatibility.

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.

以衣康酸(IA)、天冬氨酸(ASP)和2-丙烯酰胺-2-甲基丙磺酸(AMPS)为单体,在过硫酸铵引发下采用水溶液自由基聚合方法制备了新型IA/ASP/AMPS三元共聚物阻垢剂,并利用红外光谱仪对其结构进行分析表征.通过正交实验和单因素实验考察单体摩尔配比、引发剂用量、反应温度及反应时间对共聚产物阻垢性能的影响,确定其最佳合成条件.实验结果表明:共聚单体的摩尔比nIA:nASP:nAMPS为3:1:0.5,引发剂用量占单体总质量的10％,反应温度为85℃,反应时间为4 h时,合成三元共聚物对碳酸钙、硫酸钙及磷酸钙的阻垢性能最好,阻垢率分别达91％、95％及96％以上;此共聚物的固含量和黏均相对分子质量分别为30.5％、1402.静态阻垢法评价温度对IA/ASP/AMPS共聚物阻垢性能的影响,结果表明,IA/ASP/AMPS共聚物适用于含碳酸钙、磷酸钙的高温循环冷却水体系.

Dissolution of poorly soluble drugs can be improved by wet-milling their suspensions and drying the suspensions to form nanocomposites. Different classes of dispersants and their concentration can affect both nanoparticle aggregation in the suspensions and drug dissolution from the nanocomposites. In this study, we examine the impact of various classes of dispersants on nanoparticle aggregation-dissolution of itraconazole (ITZ) from spray-dried wet-milled ITZ nanosuspensions. 2.5% hydroxypropyl cellulose (HPC), 0.2% sodium dodecyl sulfate (SDS), and their combination were used as baseline dispersant formulations. Mannitol and sucrose, as model water-soluble dispersants, were added to the wet-milled ITZ suspensions with HPC. As swellable dispersants, superdisintegrants such as sodium starch glycolate (SSG), crospovidone (CP), and croscarmellose sodium (CCS) were wet-co-milled with ITZ-HPC. The wet-milled suspensions were spray-dried to prepare nanocomposites. Laser diffraction results show that wet milling with HPC-SDS and HPC with concentration at/above 4.5% led to a median drug size below similar to 0.20 mu m due to electrosteric and steric stabilizing effects, respectively. Their nanocomposites led to immediate, fast ITZ release: >%80 dissolved in 20 min. Unlike these suspensions, other suspensions with mannitol, sucrose, and superdisintegrants along with HPC exhibited more aggregation and pseudoplasticity. Nonetheless, the addition of these dispersants resulted in faster drug release especially at higher concentrations, as quantified by the higher value of the product kn of the Korsmeyer-Peppas model, due to faster erosion/disintegration of the nanocomposite matrix. Wet co-milled superdisintegrants achieved faster drug release than mannitol and sucrose. Their dissolution impact was positively correlated with their swelling capacity (SSG > CCS > CP), which signifies a swelling-induced erosion/disintegration mechanism. Surfactant-free nanocomposites with >60% drug loading that exhibited immediate drug release were prepared with either HPC-co-milled SSG/CCS or HPC with optimal concentration. (C) 2018 Elsevier B.V. All rights reserved.

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 (R) were used to stabilize wet-milled drug suspensions and form matrices of the extrudates. The wet-milled suspensions along with additional polymer (HPC/Soluplus (R)) were fed, to a co-rotating twin-screw extruder, which dried the suspensions and formed various extrudates. The extrudates were dry-milled and sieved into samples with two different sizes. A wet-milled suspension was also spray-dried in comparison to nanoextrusion. Due to differences in polymer-drug miscibility, two forms of the drug were prepared: extrudates with nano/micro-crystalline drug particles dispersed in the HPC matrix as a secondary phase (nano/microcomposites) and extrudates with amorphous drug molecularly dispersed within the Soluplus matrix (amorphous solid dispersion, ASD). Under non-supersaturating conditions in the dissolution medium, drug nanocrystals in the HPC-based nanocomposites dissolved faster than the amorphous drug in Soluplus (R)-based ASD. While smaller extrudate particles led to faster drug release for the ASD, such matrix size effect was weaker for the nanocomposites. These findings suggest that nanocrystal-based formulations could outperform ASDs for fast dissolution of low-dose drugs. (C) 2017 Elsevier B.V. All rights reserved.

Polymer strip films have emerged as a robust platform for poorly water-soluble drug delivery. However, the common conception is that films cannot exceed low drug loadings, mainly due to poor drug stability, slow release, and film brittleness. This study explores the ability to achieve high loadings of poorly water-soluble drug nanoparticles in strip films while retaining good mechanical properties and enhanced dissolution rate. Aqueous suspensions containing up to 30 wt% griseofulvin nanoparticles were prepared via wet stirred media milling and incorporated into hydroxypropyl methylcellulose (HPMC) films. Griseofulvin loading in films was adjusted to be between 9 and 49 wt% in HPMC-E15 films and 30 and 73 wt% in HPMC-E4M films by varying the mixing ratio of HPMC solution-to-griseofulvin suspension. All films exhibited good content uniformity and nanoparticle redispersibility up to 50 wt% griseofulvin, while E4M films above 50 wt% griseofulvin had slightly worse content uniformity and poor nanoparticle redispersibility. Increasing drug loading in films generally required more time to achieve 100% release during dissolution, although polymer–drug clusters dispersed from E4M films above 50 wt% griseofulvin, resulting in similar dissolution profiles. While all films exhibited good tensile strength, a significant decrease in percent elongation was observed above 40–50 wt% GF, resulting in brittle films.

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. The suspensions were milled at four different stirrer speeds (1000-4000rpm) using various sizes (50-1500μm) of zirconia beads. Laser diffraction, SEM, and XRPD were used for characterization. Our results suggest that there is an optimal bead size that achieves fastest breakage at each stirrer speed and that it shifts to a smaller size at higher speed. Calculated microhydrodynamic parameters reveal two counteracting effects of bead size: more bead-bead collisions with less energy/force upon a decrease in bead size. The optimal bead size exhibits a negative power-law correlation with either specific energy consumption or the microhydrodynamic parameters. Overall, this study rationalizes the use of smaller beads for more energetic wet media milling.

The aims of this study are to develop polymeric films loaded with nanoparticles of fenofibrate (FNB), a poorly water-soluble drug, prepared via melt emulsification (ME) and study the short-term physical stability of the ME-based suspensions, with the ultimate goal of enhancing FNB dissolution. FNB particles in water were heated above the melting point to form an oil-in-water emulsion, whose cooling turned FNB droplets into solidified FNB nanoparticles. The resulting FNB suspensions, along with a suspension of as-received FNB, were mixed with hydroxypropyl methylcellulose (HPMC)–glycerin solution to prepare film precursor suspensions, which were then casted and dried into films. The effects of the presence of Pluronic F68 (PF68) as stabilizer and the sonication during the cooling step on the physical stability of the suspensions were investigated. For films, drug content, redispersibility, and drug release in a USP IV dissolution test were studied. The results show that cooling the FNB–PF68 emulsion in the presence of sonication produced suspensions with acceptable 7-day physical stability, whereas cooling the same without sonication led to severe particle aggregation within 20 min. The film redispersion in water led to effective recovery of FNB nanoparticles only when PF68 and sonication during the cooling step were used. Good drug content uniformity and enhanced FNB dissolution were obtained from the films containing FNB nanoparticles stabilized with PF68, but the impact of sonication on the FNB dissolution was not discernible. Overall, feasibility of films carrying ME-based drug nanoparticles for enhanced dissolution has been demonstrated.

Without a proper stabilizer formulation, drug nanoparticles can aggregate during the formation of nanosuspensions and their drying into composite powders, which in turn can cause inadequate bioavailability enhancement from nanoparticles and ensuing lack of therapeutic efficacy. In this study, formulations with various polymer concentrations-molecular weights in the presence/absence of a surfactant were explored to assess their impact on redispersibility and drug dissolution from the composites. Suspensions of griseofulvin (GF), a poorly water-soluble drug, were prepared by wet stirred media milling and subsequently dried via fluidized bed drying-coating onto Pharmatose (R) carrier particles. Hydroxypropyl cellulose (HPC), with various molecular weights, sodium dodecyl sulfate (SDS), and their combinations were used as stabilizers during the milling. The dried composites were redispersed in water and SDS solution to recover the GF nanoparticles. Particle sizing via laser diffraction, SEM imaging, and dissolution testing were performed to investigate the redispersion and dissolution performance. Results show that good physical stability of the milled suspension is necessary, but not sufficient to guarantee fast redispersion-drug dissolution. For best performance, presence of SDS is critical; a minimum concentration of the polymer, as a film former, is also required to prevent the formation of hard aggregates during drying. (C) 2016 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.

Recent work established polymer strip films as a robust platform for delivery of poorly water-soluble drug particles. However, a simple means of manipulating rate of drug release from films with minimal impact on film mechanical properties has yet to be demonstrated. This study explores the impact of film-forming polymer molecular weight (MW) and concentration on properties of polymer films loaded with poorly water-soluble drug nanoparticles. Nanoparticles of griseofulvin, a model Biopharmaceutics Classification System class II drug, were prepared in aqueous suspension via wet stirred media milling. Aqueous solutions of 3 viscosity grades of hydroxypropyl methylcellulose (14, 21, and 88 kDa) at 3 viscosity levels (∼9500, ∼12,000, and ∼22,000 cP) were mixed with drug suspension, cast, and dried to produce films containing griseofulvin nanoparticles. Few differences in film tensile strength or elongation at break were observed between films within each viscosity level regardless of polymer MW despite requiring up to double the time to achieve 100% drug release. This suggests film-forming polymer MW can be used to manipulate drug release with little impact on film mechanical properties by matching polymer solution viscosity. In addition, changing polymer MW and concentration had no negative impact on drug content uniformity or nanoparticle redispersibility.

As a drug-sparing approach in early development, vibratory milling has been used for the preparation of nanosuspensions of poorly water-soluble drugs. The aim of this study was to intensify this process through a systematic increase in vibration intensity and bead loading with the optimal bead size for faster production. Griseofulvin, a poorly water-soluble drug, was wet-milled using yttrium-stabilized zirconia beads with sizes ranging from 50 to 1500 μm at low power density (0.87 W/g). Then, this process was intensified with the optimal bead size by sequentially increasing vibration intensity and bead loading. Additional experiments with several bead sizes were performed at high power density (16 W/g), and the results were compared to those from wet stirred media milling. Laser diffraction, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and dissolution tests were used for characterization. Results for the low power density indicated 800 μm as the optimal bead size which led to a median size of 545 nm with more than 10% of the drug particles greater than 1.8 μm albeit the fastest breakage. An increase in either vibration intensity or bead loading resulted in faster breakage. The most intensified process led to 90% of the particles being smaller than 300 nm. At the high power intensity, 400 μm beads were optimal, which enhanced griseofulvin dissolution significantly and signified the importance of bead size in view of the power density. Only the optimally intensified vibratory milling led to a comparable nanosuspension to that prepared by the stirred media milling.

Preparation of drug nanoparticles via wet media milling (nanomilling) is a very versatile drug delivery platform and is suitable for oral, injectable, inhalable, and buccal applications. Wet media milling followed by various drying processes has become a well-established and proven formulation approach especially for bioavailability enhancement of poorly water-soluble drugs. It has several advantages such as organic solvent-free processing, tunable and relatively high drug loading, and applicability to a multitude of poorly water-soluble drugs. Although the physical stability of the wet-milled suspensions (nanosuspensions) has attracted a lot of attention, fundamental understanding of the process has been lacking until recently. The objective of this review paper is to present fundamental insights from available published literature while summarizing the recent advances and highlighting the gap areas that have not received adequate attention. First, stabilization by conventionally used polymers/surfactants and novel stabilizers is reviewed. Then, a fundamental understanding of the process parameters, with a focus on wet stirred media milling, is revealed based on microhydrodynamic models. This review is expected to bring a holistic formulation-process perspective to the nanomilling process and pave the way for robust process development scale-up. Finally, challenges are indicated with a view to shedding light on future opportunities.

The aim of this study is to assess pullulan as a novel steric stabilizer during the wet-stirred media milling (WSMM) of griseofulvin, a model poorly water-soluble drug, and as a film-former in the preparation of strip films via casting-drying the wet-milled drug suspensions for dissolution and bioavailability enhancement. To this end, pullulan films, with xanthan gum (XG) as thickening agent and glycerin as plasticizer, were loaded with griseofulvin nanoparticles prepared by WSMM using pullulan in combination with sodium dodecyl sulfate (SDS) as an ionic stabilizer. The effects of drug loading and milling time on the particle size and suspension stability were investigated, as well as XG concentration and casting thickness on film properties and dissolution rate. The nanosuspensions prepared with pullulan-SDS combination were relatively stable over 7 days; hence, this combination was used for the film preparation. All pullulan-based strip films exhibited excellent content uniformity (most <3% RSD) despite containing only 0.3-1.3 mg drug, which was ensured by the use of precursor suspensions with >5000 cP viscosity. USP IV dissolution tests revealed fast/immediate drug release (t80 < 30 min) from films <120 μm thick. Thinner films, films with lower XG loading, or smaller drug particles led to faster drug dissolution, while drug loading had no discernible effect. Overall, these results suggest that pullulan may serve as an acceptable stabilizer for media milling in combination with surfactant as well as a fast-dissolving film former for the fast release of poorly water-soluble drug nanoparticles.

Ensuring the physical stability of drug nanosuspensions prepared via wet media milling has been a challenge for pharmaceutical scientists. The aim of this study is to assess the combined use of non-ionic cellulosic polymers and anionic surfactants in stabilizing multiple drug nanosuspensions. Particle size of five drugs, i.e. azodicarbonamide (AZD), fenofibrate (FNB), griseofulvin (GF), ibuprofen (IBU) and phenylbutazone (PB) was reduced separately in an aqueous solution of hydroxypropyl cellulose (HPC) with/without sodium dodecyl sulfate (SDS) via a stirred media mill. Laser diffraction, scanning electron microscopy, thermal analysis, rheometry and electrophoresis were used to evaluate the breakage kinetics, storage stability, electrostatic repulsion and stabilizer adsorption. Without SDS, drug particles exhibited aggregation to different extents; FNB and GF particles aggregated the most due to low zeta potential and insufficient steric stabilization. Although aggregation in all milled suspensions was reduced due to HPC-SDS combination, FNB and IBU showed notable growth during 7-day storage. It is concluded that the combination of non-ionic cellulosic polymers and anionic surfactants is generally viable for ensuring the physical stability of wet-milled drug nanosuspensions, provided that the surfactant concentration is optimized to mitigate the Ostwald ripening, whereas cellulosic polymers alone may provide stability for some drug suspensions.

The robustness of the polymer strip film platform to successfully deliver a variety of BCS Class II drug nanoparticles without the need for surfactant while retaining positive characteristics such as nanoparticle redispersibility and fast dissolution is demonstrated. Fenofibrate (FNB), griseofulvin (GF), naproxen (NPX), phenylbutazone (PB), and azodicarbonamide (AZD) were considered as model poorly water-soluble drugs. Their aqueous nanosuspensions, produced via wet stirred media milling, were mixed with hydroxypropyl methylcellulose solution containing glycerin as plasticizer, followed by casting and drying to form films. For the purpose of comparison, sodium dodecyl sulfate (SDS) was used as surfactant, but was found to be unnecessary for achieving fast dissolution (t80 between 18 and 28 min) for all five drugs. Interestingly, SDS was required for the full recovery of nanoparticles for PB, yet lack of it did not impact the dissolution. Interactions between drug and polymer were investigated with FTIR spectroscopy whereas drug crystallinity within the film was investigated via Raman spectroscopy. Films for all drugs, even for very small samples, exhibited excellent content uniformity (RSD <4%) regardless of use of surfactant. Overall, these results demonstrate the novelty and robustness of the polymer strip film platform for fast release of poorly water-soluble drugs without requiring any surfactants.

There is sustained interest in sub-100 nm particles of poorly water-soluble drugs as such small particles offer improved permeation through various biological barriers and result in rapid onset of therapeutic action. An intensified wet stirred media milling process was developed here for fast production of sub-100 nm drug particles with low bead contamination and reduced energy consumption. Griseofulvin and indomethacin, two model poorly water-soluble drugs, were wet-milled. Yttrium-stabilized zirconia beads with a nominal size ranging from 50 µm to 800 µm were used in the baseline process, which was subsequently intensified with the optimal bead size by increasing rotor tip speed, bead loading, and suspension flow rate stepwise, as guided by a microhydrodynamic model. Laser diffraction, dynamic light scattering, scanning electron microscopy, and XRD were used to characterize the milled suspensions. Results from the baseline process indicated that sub-100 nm griseofulvin particles were only produced when 50 or 100 µm beads were used in the 360 min milling experiments. Interestingly, using 50 µm beads led to the formation of sub-100 nm griseofulvin particles within 240 min with the lowest bead (zirconium) contamination and specific energy consumption. This could be explained though the microhydrodynamic model, revealing that 50 µm beads led to the highest frequency of drug particle compressions yet generated the lowest bead contact pressure. The processing time was further reduced to as low as 64 min producing griseofulvin particle size of 100 nm through step-wise intensification of the milling process with the 50 µm beads, as quantified by a milling intensity factor. Due to the enhancement of the breakage kinetics, the process intensification enabled shorter milling to attain 100 nm particles, thus resulting in significant energy savings and low bead contamination despite an increase in power consumption. The general applicability of the process intensification method was confirmed through milling of indomethacin, which also led to sub-100 nm particles faster with reduced energy consumption and low contamination.

The dissolution rate of the active pharmaceutical ingredients in pharmaceutical hot-melt extrusion is the most critical elementary step during the extrusion of amorphous solid solutions - total dissolution has to be achieved within the short residence time in the extruder. Dissolution and dissolution rates are affected by process, material and equipment variables. In this work, we examine the effect of one of the material variables and one of the equipment variables, namely, the API particle size and extruder screw configuration on the API dissolution rate, in a co-rotating, twin-screw extruder. By rapidly removing the extruder screws from the barrel after achieving a steady state, we collected samples along the length of the extruder screws that were characterized by polarized optical microscopy (POM) and differential scanning calorimetry (DSC) to determine the amount of undissolved API. Analyses of samples indicate that reduction of particle size of the API and appropriate selection of screw design can markedly improve the dissolution rate of the API during extrusion. In addition, angle of repose measurements and light microscopy images show that the reduction of particle size of the API can improve the flowability of the physical mixture feed and the adhesiveness between its components, respectively, through dry coating of the polymer particles by the API particles. (C) 2014 Elsevier B.V. All rights reserved.