Enhanced recovery and dissolution of griseofulvin nanoparticles from surfactant-free nanocomposite microparticles incorporating wet-milled swellable dispersants

Nanocomposite microparticles (NCMPs) incorporating drug nanoparticles and wet-milled swellable dispersant particles were investigated as a surfactant-free drug delivery vehicle with the goal of enhancing the nanoparticle recovery and dissolution rate of poorly water-soluble drugs. Superdisintegrants were used as inexpensive, model, swellable dispersant particles by incorporating them into NCMP structure with or without wet-stirred media milling along with the drug. Suspensions of griseofulvin (GF, model drug) along with various dispersants produced by wet-milling were coated onto Pharmatose® to prepare NCMPs in a fluidized bed process. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as base-line stabilizer/dispersant during milling. Croscarmellose sodium (CCS, superdisintegrant) and Mannitol were used as additional dispersants to prepare surfactant-free NCMPs. Nanoparticle recovery during redispersion and dissolution of the various GF-laden NCMPs were examined. Suspensions prepared by co-milling GF/HPC/CCS or milling GF/HPC/SDS were stable after 30 h of storage. After drying, due to its extensive swelling capacity, incorporation of wet-milled CCS in the NCMPs caused effective breakage of the NCMP structure and bursting of nanoparticle clusters, ultimately leading to fast recovery of the GF nanoparticles. Optimized wet co-milling and incorporation of CCS in NCMP structure led to superior dispersant performance over incorporation of unmilled CCS or physically mixed unmilled CCS with NCMPs. The enhanced redispersion correlated well with the fast GF dissolution from the NCMPs containing either CCS particles or SDS. Overall, swellable dispersant (CCS) particles, preferably in multimodal size distribution, enable a surfactant-free formulation for fast recovery/dissolution of the GF nanoparticles.     

Preparation and characterization of spray-dried submicron particles for pharmaceutical application

The versatile use of submicron-sized particles (0.1–1?μm) requires new manufacturing methods. One possibility for the preparation of submicron-sized particles is spray drying. However, the generation of small droplets at a high production rate and the precipitation of submicron particles are quite challenging. In order to produce a sufficient amount of fine and uniform droplets, a two-fluid nozzle with internal mixing was combined with a cyclone droplet separator. The precipitation of particles was realized with an electrostatic precipitator. Considering the difficulty of electrostatic precipitation concerning explosion risks and to make it capable using organic solvents, the spray dryer was integrated in a pressure resistant vessel. Based on previous experiments, the now presented design is compact and the electrostatic precipitator is shortened. In addition, enhanced drying conditions ensured a controlled and reproducible preparation of submicron-sized particles. Thus, high separation efficiencies were shown. Spray-drying experiments were conducted with the model substance mannitol. With the cyclone droplet separator, a fine and uniform spray with a droplet size smaller 2?μm was produced. This robust atomizing technique is capable for high concentrations. For a 10?wt% mannitol solution, particles in the submicron range d_50,3?=?0.7?μm were produced.     

Dissolution rate enhancement of the poorly water-soluble drug Tibolone using PVP,SiO2, and their nanocomposites as appropriate drug carriers

Background: Creation of immediate release formulations for the poorly water-soluble drug Tibolone through the use of solid dispersions (SDs). Aim: SD systems of Tibolone (Tibo) with poly(vinylpyrrolidone) (PVP), fumed SiO₂ nanoparticles, and their corresponding ternary systems (PVP/SiO₂/Tibo) were prepared and studied in order to produce formulations with enhanced drug dissolution rates. Method: The prepared SDs were characterized by the use of differential scanning calorimetry and wide-angle X-ray diffractometry techniques. Also dissolution experiments were performed. Results: From the results it was concluded that PVP as well as SiO₂ can be used as appropriate carriers for the amorphization of Tibo, even when the drug is used at high concentrations (20–30%, w/w). This is due to the evolved interactions taking place between the drug and the used carriers, as was verified by Fourier transform infrared spectroscopy. At higher concentrations the drug was recrystallized. Similar are the observations on the ternary PVP/SiO₂/Tibo SDs. The dissolution profiles of the drug in PVP/Tibo and SiO₂/Tibo SDs are directly dependent on the physical state of the drug. Immediately release rates are observed in SD with low drug concentrations, in which Tibo was in amorphous state. However, these release profiles are drastically changed in the ternary PVP/SiO₂/Tibo SDs. An immediate release profile is observed for low drug concentrations and an almost sustained release as the concentration of Tibo increases. This is due to the weak interactions that take place between PVP and SiO₂, which result in alterations of the characteristics of the carrier (PVP/SiO₂ nanocomposites). Conclusions: Immediate release formulation was created for Tibolone as well as new nanocomposite matrices of PVP/SiO₂, which drastically change the release profile of the drug to a sustained delivery.     

Spray drying of drug-swellable dispersant suspensions for preparation of fast-dissolving,high drug-loaded,surfactant-free nanocomposites

Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and slow dissolution. The aim of this study is to investigate the impact of various classes of dispersants on drug dissolution from drug NCMPs, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free NCMPs. Precursor suspensions of griseofulvin (GF, model drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the NCMPs. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. Laser diffraction, scanning electron microscopy, powder X-ray diffraction (XRD), UV spectroscopy, NCMP redispersion and dissolution tests were used for characterization. The results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the spray-dried NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS, demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites.     

Effect of matrix composition on the flowability of spray-dried detergent powders

The flowability of spray-dried laundry detergent is important for manufacturing process performance and reliability, and product quality; it is strongly dependent on formulation. In this work, a detailed study of four model formulations provides fundamental understanding of the role of particle composition, and micro-structure, on spray-dried detergent powder flow behaviour. All spray-dried powders studied contained the sodium salt of linear alkylbenzene sulphonate (NaLAS) and sodium sulphate. However, their formulation varied depending on either the initial water content (30.0 or 63.0 wt%) of the slurry or the addition of sodium silicate with molar-ratios of 1.6 and 2.35 SiO₂:Na₂O. The nil-silicate powder, made from low water content slurry, had the poorest flow characteristics. The addition of the silicate binder, significantly improved flowability, 2.35 ratio silicate, providing better flowability than 1.6 ratio. Remarkably, increasing the water content of the slurry also improved flowability significantly. Detail analysis showed that this was due to changes in composition and micro-structure of the composite matrix formed on drying the liquid components of the slurry, and that the improved flowability was due to improvements in mechanical strength of this matrix. These changes in mechanical robustness were significantly more important to the flowability than the powder shape.     

Controlled synthesis of porous particles via aerosol processing and their applications

Aerosol processes such as spray drying and/or spray pyrolysis for the controlled synthesis of porous particles were introduced in this review. Typical experimental setup, general experimental procedure for the preparation of porous particles, as well as key factors affecting the properties of final porous particles, was described. We then discussed the various routes for the controlled synthesis of porous particles: (1) the preparation of self-assembled porous particles with ordered pores by using organic template particles; (2) the preparation of pore size- and porosity-controlled particles from aggregated nanoparticles; (3) the preparation of nanoparticle-laden encapsulated porous particles from graphene nano-sheets and nanoparticles. Finally, we introduced interesting applications of the porous particles such as photocatalysts, drug delivery carriers, and biosensors.     

Selection of excipient,solvent and packaging to optimize the performance of spray-dried formulations: case example fenofibrate

Context: Along with other options, solid dispersions prepared by spray drying offer the possibility of formulating poorly soluble drugs in a rapidly dissolving format. As a wide range of potential excipients and solvents is available for spray drying, it is usually necessary to carry out a comprehensive array of studies to arrive at an optimal formulation.

Objective: To study the influence of formulation parameters such as co-sprayed excipients, solvents and packaging on the manufacture, in vitro performance and stability of spray-dried oral drug products using fenofibrate as a model drug.

Materials and methods: Solid dispersions of fenofibrate with different amorphous polymers were manufactured from two solvent systems by spray drying. These were characterized in terms of physicochemical properties, crystalline content and dissolution behavior in biorelevant media upon production and after storage in two packaging systems (Glass and Activ-Vials^?).

Results and discussion: Spray drying the same formulation from two different solvents led to different physicochemical properties, dissolution behavior and long-term stability. The dissolution behavior and long-term stability also varied significantly among excipients. The viscosity of the polymer and the packaging material proved to be important to the long-term stability.

Conclusion: For spray-dried products containing fenofibrate, the excipients were ranked according to dissolution and stability performance as follows: PVP derivatives >> HPMC 2910/15, HPMCAS-MF, HP-β-CD >> PVP:PVA 2:8. EtOH 96% proved superior to acetone/water for spray drying with polymers. The results were used to propose a general approach to developing spray-dried formulations of poorly soluble drugs.     

Accelerated ketoprofen release from spray-dried polymeric particles: importance of phase transitions and excipient distribution

HPMC-, PVPVA- and PVP-based microparticles loaded with 30% ketoprofen were prepared by spray drying suspensions or solutions in various water:ethanol blends. The inlet temperature, drying gas and feed flow rates were varied. The resulting differences in the ketoprofen release rates in 0.1?M HCl could be explained based on X-ray diffraction, mDSC, SEM and particle size analysis. Importantly, long term stable drug release could be provided, being much faster than: (i) drug release from a commercial reference product, (ii) the respective physical drug:polymer mixtures, as well as (iii) the dissolution of ketoprofen powder as received. In addition, highly supersaturated release media were obtained, which did not show any sign for re-crystallization during the observation period. Surprisingly, spraying suspensions resulted in larger microparticles exhibiting faster drug release compared to spraying solutions, which resulted in smaller particles exhibiting slower drug release. These effects could be explained based on the physico-chemical characteristics of the systems.     

Nanoparticle engineering processes for enhancing the dissolution rates of poorly water soluble drugs

Poor water solubility is an industry wide issue, especially for pharmaceutical scientists in drug discovery and drug development. In recent years, nanoparticle engineering processes have become promising approaches for the enhancement of dissolution rates of poorly water soluble drugs. Nanoparticle engineering enables manufacturing of poorly water soluble drugs into nanoparticles alone, or incorporation with a combination of pharmaceutical excipients. The use of these processes has dramatically improved in vitro dissolution rates and in vivo bioavailabilities of many poorly water soluble drugs. This review highlights several commercially or potentially commercially available nanoparticle engineering processes recently reported in the literature for increasing the dissolution properties of poorly water soluble drugs.     

Continuous production of drug nanoparticle suspensions via wet stirred media milling: a fresh look at the Rehbinder effect

Nanoparticles of BCS Class II drugs are produced in wet stirred media mills operating in batch or recirculation mode with the goal of resolving the poor water-solubility issue. Scant information is available regarding the continuous production of drug nanoparticles via wet media milling. Griseofulvin and Naproxen were milled in both recirculation mode and multi-pass continuous mode to study the breakage dynamics and to determine the effects of suspension flow rate. The evolution of the median particle size was measured and described by an empirical breakage model. We found that these two operation modes could produce drug nanosuspensions with similar particle size distributions (PSDs). A reduced suspension flow rate slowed the breakage rate and led to a wider PSD and more differentiation between the two operation modes. The latter part of this study focused on the roles of stabilizers (hydroxypropyl cellulose and sodium lauryl sulfate) and elucidation of the so-called Rehbinder effect (reduction in particle strength due to adsorbed stabilizers such as polymers and surfactants). Milling the drugs in the absence of the stabilizers produced primary nanoparticles and their aggregates, while milling with the stabilizers produced smaller primary nanoparticles with minimal aggregation. Using laser diffraction, BET nitrogen adsorption, scanning electron microscopy imaging, and a microhydrodynamic analysis of milling, this study, for the first time, provides sufficient evidence for the existence of the Rehbinder effect during the milling of drugs. Not only do the polymers and surfactants allow proper stabilization of the nanoparticles in the suspensions, but they also do facilitate drug particle breakage.     

Preparation and characterization of fast dissolving pullulan films containing BCS class II drug nanoparticles for bioavailability enhancement

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?相似文献   

The effect of selected water-soluble excipients on the dissolution of paracetamol and Ibuprofen

The purpose of this investigation was to study the dissolution behavior of paracetamol and ibuprofen in the presence of a range of selected potential excipients. First, a pH-solubility profile was generated for both drugs, and the effect of changing hydrodynamic conditions on the intrinsic dissolution rate was investigated. It was established that both drugs dissolved according to the diffusion-layer model. Paracetamol solubility (approximately 20.3 mg mL^- 1) did not vary from pH 1.2-8.0, corresponding to the in vivo range in the gastrointestinal tract. Ibuprofen had an intrinsic solubility of approximately 0.06 mg mL^- 1, and pK_a was calculated as 4.4. Second, the effects of selected potential excipients (lactose, potassium bicarbonate, sodium bicarbonate, sodium chloride, and tartaric acid) were evaluated by measuring the effect of the inclusion of each additive in the dissolution medium on drug solubility, drug intrinsic dissolution rate, and solution viscosity. The results were evaluated using the diffusion-layer model, and it was determined that for paracetamol, the collected data fitted the model for all the excipients studied. For ibuprofen, it was found that there were differences between the excipients that raised the solution pH above the pK_a to those that did not. For the excipients raising the pH above the pK_a, the effect on intrinsic dissolution rate was not as high as that expected from the change in drug solubility. It was postulated that this might be due to lack of penetration of the excipient into the drug boundary layer microenvironment. Formulators may calculate the effect of adding an excipient based on solubility increases but may not find the dissolution rate improvement expected.     

Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water-soluble drugs

Micronization and nanoparticle production of poorly water-soluble drugs was investigated using single wet milling equipment operating in the attritor and stirred media modes. The drug particles in the median size range of 0.2–2?µm were prepared by changing the milling mode and operating conditions of a Micros mill with a purpose of elucidating the dynamics of the wet milling process. It was determined that particle breakage due to mechanical stresses and aggregation due to insufficient stabilization are two competing mechanisms which together control the wet milling dynamics of the poorly water-soluble drugs. The study in the attritor mode using four different classes of stabilizers with six drugs indicated that steric stabilization worked better than electrostatic stabilization for the drugs studied. In addition, the existence of different minimum polymer concentrations for the stabilization of microsuspensions and nanosuspensions was indicated. The major role of a non-ionic polymer during the production of fine particles is its stabilization action through steric effects, and no experimental evidence was found to support the so-called Rehbinder effect. Periodic addition of the polymer as opposed to the addition of the polymer at the start of milling process was introduced as a novel processing method. This novel method of polymer addition provided effective stabilization and breakage of drug particles leading to a narrower and finer particle size distribution. Alternatively, it may allow shorter processing time and lower overall power consumption of the milling process for a desired particle size.     

Effect of annealing on the morphology and properties of ZnS:Mn nanoparticles/PVP nanofibers

As one kind of new optoelectronic materials, ZnS:Mn nanoparticles/PVP composite nanofibers are prepared by the electrospinning technique successfully. SEM, XRD, FT-IR spectroscopy, photoluminescence and TEM measurements are employed in the study. By the method of annealing, the effect on the morphology and properties of the composite nanofibers is studied. After annealing treatment, the separating state of the nanofibers is improved obviously, ZnS:Mn nanoparticles are well dispersed in the nanofiber, the PL peak originated from ⁴T₁→⁶A₁ transition of Mn ions shifts from 605 nm to 599 nm. The existence of orange emission peaks confirms that ZnS:Mn nanoparticles are formed in the fibers.     

浅析气源干燥处理的方法及应用

本文介绍了压缩空气干燥装置类型和特点，并在探论其应用的基础上，重点介绍了某特定容器产品的所用无热再生式压缩空气干部处理装置的应用背景、工作原理和设计特点。     

A quality-by-design study to develop Nifedipine nanosuspension: examining the relative impact of formulation variables,wet media milling process parameters and excipient variability on drug product quality attributes

Abstract

Wet milling is a multifunctional and the most common method to prepare a drug nanosuspension for improving the bioavailability of poorly water soluble drugs. A suitable way of preparing a high drug-loaded nifedipine nanosuspension using wet stirred media milling was investigated in the present study. Nifedipine, a poorly water soluble drug, was selected as a model drug to enhance its dissolution rate and oral bioavailability by preparing an appropriate crystalline nanosuspension. Process parameters, such as milling media volume, milling speed and milling time, were optimized using the one variable at a time (OVAT) approach. A similar method was used to select an appropriate polymeric stabilizer and a surfactant from different categories of polymeric stabilizers (HPC SL, HPC SSL Soluplus®, Kollidon^® VA 64 and HPMC E 15) and surfactants (Poloxamer 407, Kolliphor TPGS and Docusate sodium). A systematic optimization of critical formulation parameters (such as drug concentration, polymer concentration and surfactant concentration) was performed with the aid of the Box-Behnken design. Mean particle size, polydispersity index and zeta potential as critical quality attributes (CQAs) were selected in the design for the evaluation and optimization of the formulation and validation of the improved product. The nifedipine nanosuspension that was prepared using HPC and poloxamer 407 was found to be most stable with the lowest mean particle size as compared with the formulations prepared using other polymeric stabilizers and surfactants. The optimized formulation was further spray-dried and characterized using the Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), polarized light microscopy (PLM) and in-vitro dissolution study. Results have shown no interaction between the drug particles and stabilizers, nor a reduction in the crystallinity of drug, nor an increase in the saturation solubility and rapid in vitro dissolution as compared with pure nifedipine crystals. Thus, the current study supports the suitability of the wet stirred media milling method and a combination of HPC SSL and poloxamer 407 as stabilizers for the preparation of nifedipine nanosuspension.     

Stabilizing effect of the cyclodextrins additive to spray-dried particles of curcumin/polyvinylpyrrolidone on the supersaturated state of curcumin

Although curcumin is considered to have various therapeutic effects, its use as a functional food or supplement is restricted owing to its low water solubility and bioavailability. To increase the solubility of curcumin in water, the use of polyvinylpyrrolidone (PVP) and vinylpyrrolidone-vinyl acetate copolymers with a pyrrolidone skeleton was noted to be promising. In particular, the bi-component formulations of curcumin/PVP prepared through spray drying exhibited an amorphous state in powder X-ray diffraction observations and temporally increased the apparent solubility of curcumin to over 5000 times that of untreated curcumin; nevertheless, after 24 h, the solubility decreased owing to the unstable supersaturated state of curcumin. The addition of α-cyclodextrin (α-CyD) in the bi-component curcumin/PVP formulation helped maintain the supersaturated state of curcumin, whereas the addition of β- and γ-CyD led to the collapse of the supersaturated state. The addition of α-CyD can likely help inhibit the nucleation and crystal growth of curcumin, through the interaction among the solubilized units of curcumin/PVP and α-CyD.     

Effect of polymers and media type on extending the dissolution of amorphous pioglitazone and inhibiting the recrystallization from a supersaturated state

Amorphous forms of crystalline drug are widely utilized for bioavailability enhancement of low solubility drugs in the pharmaceutical industry. Polymers have been found to be effective crystallization inhibitors for amorphous forms in solid states during storage or in liquid states during dissolution process. The dissolution and crystallization behaviors of these amorphous forms in the presence or absence of polymers are still far from adequately understood especially in different dissolution environments. The objective of this study was to investigate the effects of polymers and media type on extending the dissolution of amorphous pioglitazone and inhibiting the recrystallization from a supersaturated state. Polyvinylpyrrolidone K30 (PVPK30), polyvinylpyrrolidone K90 (PVPK90), polyethylene glycol 6000 (PEG6000), polyethylene-polypropylene glycol 188 (F-68), hydroxypropylmethylcellulose (HPMC) and beta-cyclodextrin (β-CD) were employed to understand these behaviors changes because these polymers were used widely. Three solutions including neutral water and phosphate buffer solutions (PBS, pH6.8 and pH7.4) were adopted as dissolution media to determine the behaviors changes comprehensively. In the presence of polymers, dissolution and solubility were extended to different degrees in three media. Polymers can delay the crystallization routes dependently of the medium type. Buffer salts in media reduced the dissolution and accelerated the crystallization process. Crystallization inhibition of these polymers was strongly dependent on the type and pH of media. HPMC displayed the strongest crystallization inhibition effects, resulting in the greatest degree of maintaining a supersaturated state that can sustain most effectively for biologically relevant timeframes.     

The influence of organic additives on the morphologic and crystalline properties of SnO2 obtained by spray pyrolysis deposition

The paper presents a comparative analysis of the SnO₂ thin layers, obtained via spray pyrolysis deposition (SPD), using polymeric precursors with different compositions and concentrations. The changes in the crystalline structure (X-ray diffraction), morphology and surface energy (atomic force microscopy and contact angle) and electric (electrical conductivity) properties of the layers were investigated. The photocatalytic efficiency of the samples was tested considering these layers' future applications in removing organic pollutants.     

Effect of heating conditions on the magnetic properties of micron-sized carboxyl modified-magnetite particles synthesized by a spray pyrolysis and heating process

Superparamagnetic carboxyl (COOH) modified-magnetite (Fe₃O₄) (COOH-Fe₃O₄) micrometer-sized porous particles were synthesized by the spray pyrolysis of a 0.1 M Fe(NO₃)₃·9H₂O and 0.2 M citric acid solution and a subsequent heating process in either an Ar + 1% H₂ (P_O2 = 10^?20 Pa) or N₂ (P_O2 = 1 Pa) gas atmosphere. Fe₃O₄ formed due to carbon and hydrogen gas generation of thermal decomposition of citric acid, even under reduction conditions with a P_O2 below 10^?23 Pa. The COOH-Fe₃O₄ particles heated in an Ar + 1% H₂ or N₂ atmosphere were porous (40% porosity) and about 1.2 to 1.3 μm in diameter. The particles consist of nano-sized COOH-Fe₃O₄ crystallite about 7 nm in diameter. The specific surface area increased from 116 to 127 m²/g by increasing the heating time in an Ar + 1% H₂ atmosphere from 10 to 20 h. The saturation magnetization of the COOH-Fe₃O₄ particles (38.7 A·m²/kg) heated in Ar + 1% H₂ for 10 h was much higher than that of commercial magnetic microbeads (17 A·m²/kg) and the coercivity was 0 kA/m. These superparamagnetic COOH-Fe₃O₄ particles dispersed in distilled water were attracted to a NdFeB magnet for 7–10 s under a 400 Mt external magnetic field, compared with 10 s for commercial magnetic microbeads.