The Effects of Milling on the Surface Properties of Form I Paracetamol Crystals

Purpose The effects of milling and particle size on surface energies of form I paracetamol crystals are reported.Methods Paracetamol crystals (75–850 μm) were obtained by cooling methanol and acetone saturated solutions. Additionally, macroscopic (>2 cm) single crystals were grown by slow solvent evaporation from saturated solutions, ball milled and sieved into different particle size fractions. Surface properties were characterised using Inverse Gas Chromatography and compared with those calculated from sessile drop contact angle measurements on macroscopic single crystals.Results Dispersive surface energies, for milled samples increased by 20% with decreasing particle size. With decreasing particle size acceptor numbers, K _A values were constant but donor numbers, K _B decreased. For unmilled materials K _B was comparable to K _A but with a significantly lower of only 33 mJ/m². Milling resulted in fracture along the crystal's lowest attachment energy plane (010), exposing facets of different surface chemistry to that of the native external facets. θ for the (010) fracture plane confirmed a higher compared to external facets such as (011) of single crystals.Conclusions Milling exposes a hydrophobic surface for paracetamol form I crystals which becomes increasingly more dominant with decreasing particle size.     

Effect of Surface Energy on Powder Compactibility

Purpose  The influence of surface energy on the compactibility of lactose particles has been investigated. Materials and Methods  Three powders were prepared by spray drying lactose solutions without or with low proportions of the surfactant polysorbate 80. Various powder and tablet characterisation procedures were applied. The surface energy of the powders was characterized by Inverse Gas Chromatography and the compressibility of the powders was described by the relationship between tablet porosity and compression pressure. The compactibility of the powders was analyzed by studying the evolution of tablet tensile strength with increasing compaction pressure and porosity. Results  All powders were amorphous and similar in particle size, shape, and surface area. The compressibility of the powders and the microstructure of the formed tablets were equal. However, the compactibility and dispersive surface energy was dependent of the composition of the powders. Conclusion  The decrease in tablet strength correlated to the decrease in powder surface energy at constant tablet porosities. This supports the idea that tablet strength is controlled by formation of intermolecular forces over the areas of contact between the particles and that the strength of these bonding forces is controlled by surface energy which, in turn, can be altered by the presence of surfactants.     

Effect of Particle Size and Surface Charge on Nanoparticles Diffusion in the Brain White Matter

Pharmaceutical Research - Brain disorders have become a serious problem for healthcare worldwide. Nanoparticle-based drugs are one of the emerging therapies and have shown great promise to treat...     

Overcoming Poor Tabletability of Pharmaceutical Crystals by Surface Modification

Purpose  

To test the hypothesis that coating particles with a highly bonding polymer is effective in improving tabletability of poorly compressible drugs.     

Microscopic Characterization of Particle Size and Shape: An Inexpensive and Versatile Method

A variety of methods exists for measuring individual particle dimensions as a means of characterizing particle size, size distribution, and shape. The equipment described in this report belongs to the class of semiautomatic non-TV-interfaced analyzers. Unlike many existing image analysis systems, three-dimensional form measurements and texture data for the calculation of particle size and shape parameters can be determined easily and directly from each particle profile using this system. Essentially all data are collected directly from the particle and recorded by the computer with no intermediate steps. Much of the system consists of general-purpose and relatively inexpensive, commercially available hardware and software. Using this method, particle size, size distribution, and qualitative or quantitative shape information can easily and rapidly be obtained simultaneously. Particle length and width characterization, for example, can take less than 15 min. The equipment is versatile and flexible in measurements and calculations. The size and shape parameters to be measured are determined by the researcher and not the instrument. The ease with which this information can be obtained from small samples early in the development process makes it a valuable tool for the formulator.     

Decoupling the Contribution of Surface Energy and Surface Area on the Cohesion of Pharmaceutical Powders

Pharmaceutical Research - Surface area and surface energy of pharmaceutical powders are affected by milling and may influence formulation, performance and handling. This study aims to decouple the...     

Effects of Particle Surface Roughness on In-Die Flow and Tableting Behavior of Lactose

Particle rearrangement takes place during the initial phase of tablet compaction. In this study, rough lactose particles were prepared by roller compaction, and their surface roughness modified by partial surface dissolution using a fluidized bed processor. Flow characteristics of the particles were determined using various flow methods, and their compaction characteristics studied using a compaction simulator with punches of different geometry and compaction pressure. Rougher particles demonstrated poorer compressibility and powder flow due to the higher interparticulate frictional forces required for particle movement. Rearrangement energy during tablet compaction was found to be correlated with compressibility (R² = 0.92) and increased with surface roughness of the particles. Particle rearrangement was found to be dependent on interparticulate frictional forces, which could be measured using FT4 powder rheometer variable flow rate test and compressibility test. Plastic energy decreased as a result of the increased rearrangement energy requirements. Decrease in tensile strength as a result of decrease in plastic energy was not significantly different. Roller-compacted lactose particles produced tablets of higher tensile strength than crystalline lactose because of prefragmentation of the crystalline structure during roller compaction.     

The Effect of Relative Humidity on the Physical Properties of Two Melibiose Monohydrate batches with Differing Particle Size Distributions and Surface Properties

Melibiose monohydrate has shown promise when employed as a pharmaceutical excipient, but its physical properties have not been adequately characterized. Therefore, two different melibiose monohydrate batches were analyzed as received or after storage under different relative humidity (RH) atmospheres. The particle size distributions and specific surface areas of the two batches were shown to differ considerably, which also had an effect on their water sorption tendencies and on the intermolecular structure of melibiose after storage. The relatively large primary particles that were more abundant in one of the batches were shown to possess a porous surface structure, and water evaporation from them occurred in two phases when heated. Furthermore, storing the batch with smaller mean particle size under dry conditions affected the crystal structure and molecular vibrations of the sample more than in the case of the batch with larger mean particle size. It was concluded that the physical properties of melibiose monohydrate after storage at different RH atmospheres is largely governed by the primary particle size and porosity.     

The Mode of Drug Particle Detachment from Carrier Crystals in an Air Classifier-Based Inhaler

No HeadingPurpose. To investigate the mode of drug particle detachment from carrier crystals in an air classifier as a function of the carrier size fraction, payload, and the circulation time in the classifier.Methods. Laser diffraction analysis of the aerosol cloud from the classifier has been performed at 10, 20, 30, and 60 l/min, using a special adapter, for different adhesive mixture compositions.Results. A significant part of the drug particles is detached from carrier crystals during inhalation as small agglomerates. Such agglomerates originate from the starting material or are newly formed on the carrier surface during mixing. The degree of agglomeration during mixing depends on the carrier size, payload, and surface rugosity. The size of the agglomerates that are formed during mixing, increases with the size of the carrier particles. Predominantly the largest drug particles and agglomerates are detached within the first 0.5 s of inhalation. After 0.5 s, smaller primary particles are dislodged.Conclusions. A high ratio of removal forces to adhesive forces causes a high drug detachment rate from carrier crystals in a classifier within the first 0.5 s of inhalation. The high ratio can be explained by dislodgment of agglomerates and the largest primary particles in the early phases of inhalation. At higher flow rates, detached agglomerates may be further disintegrated into primary particles before they are discharged from the classifier. Agglomeration of drug particles on the carrier surface is the result of the same forces that are responsible for pressing these particles firmly to the carrier crystals during mixing.     

The Rate of Drug Particle Detachment from Carrier Crystals in an Air Classifier-Based Inhaler

No HeadingPurpose. To investigate the rate with which drug particles are detached from carrier particles in adhesive mixtures when the action of the separation forces during inhalation is sustained by circulation of the powder dose in an air classifier.Methods. Residual drug on retained carrier particles from different adhesive mixture compositions has been analyzed after different circulation times in the classifier (0.5 to 6 s). For calculation of the detachment rate within the first 0.5 s of inhalation, the optical concentration of the aerosol from the classifier has been measured with laser diffraction technique.Results. Drug detachment from carrier crystals during inhalation increases not only with the flow rate but also with the time during which the action of the separation forces (at a constant flow rate) is sustained. The detachment rate at the same flow rate varies with the carrier size fraction and carrier payload and is clearly highest within the first 0.5 s of inhalation.Conclusions. Drug detachment from carrier approaches first-order reaction within the first half-second of inhalation. But at longer circulation times in the classifier, the ratio of removal to adhesive forces decreases dramatically. To increase the detached fraction of drug during inhalation at a constant flow rate, a short residence time for the powder in the de-agglomerator between 0.5 and 2 s is desired.     

Dehydration and Rehydration Mechanisms of Pharmaceutical Crystals: Classification Of Hydrates by Activation Energy

Dehydration strongly influences the stability of hydrate drug substances. Consequently, the ability to predict dehydration of crystalline hydrate using the intermolecular interactions of water molecules contained in the crystals is essential for drug development. The conventional method employed to predict the propensity for dehydration uses the dehydration temperature, which is related to how tightly water molecules are bound in the crystal lattice. However, it is difficult to predict the dehydration propensity of a particular hydrate using only the dehydration temperature because other kinetic factors affect dehydration behavior, such as intermolecular interactions, and drug-substance-to-water molar ratio in a hydrate. In this study, we explored the use of the dehydration activation energy E_a and rehydration behavior to classify 11 pharmaceutical hydrates into three classes according to their kinetic behavior related to the thermodynamic factors of hydrates. There is good agreement between these classes and hydrate crystal structures determined from single-crystal X-ray diffraction, and thus, the classification reflects their crystal structural features. We compared E_a to the dehydration temperatures for each class and found that E_a plays a crucial role and is better than the temperature for quantitative differentiation of the dehydration propensities in these hydrates.     

Effect of Race on Fine Particle Deposition for Oral and Nasal Breathing

Abstract

Nasal efficiency for removing fine particles from inhaled air may be affected by variations in nasal structure associated with race. In 11 African American and 11 Caucasian adults (age 18–31 yr) we measured the fractional deposition (DF) of fine particles (1 and 2 μm mass median aerodynamic diameter) (MMAD) for oral and nasal breathing using individual breathing patterns previously measured by respiratory inductance plethysmography during a graded exercise protocol. DF for both nasal and mouth breathing was measured separately by laser photometry at the same tidal volume and breathing rate for resting and light exercise (20% of maximum work load) conditions. From these DF measures, nasal deposition efficiency (NDE) was calculated for each condition. For light exercise conditions, NDE for both 1- and 2-μm particles was less in African Americans versus Caucasians, 0.15 ± 0.07 (SD) versus 0.24 ± 0.11 for 1-μm particles (p = .03), and 0.29 ± 0.13 versus 0.44 ± 0.11 for 2-μm particles (p = .006). The racial differences in NDE were associated with racial differences in nasal resistance and nostril shape. These race-dependent nasal efficiencies are dosimetric factors that should be considered in modeling and assessing particulate dose from human exposure to air pollutants.     

Effects of Particle Size and Surface Modification on Cellular Uptake and Biodistribution of Polymeric Nanoparticles for Drug Delivery

Purpose

To investigate the effects of the particle size and surface coating on the cellular uptake of the polymeric nanoparticles for drug delivery across the physiological drug barrier with emphasis on the gastrointestinal (GI) barrier for oral chemotherapy and the blood–brain barrier (BBB) for imaging and therapy of brain cancer.

Methods

Various sizes of commercial fluorescent polystyrene nanoparticles (PS NPs) (viz 20 50, 100, 200 and 500 nm) were modified with the d-α-tocopheryl polyethylene glycol 1,000 succinate (vitamin E TPGS or TPGS). The size, surface charge and surface morphology of PS NPs before and after TPGS modification were characterized. The Caco-2 and MDCK cells were employed as an in vitro model of the GI barrier for oral and the BBB for drug delivery into the central nerve system respectively. The distribution of fluorescent NPs after i.v. administration to rats was analyzed by the high performance liquid chromatography (HPLC).

Results

The in vitro investigation showed enhanced cellular uptake efficiency for PS NPs in both of Caco-2 and MDCK cells after TPGS surface coating. In vivo investigation showed that the particle size and surface coating are the two parameters which can dramatically influence the NPs biodistribution after intravenous administration. The TPGS coated NPs of smaller size (< 200 nm) can escape from recognition by the reticuloendothelial system (RES) and thus prolong the half-life of the NPs in the blood system.

Conclusions

TPGS-coated PS NPs of 100 and 200 nm sizes have potential to deliver the drug across the GI barrier and the BBB.     

辅料和粒径对黄芪浸膏吸湿性的影响

目的 研究辅料和黄芪浸膏粒径大小等因素对其吸湿性的影响。方法 制备粒径为50~65目,65~80目,80~100目,100~120目,120~150目之间的黄芪浸膏,进行吸湿动力学测试和临界相对湿度测定;向黄芪浸膏中添加不同辅料,并研究辅料种类及用量对浸膏吸湿性的影响。结果 浸膏粒径和辅料种类对黄芪浸膏吸湿性有明显的影响。结论 粒径较大的黄芪浸膏临界相对湿度较大,吸湿性较差;黄芪浸膏与16种辅料混合,最佳防潮辅料为乳糖,且乳糖的添加量对浸膏吸湿性有明显的影响。     

Fill Volume as an Indicator of Surface Heterogeneity in Glass Vials for Parenteral Packaging

The chemical durability of glass vials for parenteral packaging is typically assessed by completely filling the vial with a medium of interest. This testing approach can mask the heterogeneous dissolution behavior of vials produced by conversion of glass tubing. In this study, the corrosion behavior of vials provided by four suppliers was evaluated as a function of fill volume. Vials were filled with incrementally increasing volumes of water for injection (WFI) up to near-maximum capacity and then autoclaved. The pH and levels of extracted ions were measured. The pH of autoclaved WFI generally increased for low fill volumes relative to pure WFI, presumably because of extraction of alkali from the heel region. The pH was found to generally decrease with increasing fill volume as the concentration of extractables was diluted. Analysis of dissolution profiles supports the altered surface chemistry of the heel region relative to the body. The results of this study demonstrate the potential limitations of conventional hydrolytic resistance tests and the susceptibility of the heel region to aqueous corrosion.     

Surface Energy and Interparticle Force Correlation in Model pMDI Formulations

Purpose. To compare experimental measurements of particle cohesion and adhesion forces in a model propellant with theoretical measurements of the interfacial free energy of particulate interactions; with the aim of characterizing suspension stability of pressurized metered dose inhalers (pMDIs).Methods. Interparticulate forces of salbutamol sulfate, budesonide, and formoterol fumarate dihydrate were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H,3H perfluoropentane. The surface thermodynamic properties were determined by contact angle (CA) and inverse gas chromatography (IGC). Experimental data were compared with theoretical work of adhesion/cohesion using a surface component approach (SCA), taking into account both dispersive and polar contributions of the surface free energy.Results. Results indicated that the measured forces of interaction between particles in model propellant could not be accounted for by theoretical treatment of the dispersive surface free energies via CA and IGC. A correlation between theoretical work of adhesion/cohesion and AFM measurements was observed upon the introduction of the polar interfacial interactions within the SCA model.Conclusions. It is suggested that the polar contributions of the surface free energy measurements of particles may play a crucial role in particle interaction within propellant-based systems. Together with the application of a SCA model, this approach may be capable of predicting suspension stability of pMDI formulations. Note: This revised article was published online in May 2005 and now shows a corrected title.     

Protein Spray-Freeze Drying. Effect of Atomization Conditions on Particle Size and Stability

Purpose. To investigate the effect of atomization conditions on particle size and stability of spray-freeze dried protein. Methods. Atomization variables were explored for excipient-free (no zinc added) and zinc-complexed bovine serum albumin (BSA). Particle size was measured by laser diffraction light scattering following sonication in organic solvent containing poly(lactide-co-glycolide) (PLG). Powder surface area was determined from the N₂ vapor sorption isotherm. Size-exclusion chromatography (SEC) was used to assess decrease in percent protein monomer. Fourier-transform infrared (FTIR) spectroscopy was employed to estimate protein secondary structure. PLG microspheres were made using a non-aqueous, cryogenic process and release of spray-freeze dried BSA was assessed in vitro. Results. The most significant atomization parameter affecting particle size was the mass flow ratio (mass of atomization N₂ relative to that for liquid feed). Particle size was inversely related to specific surface area and the amount of protein aggregates formed. Zinc-complexation reduced the specific surface area and stabilized the protein against aggregation. FTIR data indicated perturbations in secondary structure upon spray-freeze drying for both excipient-free and zinc-complexed protein. Conclusions. Upon sonication, spray-freeze dried protein powders exhibited friability, or susceptibility towards disintegration. For excipient-free protein, conditions where the mass flow ratio was > 0.3 yielded sub-micron powders with relatively large specific surface areas. Reduced particle size was also linked to a decrease in the percentage of protein monomer upon drying. This effect was ameliorated by zinc-complexation, via a mechanism involving reduction in specific surface area of the powder rather than stabilization of secondary structure. Reduction of protein particle size was beneficial in reducing the initial release (burst) of the protein encapsulated in PLG microspheres.     

Simultaneous Particle Size Reduction and Homogeneous Mixing to Produce Combinational Powder Formulations for Inhalation by the Single-Step Co-Jet Milling

Homogeneous mixing of 2 cohesive jet-milled drug powders is a challenge for pharmaceutical manufacturing on account of their cohesive nature resulting in the formation of strong and random agglomerates. In this study, colistin and ciprofloxacin were co-jet milled to develop combinational antibiotic dry powder formulations for inhalation. The properties of particle size, morphology, content uniformity, and in vitro aerosolization were evaluated. The distribution of 2 drugs in the co-jet milled powders was assessed using time-of-flight–secondary ion mass spectrometry. The co-jet milled powders demonstrated an acceptable content uniformity indicating homogeneity. In general, time-of-flight–secondary ion mass spectrometry images showed relatively homogeneous distributions of ciprofloxacin and colistin in the co-milled formulations. Importantly, the 2 drugs generally had the similar fine particle fraction and deposition behavior in each combinational formulation supporting that the particle mixtures were relatively homogenous and could maximize the antimicrobial synergy. In conclusion, co-jet milling could be a viable technique to produce the combination powders for inhalation.     

白内障手术切口对眼表影响的探究

目的:探讨不同白内障手术切口对患者眼表所产生的影响。方法:选取某院收治的71例(82眼)行白内障手术患者的临床资料,根据患者的白内障手术切口部位,将其分为两组,分别为上方组(角膜上方切口组)与颞侧组(角膜颞侧切口组),比较两组患者的眼科检查结果。结果:(1)从患者的角膜内皮细胞计数、角膜染色分级、泪河高度上看,两组在术前、术后7d末、术后30d末3个时间段对比无统计学意义(P>0.05);(2)就泪膜破裂时间、眼压、视力指标而言,两组患者在术前、术后7d末、术后30d末3个时间段对比无统计学意义(P>0.05)。结论:对于行白内障手术的患者而言,选取角膜颞侧切口与角膜上方切口,都不会对患者眼表产生太大影响。