Development of a novel approach towards predicting the milling behaviour of pharmaceutical powders

A novel approach has been developed for evaluating the milling behaviour of pharmaceutical powders based on their material and mechanical properties obtained by single particle impact testing. Milling behaviour of two widely used pharmaceutical excipients, namely microcrystalline cellulose and alpha-lactose monohydrate has been analysed in an oscillatory single ball mill. It is found that the milling behaviour of these two powders can be described by analogy with a first-order rate process except for alphaLM at 18Hz of milling frequency. At the same time, single particle impact testing has been used to infer the material properties that are related to breakage. The milling rate of these powders is found to correlate well with the parameter representing the material properties including the particle size, density, hardness and critical stress intensity factor. This provides the basis for a novel approach towards analyzing the milling behaviour of a material based on a simple and reliable approach.     

The effect of crystal imperfections on particle fracture behaviour

Micronisation of active pharmaceutical ingredients is a process which is sometimes difficult to control. The main purpose of this study was to assess the effect of the pre-existing flaws in the material to be milled. The rate of breakage of four samples of a model compound (sodium chloride), originating from different sources, was determined in a jet mill. It appeared that each type of sodium chloride has a distinct particle rate of breakage and breakage pattern. The numbers of flaws in the different types of sodium chloride have been determined by immersing the sodium chloride particles in a liquid with the same refractive index. This makes the cracks better visible. Microphotographs were made and flaws were counted manually. The study shows that the flaw density has an impact on the fracture behaviour of particles. The degree of fracture tends to increase with increasing flaw density. The paper shows however that the mechanical properties of the material as well as the starting particle size dominate the significance of the impact of flaws on fracture behaviour.     

A method of comminuting natural zeolite for the production of biologically active additives

This article describes a method of grinding a solid mineral material (zeolite), which can be used in medical applications, for the preparation of starting components for biologically active additives. Our method of preparing a solid natural material includes mechanical grinding, ultrasound comminution, and grading of natural zeolite. It differs from previously described methods in that material already ground mechanically to particle sizes of 5–20 mm is subjected to comminution and this process continues until particles of 1–2 to 10 μm are obtained. Zeolite particles obtained after processing in the homogenizer have greater roundness and smaller sizes than those obtained by mechanical crushing. Furthermore, our ultrasound method of comminuting zeolites also reduces the comminution process time by factors of 1.5–12.     

Enhanced nasal absorption of hydrophilic markers after dosing with AT1002, a tight junction modulator

AT1002 is a six-mer synthetic peptide, H-FCIGRL-OH, that retains the delta G and Zot biological activity of reversibly opening tight junctions and increases the paracellular transport of drugs. The objective of this study was to evaluate the possible use of AT1002 in enhancing the nasal availability of macromolecules using large paracellular markers as model agents. Male Sprague–Dawley rats cannulated in the jugular vein were randomly assigned to receive radiolabelled paracellular markers, [¹⁴C]PEG4000 or [¹⁴C]inulin, with/without AT1002, for each intranasal study. The plasma concentration of PEG4000 with AT1002 (10 mg/kg) was significantly higher than that from PEG4000 control over 360 min following intranasal administration. The AUC_0–360 min and C_max from the PEG4000/AT1002 (10 mg/kg) treatment were statistically (p < 0.05) increased to 235% and 357%, of control, respectively. When inulin was administered with AT1002 (10 mg/kg), the plasma concentration was significantly higher (p < 0.05) than control over 360 min, and increases (p < 0.05) of 292% and 315% for AUC_0–360 min and C_max over control were observed, respectively. AT1002 significantly increased the nasal absorption of molecular weight markers, PEG4000 and inulin. This study suggests that AT1002 may be used to enhance the systemic availability of macromolecules when administered concurrently.     

A new principal component analysis-based approach for testing “similarity” of drug dissolution profiles

A new approach for testing batch “similarity” through comparison of drug dissolution profiles, based on principal component analysis with the establishment of a confidence region (PCA-CR), is presented. The dissolution curves corresponding to three brands each of Furosemide and Acetaminophen tablets, taken as model drugs, were prepared by dissolution measurements at multiple pre-specified time points. Reference and test data were simultaneously subjected to PCA and pairwise comparisons between the dissolution characteristics of lots of the same and different brands were carried out. The comparisons involved plotting the weighed scores of the first two principal components of reference and test lots, while decision about “similarity” was made by checking for inclusion of more than 80% of the tablets of the test lot in the 95% confidence ellipse of the reference samples. Two published datasets were also analyzed in the same fashion and all the results were compared with information provided by the difference (f₁) and similarity (f₂) factor tests. Unlike the f₂ criterion, the proposed method reflects variability within the individual dissolution curves, being also highly sensitive to profile (shape and size) variations. Comparison between the area enclosed by the confidence ellipses of the weighed scores plot and the region obtained from the bootstrap-calculated acceptable values of the corresponding f₂ tests suggested that PCA-CR represents, in general, a more discriminating standard.     

High-resolution method for regulatory control of Echinacea species in Nutraceuticals by CD-MEKC

One problem in the international regulatory control of Echinacea, a therapeutic Nutraceutical, is recognition of caffeoyl solutes and alkamides in different products. Cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) has been applied to Echinacea spp. in combination with pattern recognition of some caffeoyl solutes. A novel metric based on relative migration time (RMT) data has been developed in CE to address the problem of variable reported migration time.

The CD-MEKC method of Gotti's group using hydroxypropyl-β-cyclodexrin (HP-β-CD; 100 mM) with sodium dodecyl sulphate (SDS; 110 mM), in a triacid background electrolyte (10 mM, pH 8) under 19 kV was adapted to identify two key hydrophilic solutes: chlorogenic acid and cichoric acid present in all commercial products. Two internal markers were taken as reference points to calculate the RMT of any target peak: RMT = t_{m (target)}/t_{m (marker)}.

The RMT method was robust to temperature change from 20 to 40 °C, but sensitive to pH. The lateral shift and reproducibility of the target peak t_{m (target)} were significantly reduced by this novel transformation. In the worst cases migration time variability ranged up to 12% (n = 6); the RMT algorithm reduced this to less than 1%. In general, the RMT transformation reduced the variability of migration time data by a factor of 2–5.

For systematic comparison of electrophoretic profiles for test sample and standard, a new pattern recognition algorithm permits sequential peak-by-peak comparison using specified segments of the electropherograms for comparison of test and Echinacea purpurea (root product) as a standard. This algorithm was capable of rapidly characterising the similarity of target peaks in a test sample relative to those in the reference standard. Combination of the RMT algorithm and pattern recognition in CE is expected to offer a robust approach to international regulatory characterisation and control of Nutraceuticals.     

硫酸沙丁胺醇吸入气雾剂药动学等效性评价技术与流程研究

目的： 建立硫酸沙丁胺醇吸入气雾剂药动学等效性评价技术与流程。方法： 6名健康受试者双周期空腹经口吸入硫酸沙丁胺醇吸入气雾剂200 μg（2掀）,2周期间清洗期为7 d。采用超高效液相色谱-质谱联用法测定人血浆中沙丁胺醇浓度。DAS 3.2.8软件统计血药浓度-时间数据。计算药动学参数C_max、AUC_{0-20 min}、AUC_0-t和AUC_0-∞及其个体内变异系数。结果： 硫酸沙丁胺醇吸入气雾剂第一周期和第二周期的主要药动学参数C_max分别为（285.33±158.83）pg·mL^-1和（222.12±108.02）pg·mL^-1,t_max分别为（0.72±0.52）h和（1.03±1.03）h,t_1/2z分别为（6.39±1.75）h和（5.91±1.22）h,AUC_{0-20 min}分别为（63.77±42.27）pg·h·mL^-1和（47.56±33.54）pg·h·mL^-1,AUC_0-t分别为（1 469.79±701.96）pg·h·mL^-1和（1 292.24±498.59）pg·h·mL^-1,AUC_0-∞分别为（1 596.30±772.95）pg·h·mL^-1和（1 383.21±488.82）pg·h·mL^-1。药动学参数C_max、AUC_{0-20 min}、AUC_0-t和AUC_0-∞的个体内变异系数分别为29.04%、17.64%、27.12%和27.63%。结论： 本研究建立了一种简便、经济和准确的硫酸沙丁胺醇吸入气雾剂药动学等效性评价技术与流程。     

Efficacy and pharmacodynamics of gemifloxacin versus levofloxacin in guinea pig pneumococcal pneumonia induced by strains with decreased ciprofloxacin susceptibility

Quinolone in vivo bactericidal activity was investigated in a guinea pig pneumonia model using three Streptococcus pneumoniae strains with decreasing susceptibility to ciprofloxacin. Treatment regimens resulted in values of AUC_{0–24 h} and C_{30 min} similar to those of standard oral regimens in human serum. Efficacy was defined as a significant difference in number of viable bacteria in the lungs compared with the control. Ciprofloxacin, levofloxacin and gemifloxacin were effective against the levofloxacin-susceptible strain. Only gemifloxacin achieved a ≥99.9% reduction versus control against the levofloxacin intermediate-resistant strain. Gemifloxacin achieved a 99.69% reduction and was the only quinolone significantly different from the control (P<0.05) against the levofloxacin-resistant strain. Gemifloxacin offers in vivo activity against ciprofloxacin- to levofloxacin-resistant pneumococci.     

An alternative method to the evaluation of similarity factor in dissolution testing

This paper addresses an alternative method to the evaluation of similarity factor f₂ as a criterion for assessment of similarity between two in-vitro dissolution profiles as proposed in the SUPAC-IR Guidance (1995). Diltiazem hydrochloride Sustained-Release (SR) tablets were tested and the following independent-model dissolution parameters were used: t_10% dissolution time, t_25% dissolution time, t_50% dissolution time, mean dissolution time (MDT), dissolution efficiency (DE) at t₁₂₀, and at t₃₆₀. To compare the dissolution profiles, several release models were tested such as Higuchi, zero order, first order, Baker-Lonsdale, Hixson-Crowell, Weibull and Korsmeyer-Peppas. The similarities between two in-vitro dissolution profiles were assessed by pair-wise independent-model procedures such as difference factor (f₁), similarity factor (f₂) and Rescigno index (ξ₁ and ξ₂). The in vitro release kinetics of diltiazem hydrochloride sustained release tablets were evaluated using USP apparatus 2.     

Spray-dried indomethacin-loaded polyester nanocapsules and nanospheres: development, stability evaluation and nanostructure models

The industrial development of polymeric nanoparticle suspensions, as drug delivery systems, is limited due to the problems in maintaining stability of suspensions. In this work, a spray-drying technique was applied to dry nanocapsule and nanosphere suspensions prepared by nanoprecipitation of polyesters using SiO₂ as adjuvant. Powders obtained from nanocapsules presented stable drug recoveries and morphological characteristics after 5 months. For nanocapsules, nanostructures around 200 nm were observed by scanning electron microscopy (SEM) on the surface of microparticles of SiO₂, whereas for the nanosphere formulation, nanostructures with a reduced diameter (60–90 nm) were observed, despite the particle sizes of each original suspension being similar, when measured by photon correlation spectroscopy (PCS). In order to investigate the morphological aspects of nanocapsule and nanosphere powders, several nanosphere formulations were spray-dried using different concentrations of SiO₂ and a comparative study of the different colloidal systems (nanocapsules, nanospheres, nanoemulsion or nanodispersion) was carried out by PCS. SEM analyses showed that nanostructures with reduced diameter are formed independently of the adjuvant concentration. The dynamic properties of these systems allowed to suggest that the structure of the nanosphere particle (polymer, sorbitan monostearate and polysorbate 80) was a polymeric matrix dispersing the sorbitan monostearate which, when submitted to the spray-drying process in the presence of SiO₂, gave nanostructures presenting diameters around 80 nm covering the microparticles due to the release of lipophilic surfactant from the polymeric matrix.     

Effect of particle size and density on the die fill of powders

The flow behaviour of powders during the process of die fill was examined. Gravity and suction fill experiments were carried out using a model shoe–die system. Five grades of microcrystalline cellulose were studied to identify the effect of particle size and density on flow. Flowability was quantified using the concept of critical velocity. Under gravity fill, the critical velocity was one order of magnitude higher for powders with large particle size compared to smaller particles. Under suction fill conditions, the critical velocity increased significantly compared to gravity fill, showed no consistent relationship with particle size, and the powders performed more similar to one another. Using high speed video, the gravity and suction fill mechanisms were discussed in the context of air flow and pressure build-up. The effect of shoe velocity, suction velocity and height of the powder in the shoe was explored in more detail. It was shown that one can identify individual contributions from material properties and process parameters to the flow behaviour during die fill; however, the flow performance depends on the inter-relationships between powder characteristics and process parameters. The die fill mechanisms described can be used to assist the optimisation of powder formulation and process design.     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.     

均匀设计法优选连翘超微粉碎工艺的研究

目的均匀设计法优选连翘超微粉碎工艺技术参数。方法采用单因素考察各粉碎工艺参数的范围,结合均匀设计、逐步回归法优选超微粉碎工艺条件。结果逐步回归方程为Y=41.083-1.029X2,r=0.9998;参照粉碎工艺参数范围及生产实际,选择连翘超微粉碎工艺条件为粉碎时间18min,温度？10～10℃,水分5%～9%,介质填充率60%～70%,预测粒径D50为22.56μm,验证粒径D50为22.81μm。结论超微粉碎工艺条件参数与粒径相关性良好,均匀设计法对超微粉碎工艺具有较好的指导意义。     

Chamomile blooms--a heterogenous drug (manufacture of mixed teas with Matricariae flos)

Sieve analyses have proved that the camomile commercial drug is an extremely heterogeneous material which contains ultracoarse particles greater than 4 mm (aprox. 70%) in addition to fine particles less than 0.71 mm (approx. 15%). The ultra-coarse particles are not usable in tea mixtures. For camomile, it is proposed a homogeneous infusion drug (less than 2 mm). The comminution should be performed in the pharmacy. Where species are mixed with camomile, the particle sizes should not exceed 2 mm. The homogeneity of these mixtures is determined by weight comparison of a series of tea-spoon weights. For the comminution of the drugs the authors suggest the use of a "Retsch" cutting mill or a similar appliance which ensures that only few fine particles to be produced. For the removal of suspended fine particles in the infusum of camomile the use of Cilia filter bags is suitable.     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.     

Comparison of particle sizing techniques in the case of inhalation dry powders.

The objectives of this work were (i) to validate electrical zone sensing and laser diffraction for the analysis of primary particle size in the case of inhalation dry powders and (ii) to study the influence of the aggregation state of the powder on the sizing techniques. Free-flowing dry powders were prepared by spray-drying with a combination of albumin, lactose, and dipalmitoylphosphatidylcholine. The replacement of lactose by mannitol, the removal of albumin, and the atomization at high relative humidity all increased powder cohesion. Automated measurements were compared with primary particle sizes collected by light and electron microscopy. The mass mode obtained by electrical zone sensing and the mass median diameter measured by laser diffraction following dispersion with compressed air at a pressure of 3 bar or following suspension in water and ultrasonic dispersion at a power of 60 W for 30 s each provided primary particle sizes close to microscopy measurements. However, these conditions only applied in the case of slightly to moderately aggregated powders. For strongly agglomerated powders, an exact measurement of the size was only collected by laser diffraction in the wet state combined with ultrasonic dispersion. Our study underlies how measurement of primary particle size highly depends on both powder material and proper particle dispersion.     

Does a powder surface contain all necessary information for particle size distribution analysis?

The aim of this study was to utilise a new approach where digital image information is used in the characterisation of particle size distributions of a large set of pharmaceutical powders. A novel optical set-up was employed to create images and calculate a stereometric parameter from the digital images of powder surfaces. Analysis was made of 40 granule batches with varying particle sizes and compositions prepared with fluidised bed granulation. The extracted digital image information was then connected to particle size using multivariate modelling. The modelled particle size distributions were compared to particle size determinations with sieve analysis and laser diffraction. The results revealed that the created models corresponded well with the particle size distributions measured with sieve analysis and laser diffraction. This study shows that digital images taken from powder surfaces contain all necessary data that is needed for particle size distribution analysis. To obtain this information from images careful consideration has to be given on the imaging conditions. In conclusion, the results of this study suggest that the new approach is a powerful means of analysis in particle size determination. The method is fast, the sample size needed is very small and the technique enables non-destructive analysis of samples. The method is suitable in the particle size range of approximately 20–1500 μm. However, further investigations with a broad range of powders have to be made to obtain information of the possibilities and limitations of the introduced method in powder characterisation.     

Development of a multivariate light-induced fluorescence (LIF) PAT tool for in-line quantitative analysis of pharmaceutical granules in a V-blender

Process analytical technologies (PAT) enable process insight, process control and real-time testing. Light-induced fluorescence (LIF) spectroscopy is especially well suited for low-concentration ingredients as, in many cases, it is the most sensitive probe of the in-line PAT toolbox. This study is aimed at verifying the applicability of a multivariate LIF analyzer to monitor granulated powder blends in industrial settings. Its targets are to: (1) evaluate the critical parameters of powders to obtain robust, precise and accurate concentration predictions and (2) assess technology performance for in-line monitoring of blending operations. Varying dye properties, moisture levels and particle sizes have been shown to have the most significant impact on fluorescence emission. Reliable quantitative models can be obtained by controlling and/or mitigating these factors.     

Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated

The 5-HT_2B receptor agonist, BW 723C86 (10, 30 mg/kg i.p. 30 min pre-test), increased the number of punishments accepted in a rat Vogel drinking conflict paradigm over 3 min, as did the benzodiazepine anxiolytics, chlordiazepoxide (2.5–10 mg/kg p.o. 1 h pre-test) and alprazolam (0.2–5 mg/kg p.o. 1 h pre-test), but not the 5-HT_2C/2B receptor agonist, m-chlorophenylpiperazine (mCPP, 0.3–3 mg/kg i.p) or the 5-HT_1A receptor agonist, buspirone (5–20 mg/kg p.o. 1 h pre-test). The effect of BW 723C86 was unlikely to be secondary to enhanced thirst, as BW 723C86 did not increase the time that rats with free access to water spent drinking, nor did it reduce sensitivity to shock in the apparatus. The anti-punishment effect of BW 723C86 was opposed by prior treatment with the 5-HT_2C/2B receptor antagonist, SB-206553 (10 and 20 mg/kg p.o. 1 h pre-test), and the selective 5-HT_2B receptor antagonist, SB-215505 (1 and 3 mg/kg p.o. 1 h pre-test), but not by the selective 5-HT_2C receptor antagonist, SB-242084 (5 mg/kg p.o.), or the 5-HT_1A receptor antagonist, WAY 100635 (0.1 or 0.3 mg/kg s.c. 30 min pre-test). Thus, the anti-punishment action of BW 723C86 is likely to be 5-HT_2B receptor mediated. This is consistent with previous reports that BW 723C86 exhibited anxiolytic-like properties in both the social interaction and Geller-Seifter conflict tests.     

Penetration of crystalline powder particles into excised human skin membranes and model gels from a supersonic powder injector

The penetration of crystalline ibuprofen particles into excised human skin membranes and model target gels on actuation with the PowderJect ND1 ballistic needle-free injector has been examined. The deliverable dose of powder exiting the device is approximately 50% of the total cassette loading; the rest is lost via a gap forced open between the injector base and the surface of the target gel. It could be shown that substantial comminution of two different ibuprofen particle size fraction (38-53 microm, 53-75 microm) occurs within the injector on actuation. This resulted in an equiparation of the two initially different size fractions. Reduced comminution occurs with an ibuprofen/PVP (95:5) particulate formed by spray-drying/compaction/milling. On actuation into excised human skin membranes approximately 37% of cassette dose is recovered from the stratum corneum by stripping, and only 3% from the epidermis. It is concluded that powder delivery is mainly intra-epidermal with few particles fully breaching the stratum corneum. This is a consequence of the relative magnitude of the particle diameter (approximately 48 microm) and the stratum corneum thickness (approximately 10 microm). A 'soft' polyethylene glycol monolayer target gel gives the closest total percentage recovery of powder to that seen with the excised human skin membranes. Bilayer gels differentiated between surface impact/retention and penetration, but were difficult to handle. Powder penetration studies should therefore preferentially to be performed with human skin-membranes.