Optimization of the high-shear wet granulation wetting process using fuzzy logic modeling

A fuzzy model has been developed for the optimization of high-shear wet granulation wetting on a plant scale depending on the characteristics of pharmaceutical active substance particles. The model optimized on the basis of experimental data involves a set of rules obtained from expert knowledge and full-scale process data. The skewness coefficient of particle size distribution and the tapped density of the granulated mixture were chosen as the model input variables. The output of the fuzzy ruled system is the optimal quantity of wetting liquid. In comparison to manufacturing practice, a very strong sensitivity of the optimal quantity of the added wetting liquid to the size and shape of the active substance particles has been identified by fuzzy modeling.     

Clarithromycin targeting to lung: optimization of the size, morphology and release characteristics of albumin microspheres

Micropheres are drug carrier system which ensures controlled release in the shape of solid sphere particles with variable diameter distributions from a few microns to a milimeter of size. The active substance is dispersed in molecular level or in forms of macroscopic particles. Clarithromycin was selected as the model active substance in our study. Clarithromycin microspheres were prepared and evaluated by an emulsion polymerization technique. Two matrix materials have been considered as the basis in preparing the selected model active substance. Natural human serum albumin and bovine serum albumin, which were frequently used in early microsphere studies and are being used in some studies as microshpere matrix material were used. Albumin microspheres containing clarithromycin were prepared by heat stabilization at different stirring rate. In the first part of our study, drug content, payload, particle size, surface morphology and release characteristics from microspheres prepared.     

Importance of interfacial characteristics in pharmaceutical technology

Since drug release from the dosage forms has priority to absorption from the gastrointestinal system, physico-chemical characterisation of pharmaceutical systems is essential during the development of an optimal formulation with high efficacy and quality. Interfacial parameters of several pharmaceutical excipients were studied regarding their possible modifying effect on drug release from the dosage form. These inactive ingredients may influence the interfacial phenomena of the drug carrier system, which behaviour determines both the efficacy and the quality of the pharmaceutical preparation In this work authors deal mainly with the two introducing steps of the LADME model influenced by interfacial parameters on them, namely with the liberation of drug from the dosage form and with the characteristics influencing the absorption through biological membranes, respectively. The objective of the present work was to study modifying effects of excipients on drug liberation in connection with their physical and chemical characteristics such as interfacial tension of solid and liquid phases, wetting contact angle of solid phase and--a calculated quantity,--adhesion tension of the solid particles.     

Combining formulation and process aspects for optimizing the high-shear wet granulation of common drugs

The purpose of this research was to determine the effects of some important drug properties (such as particle size distribution, hygroscopicity and solubility) and process variables on the granule growth behaviour and final drug distribution in high shear wet granulation. Results have been analyzed in the light of widely accepted theories and some recently developed approaches.A mixture composed of drug, some excipients and a dry binder was processed using a lab-scale high-shear mixer. Three common active pharmaceutical ingredients (paracetamol, caffeine and acetylsalicylic acid) were used within the initial formulation. Drug load was 50% (on weight basis).Influences of drug particle properties (e.g. particle size and shape, hygroscopicity) on the granule growth behaviour were evaluated. Particle size distribution (PSD) and granule morphology were monitored during the entire process through sieve analysis and scanning electron microscope (SEM) image analysis. Resistance of the wet mass to mixing was furthermore measured using the impeller torque monitoring technique. The observed differences in the granule growth behaviour as well as the discrepancies between the actual and the ideal drug content in the final granules have been interpreted in terms of dimensionless quantity (spray flux number, bed penetration time) and related to torque measurements. Analysis highlighted the role of liquid distribution on the process. It was demonstrated that where the liquid penetration time was higher (e.g. paracetamol-based formulations), the liquid distribution was poorer leading to retarded granule growth and selective agglomeration. On the other hand where penetration time was lower (e.g. acetylsalicylic acid-based formulations), the growth was much faster but uniformity content problem arose because of the onset of crushing and layering phenomena.     

Studies on the release of solubilized drugs from ointment bases. Part 9: Modelling of drug release process of active substance from emulsive ointments (W/O)--the mathematical model

A new mathematical model of the release process of solubilized active substance from emulsive (W/O) ointments is proposed. This model is based on Fick's diffusion law and additional assumptions. The most important assumption is recognition of the heterogeneous character of emulsive ointments. An equation has been derived, which expresses the functional relationship between the quantity of substance liberated from the ointment and the period of release.     

A priori performance prediction in pharmaceutical wet granulation: testing the applicability of the nucleation regime map to a formulation with a broad size distribution and dry binder addition

In this study, Hapgood's nucleation regime map (Hapgood et al., 2003) was tested for a formulation that consists of an active pharmaceutical ingredient (API) of broad size distribution and a fine dry binder. Gabapentin was used as the API and hydroxypropyl cellulose (HPC) as the dry binder with deionized water as the liquid binder. The formulation was granulated in a 6 l Diosna high shear granulator. The effect of liquid addition method (spray, dripping), liquid addition rate (29-245 g/min), total liquid content (2, 4 and 10%), and impeller speed (250 and 500 rpm) on the granule size distribution and lump formation were investigated. Standard methods were successfully used to characterize the process parameters (spray drop size, spray geometry and powder surface velocity) for calculating the dimensionless spray flux. However, the addition of dry binder had a very strong effect on drop penetration time that could not be predicted from simple capillary flow considerations. This is most likely due to preferential liquid penetration into the fine pores related to the dry binder particles and subsequent partial softening and dissolution of the binder. For systems containing a dry binder or other amorphous powders, it is recommended that drop penetration time be measured directly for the blended formulation and then scaled to the drop size during spraying.Using these approaches to characterize the key dimensionless groups (dimensionless spray flux and drop penetration time), Hapgood's nucleation regime map was successfully used to predict a priori the effect of process conditions on the quality of the granule size distribution as measured by lump formation and the span of the size distribution, both before and after wet massing for range of conditions studied. Wider granule size distributions and higher amount of lumps were obtained moving from intermediate to mechanical dispersion regime. Addition of the liquid in the dripping mode gave the broadest size distribution with ungranulated fines and highest percentage of lumps compared to spraying mode. Addition of the liquid by spraying in the intermediate regime gave the narrowest size distribution with the lowest amount of lumps. The effects of impeller speed and wet massing time on granule size distribution were complex. At 2% liquid content, increasing the impeller speed and adding wet massing time caused some breakage of lumps and the production of fines. At higher liquid contents, the effects were less clear, likely due to a balance between increased breakage and increased granule consolidation and growth. Nevertheless, this work has demonstrated that for complex formulations with dry binder addition, the final granule size distribution still depends strongly on the homogeneity of the initial liquid distribution which is well predicted by the nucleation regime map analysis.     

Particle formation and capture during spray drying of inhalable particles

An investigation of the spray drying process is made in great detail regarding particle formation and capture efficiency with focus on the production of inhalable particles. Mannitol was spray dried as model substance and the spray-dried products were characterized. The resulting products consisted of smooth spheres with a volume median diameter of 2.2-5.5 microm, and narrow size distributions. The investigation was performed in pilot scale of sufficient size to draw general conclusions and make some recommendations. It has been shown that the size of particles is decreased when the feed concentration is decreased, the nozzle gas/feed flow mass ratio increased, and the droplet size decreased. The collection efficiency of the cyclone device used in this study was shown to have a cut-off of 2 microm, i.e., 50% of the particles less than 2 microm are not captured. The data reported indicate that the majority of the single particles formed here, <5 microm, arise from single droplets (of about 10 microm) and are solid, nonporous particles.     

异丙醇对阿替洛尔片溶出行为的影响

目的考察异丙醇用量对阿替洛尔片溶出行为的影响。方法以不同用量的异丙醇为润湿剂,通过湿法制粒制备阿替洛尔片(规格为每粒50 mg),分别测定其5,10,15,25,45,60 min时的累积溶出度,绘制溶出曲线并与参比制剂比较,计算其f2值。结果异丙醇用量对阿替洛尔片的溶出行为影响显著。结论随着异丙醇用量的增加,阿替洛尔的溶出速率加快;当异丙醇用量为0.080 mL/片时,阿替洛尔的溶出行为与参比制剂相似。     

Assessment of spatial heterogeneity in continuous twin screw wet granulation process using three-compartmental population balance model

In this study, a novel three-compartmental population balance model (PBM) for a continuous twin screw wet granulation process is developed, combining the techniques of PBM and regression process modeling. The developed model links screw configuration, screw speed, and blend throughput with granule properties to predict the granule size distribution (GSD) and volume-average granule diameter. The granulator screw barrel was divided into three compartments along barrel length: wetting compartment, mixing compartment, and steady growth compartment. Different granulation mechanisms are assumed in each compartment. The proposed model therefore considers spatial heterogeneity, improving model prediction accuracy. An industrial data set containing 14 experiments is applied for model development. Three validation experiments show that the three-compartmental PBM can accurately predict granule diameter and size distribution at randomly selected operating conditions. Sixteen combinations of aggregation and breakage kernels are investigated in predicting the experimental GSD to best judge the granulation mechanism. The three-compartmental model is compared with a one-compartmental model in predicting granule diameter at different experimental conditions to demonstrate its advantage. The influence of the screw configuration, screw speed and blend throughput on the volume-average granule diameter is analyzed based on the developed model.     

Considerations for Defining the Intravenous Administration Procedure for Nano-dose Sterile Drug Product in Clinical Studies

The loss of active substance, both small and large molecules, from sterile liquid drug products after contact with an administration kit has been extensively reported in the literature. This loss has been reported to be caused by incompatibility of the active substances with the contact surfaces of the administration kit and adsorption or sticking of the active substance to the surfaces of the administration kit. This paper investigates the mechanism for loss of a highly potent active substance based on the type and design of the administration kit. Two administration kits (syringe/Insyte Catheter and syringe/Nexiva Catheter) of different designs were used to administer a solution formulation of an ultra-low dose (nanograms) of a model hydrophobic active substance Compound X. The Nexiva Catheter was longer with tubing and Y connectors while the Insyte Catheter was shorter with no split septum tubing. Dose recovery from both administration kits was determined using high pressure liquid chromatography. The results indicated that the full dose was recovered from the syringes and Insyte Catheter. However, there was a significant loss of active substance from the Nexiva Catheter configuration even after post administration flush, which was due to holdup volume of the formulation within dead spaces of the Nexiva Catheter. It was also demonstrated that the dose recovery from the Nexiva Catheter can be significantly increased with increase in the post administration flush volume, which further confirms that the observed loss of active substance was not due to incompatibility or surface adsorption. The significance of this work is to provide awareness to formulation scientists that closed system Catheter design with Y connectors can be the main contributor for the loss in active substance, especially at ultra-low doses, and therefore dose recovery experiments should be expanded to include proper flushing of the Y connectors to expel any holdup volume from the Catheter.     

高剪切方法制备穿心莲干浸膏颗粒的影响因素考察

目的以3批流动性不同的穿心莲干浸膏为模型药,研究高剪切方法在制粒过程中的主要影响因素。方法分别以3批穿心莲干浸膏为原料,以颗粒粒径分布及各粒径范围内脱水穿心莲内酯含量分布的相对标准偏差(RSD%)为指标,对高剪切制粒过程中黏合剂用量、搅拌桨转速及制粒时间进行三因素两水平完全析因设计实验。结果黏合剂用量及制粒时间对3批流动性不同穿心莲干浸膏制得颗粒的几何平均粒径均有显著影响;流动性较差穿心莲干浸膏进行高剪切制粒时,最终颗粒群中脱水穿心莲内酯含量均匀度受搅拌桨转速影响程度最大;浸膏流动性不同,三因素之间交互作用有所不同。结论控制高剪切制粒过程的技术参数,可以改善流动性不同的中药浸膏制得颗粒的粒径分布及含量均匀度。     

Influence of mechanical activation on the physical stability of salbutamol sulphate.

In order to obtain the optimal particle size distribution for pharmaceutical powders in dry powder inhalers the particles have to be micronised. In most cases the process of micronisation is connected with a high input of energy which induces disorder and defects on the surface of the drug particles and as a result changes in the crystallinity. Consequently, changes in the physical stability of the powders may occur. To investigate changes on the physical stability of the powder, different analytical methods are used in the present investigation: laser diffraction, Differential Scanning Calorimetry (DSC), isothermal microcalorimetry and DVS-method.Air-jet-milling is one of the most frequently used techniques in the pharmaceutical industry, in order to obtain particles of respirable size. In the treatise described here the influence of the critical parameters of the process, i.e. feed pressure, grind pressure and feed rate is assessed for salbutamol sulphate. The grind pressure is of utmost importance with respect to particle size distribution and the physical powder stability. For salbutamol sulphate, ground with a MC Jetmill 50, a grind pressure of 6 bar has been found optimal. Pressures below 6 bar are not sufficient to produce the required reduction in particle size. The feed pressure and rate have negligible influence on the powder quality. Furthermore, the micronisation process is optimised to achieve respirable particles while minimising the amorphous content. A correlation between mechanical activation and the amount of the amorphous regions is showed clearly.Air-jet-milling has been compared to ball milling in this investigation. In pilot tests ball milling was not suitable to achieve the needed particle size distribution, however, it generates a specific quantity of amorphous material. With the help of specific amorphous regions in the powder, the sensitivity of the used methods for salbutamol sulphate can be examined.     

Using the Box–Behnken experimental design to optimise operating parameters in pulsed spray fluidised bed granulation

In this work, the influence factors of pulsed frequency, binder spray rate and atomisation pressure of a top-spray fluidised bed granulation process were studied using the Box–Behnken experimental design method. Different mathematical models were developed to predict the mean size of granules, yield, relative width of granule distribution, Hausner ratio and final granule moisture content. The study has supported the theory that the granule size can be controlled through the liquid feed pulsing. However, care has to be taken when the pulsed frequency is chosen for controlling the granule size due to the nonlinear quadratic relation in the regression model. The design space of the ranges of operating parameters has been determined based on constraints of the mean size of granules and granule yield. High degree of prediction obtained from validation experiments has shown the reliability and effectiveness of using the Box–Behnken experimental design method to study a fluidised bed granulation process.     

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.     

Cryogenic liquids, nanoparticles, and microencapsulation

The biopharmaceutical classification system (BCS) is used to group pharmaceutical actives depending upon the solubility and permeability characteristics of the drug. BCS class II compounds are poorly soluble but highly permeable, exhibiting bioavailability that is limited by dissolution. The dissolution rate of BCS class II drug substances may be accelerated by enhancing the wetting of the bulk powder and by reducing the primary particle size of the drug to increase the surface area. These goals may be achieved by nucleating drug particles from solution in the presence of stabilizing excipients. In the spray freezing into liquid (SFL) process, a drug containing solution is atomized and frozen rapidly to engineer porous amorphous drug/excipient particles with high surface areas and dissolution rates. Aqueous suspensions of nanostructured particles may be produced from organic solutions by evaporative precipitation into aqueous solution (EPAS). The suspensions may be dried by lyophilization. The particle size and morphology may be controlled by the type and level of stabilizers. In vivo studies have shown increased bioavailability of a wide variety of drugs particles formed by SFL or EPAS. For both processes, increased serum levels of danazol (DAN) were observed in mice relative to bulk DAN and the commercial product, Danocrine. Orally dosed itraconazole (ITZ) compositions, formed by SFL, produce higher serum levels of the drug compared to the commercial product, Sporanox oral solution. Additionally, nebulized SFL processed ITZ particles suspended in normal saline have been dosed via the pulmonary route and led to extended survival times for mice inoculated with Aspergillis flavus. SFL and EPAS processes produce amorphous drug particles with increased wetting and dissolution rates, which will subsequently supersaturate biological fluids in vivo, resulting in increased drug bioavailability and efficacy.     

益智丸成型工艺研究

目的确立益智丸的最佳成型工艺。方法采用正交试验法，从基质（聚乙二醇）、冷却剂（液体石蜡）温度、提取物与基质用量配比等方面进行优选。结果最佳成型工艺为聚乙二醇4000，冷却温度10℃，用量配比为1：1．70结论该工艺所得益智丸成型最好，稳定性和重现性好，可为益智丸的生产提供参考依据。     

Characterisation of the aggregation behaviour in a salmeterol and fluticasone propionate inhalation aerosol system

The nature of the drug-drug aggregation phenomena between salmeterol xinafoate and fluticasone propionate used in a metered-dose inhaler system has been examined. Interactions between the drugs in the solvents 1,1,2-trichlorotrifloroethane (CFC-113) and 1,1,1,2-tetrafluoroethane (HFA-134a) have been characterised using a focused beam reflectance measurement probe by measuring the average floc size of the drug particles individually and in combination as a function of stirrer rate. The floc composition in the CFC-113 system, where the drug particles cream, was determined by high-performance liquid chromatography analysis. The aggregation behaviour of the individual drugs was shown to depend on the physical and chemical properties of both the drug substance and the media. Larger flocs were observed for salmeterol xinafoate compared with fluticasone propionate, while both drugs formed larger aggregates in HFA-134a compared with in CFC-113. The floc composition studies demonstrated that, in the combined formulation in CFC-113, salmeterol xinafoate and fluticasone propionate aggregate together to form hetero-flocs. The interaction between the two drugs was such that they did not separate on creaming, despite having different densities. The average floc size of the combined drug suspension was also found to depend on the dispersion medium.     

Preparation and investigation of gemfibrozil + dimethyl-beta-cyclodextrin products and solid dosage forms

Gemfibrozil is a lipid-regulating active substance. Dimethyl-beta-cyclodextrin products were prepared from this sparingly soluble pharmacon by means of methods such as physical mixing, kneading, spray drying and ultrasonication. Solid dosage forms (hydroxypropylmethyl cellulose /HPMC/ capsules and tablets) were prepared from the selected products on the basis of their dissolution profile and the in vitro membrane diffusion results. This publication details the results of electronmicroscopic morphological studies, particle size analysis and wetting contact angle determinations, and also the preparation and examination of the resulting solid dosage forms.     

In vitro release studies on drugs suspended in non-polar media I. Release of sodium chloride from suspensions in liquid paraffin

The release of a readily water-soluble substance (sodium chloride) from a liquid paraffin phase to an underlying water phase was investigated as a function of particle size (10–50 μm) and concentration (up to 10% m/m). Transport of the suspended particles to the interface by sedimentation was the rate limiting step. The release rate increased with primary particle size and concentration. The small particles showed a more pronounced concentration dependence than the large ones. During settling, agglomerates were formed. But, mild shear rates kept the primary particles in the deglomerated state. Low concentrations of DOSS-Na (di(2-ethylhexyl) sodium sulphosuccinate) up to 0.2% m/m in liquid paraffin reduced the degree of agglomeration, while trace amounts of water (0.01 and 0.05% m/m) showed the opposite effect. The observed phenomena are discussed on basis of the DLVO-theory, supplemented with considerations about forces due to gravity, shear and liquid bridge formation, and the kinetics of agglomeration.     

Agglomerative crystallization of ABT-510 in a partially miscible solvent system

A modification of wet agglomeration technique is developed and demonstrated by agglomerative crystallization process for a nonapeptide (ABT-510) to improve processing of needle like crystals. Our procedure involves exploiting partial miscibility of the crystallization solvent system for in situ generation of a wetting agent with suitable agglomerative properties. Experiences with ABT-510 show that a relatively small fraction of phase separation (1-5%) is needed to create enough wetting agent for effective agglomeration. Manipulations in the properties and quantity of the wetting agent easily achieved by modifying process trajectories in the solvent space lead to significant variations in agglomerative particle shapes. An optimal process trajectory is established by thorough evaluation of solid-liquid equilibria, liquid-liquid equilibria, properties of the wetting agent and agglomerative particle shape. Optimum antisolvent addition profile is also established and the process scaled up using suitable process analytical tools (PAT) to monitor for consistent performance. This optimally designed agglomerative crystallization process consistently lead to agglomeration of the particles just inside the biphasic solvent region. Extremely rapid crystal form conversion to the desired crystalline form is also observed in the vicinity of the biphasic solvent region, probably as a consequence of density fluctuations generated by the onset of solvent immiscibility.