Quantitative evaluation of kneading and extrusion processes by pressure transmission characteristics of wet kneaded masses

This study is devoted to the quantitative evaluation of wet kneaded masses prepared by a paddle-type kneader, and the analysis of the kneading process and the following extrusion granulation process. A compaction tester of wet kneaded masses has been developed and the compression properties of the masses are characterized by a pressure transmission between the upper and lower punches of the tester. The dispersion condition of a binder liquid among the wet kneaded masses prepared under various kneading times is investigated. The extrusion pressure through a single ejection hole on the lower punch is also measured. The pressure transmission is found to have a linear relationship between the dispersion of binder liquid and the extrusion pressure. This results lead to a conclusion that the proposed method provides the generalized measuring means of wet kneaded masses. An extrusion granulation by a dome-type extruder is conducted using wet kneaded masses and physical properties of the extruded pellets (granules), such as friability, specific surface area and disintegration time, are investigated. Good linearity can be found between the pressure transmission and the physical properties of the pellets. As the result of these findings, the kneading condition, i.e. the dispersion of binder liquid among the wet kneaded masses, can be quantitatively analyzed and the physical properties of pellets prepared by extrusion granulation can be accurately predicted by the pressure transmission measured by the newly developed compression tester.     

Effect of the granulation process on nitrofurantoin granule characteristics

We studied four granulation methods on the same quantitative and qualitative formula: wet massing by forced agglomeration (L?dige) and free agglomeration (Glatt); and dry massing by slugging and roller compaction technique. Three different particle sizes of nitrofurantoin (bioinequivalent drug) were used. The nitrofurantoin particle size has a very low influence on the physical characteristics of the granules. The granulating process influenced the binding of the particles. Granules processed using the wet granulating method were harder than those made by dry process. L?dige granules were more bonded than Glatt granules. Granules prepared by dry massing presented broken particles. The surface area and the porosity of Glatt granules were the most important parameters. Dissolution studies must be effected to make a correlation between the physical results and the dissolution rates. It is necessary to effect a new validation and a comparison of the results when a new granulating apparatus is used.     

Comparison of Moisture-Activated Dry Granulation Profess with Conventional Granulation Methods for Sematilide Hydrochloride Tablets

During the development of a tablet formulation of a cohesive, fluffy investigational drug, a novel moisture-activated dry granulation (MADG) process was studied in comparison with two conventional granulation methods, i.e., wet granulation and dry granulation with a roller compactor, as well as with a direct compression formulation method. The MADG method produced granules with excellent flowability which were equivalent in a number of ways to those produced by either conventional wet granulation or dry granulation methods and which were much better than the powder blend from the direct compression formulation. The tablets prepared using the MADG method had better content uniformity than those made using material from wet and dry granulation processes. Other tablet properties, such as weight variation, friability and dissolution, were similar among the tablets produced by the four processes     

A dimensionless variable for the scale up and transfer of a roller compaction formulation

Roller compaction is the most commonly employed dry granulation process in the pharmaceutical industry. While this process is increasingly used as an alternative to wet granulation, there are no parameter sets or system of equations to quickly scale up or transfer a formulation between two pieces of equipment. In this work, dimensionless variable was examined as a method to transfer the operating parameters of a formulation between two different pieces of equipment. This work was completed to establish the ground work for the development of a dimensionless relationship relating the operating parameters of the equipment to the porosity of the ribbon. The working hypothesis was three-fold, namely (i) that ribbons of the same porosity made with different equipment will have similar properties, (ii) that it is possible to establish an objective relationship between ribbon porosity and a combination of operating parameters and raw material attributes and (iii) that by expressing such parameter combination as a dimensionless variable, it will be possible to use the same relationship for different pieces of roller compaction equipment. The dimensionless variable RP/RS*HFS*True Density*D² was found to correlate well with the ribbon porosity for the formulations and equipment used in these experiments. Depending on the formulation, the average difference in ribbon porosity between the two units varied between 0.012 and 0.024.     

Eudragit(®) RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets

The influence of plasticizer level, roll pressure and sintering temperature was investigated on the granule properties, tablet breaking force and theophylline release from tablets. Nine formulations using theophylline as a model drug, Eudragit(?) RL PO, Eudragit(?) RS PO, or both as a matrix former and triethyl citrate (TEC) as a plasticizer were prepared. The formulations were roller compacted and the granules obtained were evaluated for particle size distribution and flowability. These granules were compacted into tablets at a compression force of 7?kN. The tablets were thermally treated at different temperatures (50 and 75°C) for 5?h and were evaluated for breaking force and dissolution. Increase in roll pressure and TEC levels resulted in a progressive increase in the mean particle size of the granules. The flowability of the granules also improved with increasing roll pressures and TEC levels. Tablet breaking force increased with an increase in TEC levels and sintering temperatures. But these effects were significant only at the highest level of plasticizer and sintering temperature respectively. For the tablets containing Eudragit(?) RS PO, theophylline release decreased proportionately with increase in TEC levels and sintering temperatures. Tablets containing either Eudragit(?) RL PO or a mixture of RS PO and RL PO failed to impart an extended-release property to the tablets at the studied variables i.e. roll pressure, TEC levels and sintering temperature. It was clearly demonstrated that with suitable optimization of these parameters, the release-rate of a water soluble drug from the matrix tablets prepared via roller compaction can be finely controlled.     

Eudragit® RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets

The influence of plasticizer level, roll pressure and sintering temperature was investigated on the granule properties, tablet breaking force and theophylline release from tablets. Nine formulations using theophylline as a model drug, Eudragit^® RL PO, Eudragit^® RS PO, or both as a matrix former and triethyl citrate (TEC) as a plasticizer were prepared. The formulations were roller compacted and the granules obtained were evaluated for particle size distribution and flowability. These granules were compacted into tablets at a compression force of 7?kN. The tablets were thermally treated at different temperatures (50 and 75°C) for 5?h and were evaluated for breaking force and dissolution. Increase in roll pressure and TEC levels resulted in a progressive increase in the mean particle size of the granules. The flowability of the granules also improved with increasing roll pressures and TEC levels. Tablet breaking force increased with an increase in TEC levels and sintering temperatures. But these effects were significant only at the highest level of plasticizer and sintering temperature respectively. For the tablets containing Eudragit^® RS PO, theophylline release decreased proportionately with increase in TEC levels and sintering temperatures. Tablets containing either Eudragit^® RL PO or a mixture of RS PO and RL PO failed to impart an extended-release property to the tablets at the studied variables i.e. roll pressure, TEC levels and sintering temperature. It was clearly demonstrated that with suitable optimization of these parameters, the release-rate of a water soluble drug from the matrix tablets prepared via roller compaction can be finely controlled.     

Utility of multivariate analysis in modeling the effects of raw material properties and operating parameters on granule and ribbon properties prepared in roller compaction

This article aimed to model the effects of raw material properties and roller compactor operating parameters (OPs) on the properties of roller compacted ribbons and granules with the aid of principal component analysis (PCA) and partial least squares (PLS) projection. A database of raw material properties was established through extensive physical and mechanical characterization of several microcrystalline cellulose (MCC) and lactose grades and their blends. A design of experiment (DoE) was used for ribbon production. PLS models constructed with only OP-modeled roller compaction (RC) responded poorly. Inclusion of raw material properties markedly improved the goodness of fit (R(2) = .897) and model predictability (Q(2) = 0.72).     

A novel method for estimating solid fraction of roller-compacted ribbons

A simple method has been developed to estimate solid fraction or relative density of compacts using the weight of ribbons produced during roller compaction. The method provides an alternative to the commonly used dimensional measurement, especially for formulations not amenable to forming quality ribbons. Surface texture of the compaction rolls has been taken into consideration in our mathematical treatment along with correction for ribbon relaxation. Ribbon relaxation occurring upon ribbon exiting the compaction zone is estimated using roll geometry, roll gap, and ribbon thickness. Detailed experimental runs have been carried out to confirm the validity of the proposed theory. The predicted solid fraction was found comparable to that from actual dimensional measurement by caliper. In the case of the microcrystalline cellulose/dicalcium phosphate one:one formulation, the predicted solid fraction had an error sum of squares (SSE) of 2.64E-03 when compared to the dimensional method. When relaxation was included, the SSE decreased by four folds. Similarly, for the microcrystalline cellulose/lactose monohydrate 2:1 formulation, the SSE decreased twelfth folds when relaxation was taken into consideration. These results further confirm the utility of the proposed throughput method for estimating the solid fraction of ribbons.     

A Novel Method for Estimating Solid Fraction of Roller-Compacted Ribbons

A simple method has been developed to estimate solid fraction or relative density of compacts using the weight of ribbons produced during roller compaction. The method provides an alternative to the commonly used dimensional measurement, especially for formulations not amenable to forming quality ribbons. Surface texture of the compaction rolls has been taken into consideration in our mathematical treatment along with correction for ribbon relaxation. Ribbon relaxation occurring upon ribbon exiting the compaction zone is estimated using roll geometry, roll gap, and ribbon thickness. Detailed experimental runs have been carried out to confirm the validity of the proposed theory. The predicted solid fraction was found comparable to that from actual dimensional measurement by caliper. In the case of the microcrystalline cellulose/dicalcium phosphate one:one formulation, the predicted solid fraction had an error sum of squares (SSE) of 2.64E-03 when compared to the dimensional method. When relaxation was included, the SSE decreased by four folds. Similarly, for the microcrystalline cellulose/lactose monohydrate 2:1 formulation, the SSE decreased twelfth folds when relaxation was taken into consideration. These results further confirm the utility of the proposed throughput method for estimating the solid fraction of ribbons.     

Effect of Moisture on the Stability of Solid Dosage Forms

Abstract

It has long been known that moisture affects the stability of some drug substances. Aspirin is a classical example. Aspirin is not wet granulated. Even though the water is driven off in a wet granulation, there is still sufficient moisture stress in the process to induce excessive decomposition on subsequent storage. Dry methods (slugging, roller compaction) are therefore resorted to. In other instances, the moisture sensitivity of a drug may warrant using a hard shall capsule approach. This presumes that the drug substance is not particularly hygroscopic, since, otherwise, the capsule shell will provide an unwanted source of moisture.     

Utility of Multivariate Analysis in Modeling the Effects of Raw Material Properties and Operating Parameters on Granule and Ribbon Properties Prepared in Roller Compaction

This article aimed to model the effects of raw material properties and roller compactor operating parameters (OPs) on the properties of roller compacted ribbons and granules with the aid of principal component analysis (PCA) and partial least squares (PLS) projection. A database of raw material properties was established through extensive physical and mechanical characterization of several microcrystalline cellulose (MCC) and lactose grades and their blends. A design of experiment (DoE) was used for ribbon production. PLS models constructed with only OP-modeled roller compaction (RC) responded poorly. Inclusion of raw material properties markedly improved the goodness of fit (R²?=?.897) and model predictability (Q²?=?0.72).     

Comparison of low-shear and high-shear granulation processes: effect on implantable calcium phosphate granule properties

Background: Calcium phosphate porous ceramics present a great interest not only as complex bone defect fillers but also as drug delivery systems. Most of the methods described in the literature to fabricate pellets are based on compaction, casting into spherical molds, or on processes such as liquid immiscibility or foaming. Despite wet granulation is used in a wide range of applications in pharmaceuticals, food, detergents, fertilizers, and minerals, it is not applied in the biomaterial field to produce granules. Methods: In this study physicochemical and in vitro drug delivery properties of implantable calcium phosphate granules, produced by two wet agglomeration processes, were compared. Pellets obtained by high shear granulation (granulation in a Mi-Pro apparatus) were shown to be more spherical and less friable than granules elaborated by low shear process (granulation in a Kenwood apparatus). Although Mi-Pro pellets had a slightly lower porosity compared to Kenwood granules, ibuprofen loading efficiency and dissolution profiles were not statistically different and the release mechanism was mainly controlled by diffusion, in both cases. Conclusion: Mi-Pro pellets appeared to be better candidates as bone defect fillers and local drug delivery systems as far as they were more spherical and less friable than Kenwood agglomerates.     

Melt granulation and heat treatment for wax matrix-controlled drug release

The purpose of this study was to evaluate sustained drug release after melt granulation and heat treatment. Theophylline (anhydrous) and phenylpropanolamine hydrochloride (PPA) were used as model drugs. Compritol® 888 ATO (Glyceryl Behenate NF) was incorporated as the wax matrix material. Formulations with drug:wax in 3:1 and 1:1 ratios were evaluated. Tablets were made by dry blending or melt granulation; some of the tablets were heat treated at 80°C for 30 min. Tablets with or without heat treatment were tested for drug release using in vitro drug dissolution. The results showed that melt granulation gave slower drug release than dry blending. Heat treatment further retarded drug release for both dry blending and melt granulation. The drug release rates for theophylline were slower than for PPA at the same wax level and processing method. The drug release profiles were linear using a square root of time scale. In conclusion, melt granulation and heat treatment slowed drug release for the wax matrix-controlled release tablets. Heat treatment of the tablets made by melt granulation further retarded drug release. Heat treatment redistributed the wax, forming a new matrix system with higher tortuosity. The application of melt granulation or heat treatment can successfully retard drug release.     

Preparation and evaluation of metoprolol tartrate sustained-release pellets using hot melt extrusion combined with hot melt coating

The objective of this study was to prepare and evaluate metoprolol tartrate sustained-release pellets. Cores were prepared by hot melt extrusion and coated pellets were prepared by hot melt coating. Cores were found to exist in a single-phase state and drug in amorphous form. Plasticizers had a significant effect on torque and drug content, while release modifiers and coating level significantly affected the drug-release behavior. The mechanisms of drug release from cores and coated pellets were Fickian diffusion and diffusion–erosion. The coated pellets exhibited sustained-release properties in vitro and in vivo.     

Preparation of Essential Oils Loaded Granule by Melt Granulation

Abstract

A comparative study on three granulation methods; melt granulation, fluidized bed granulation and wet granulation was performed to fabricate an essential oils loaded granule. The granule properties such as particle size distribution and the loading efficiency of anethole from fennel and cinnamaldehyde from cinnamon showed that the melt granulation in a high shear mixer was the most feasible method among the three methods.

In melt granulation, the granule particle size was well controlled by polyethylene glycol 6000 (PEG) content of which the optimum value was found to De 20%. Impeller speed and massing time in high shear mixer had small contribution to the particle growth when PEG content was optimized, while PEG particle size had some effect. Finer PEG powder improved the uniformity of granule size. Moreover, the cooling method of the hot mass affected the final granule properties significantly. The cooling with a fluid bed dryer was the best method.

Both of the retention rates of anethole and cinnamaldehyde in the final granule were more than 95% of initial doses irrespective of cooling method. Further, the adoption of a fluid bed dryer enabled very rapid cooling of hot granule with negligible loss of essential oils.     

聚丙烯纤维料树脂对无纺布性能的影响研究

目的 研究聚丙烯原料对无纺布的力学和加工性能的影响规律，从而制备出力学性能高、纺丝性能好的无纺布。方法 以不同熔融指数的聚丙烯粉料为基础树脂，使用不同的过氧化物与其进行共混熔融挤出造粒，然后采用气相色谱、高温凝胶渗透色谱、拉伸等测试手段对样品的基础物性、分子结构、气味、VOC、残留物和无纺布的力学性能及加工稳定性等方面进行表征与分析。结果 以熔融指数8 g/10 min(GB/T 3682.1—2018)的粉料为基础树脂，加入少量的3,6,9-三甲基-1,4,7-三过氧壬烷，挤出造粒制备出的4号树脂原料样品。该样品具有高的熔体流动性(MFR为35~40 g/10 min)、窄的分子量分布(3~5)、低灰分和鱼眼数、低气味、低残留的过氧化物等性能，从而制成拉伸强度高、纺丝效率高且加工稳定的无纺布成品。结论 基础聚丙烯树脂的分子量设计、原料的配方体系、工艺路线都对无纺布制品的力学性能和可纺性产生重要影响。     

熔体过热处理技术及其在镍基高温合金中的应用研究进展

镍基高温合金是先进航空发动机高温叶片不可或缺的关键核心材料,目前通过合金化来提高其承温能力已趋于极限。研究表明,材料熔体结构对合金凝固过程、凝固组织、性能以及成形质量具有重要的影响。熔体结构的变化能够直接导致熔体特性发生改变,进而对性能产生影响,然而在实际合金的制备过程中,熔体结构的作用通常被忽略。熔体过热处理技术通过利用合金熔体的遗传效应,将高温熔体的结构保留到低温熔体,从而大幅提高合金性能。系统介绍了熔体过热的原理、主要处理技术以及如何通过X射线衍射和物性参数测量来确定熔体过热处理参数,重点介绍了熔体过热处理技术在优化高温合金凝固组织和提升性能方面的应用,最后提出了熔体过热处理技术发展的方向和面临的挑战。     

Rapid quenching and properties of hard magnetic materials in MnAl-X (X=Ti,Cu, Ni,C, B) systems

MnAl-X (X=Ti, Cu, Ni, C, B) ribbons were fabricated by a rapid quenching from the melt using a single roller method. As-rapid quenched ribbons were quenched completely into high temperature h c p phase. The rapid quenched ribbons were brittle especially carbon doped ribbons, however, the titanium doped ribbons were relatively ductile. Hard magnetic properties were measured using a vibrating sample magnetometer for the ten kinds of ribbons annealed at 410–700° C for 10 min–100 h. Phase transformation characteristics and magnetic properties were discussed by comparison with the samples produced by the conventional method. Titanium, boron and carbon doped ribbons showed good hard magnetic properties.     

Properties of Hot-Melt Extruded Theophylline Tablets Containing Poly(Vinyl Acetate)

The objectives of this study were to investigate the properties of poly(vinyl acetate) (PVAc) as a retardant polymer and to study the drug release mechanism of theophylline from matrix tablets prepared by hot-melt extrusion. A physical mixture of drug, polymer, and drug release modifiers was fed into the equipment and heated inside the barrel of the extruder. The cylindrical extrudates were either cut into tablets or ground into granules and compressed with other excipients into tablets. Due to the low glass transition temperature of the PVAc, the melt extrusion process was conducted at approximately 70°C. Theophylline was used as the model drug in this study. Theophylline was present in the extrudate in its crystalline form and was released from the tablets by diffusion. The Higuchi diffusion model and percolation theories were applied to the dissolution data to explain the drug release properties of the matrix systems. The release rate was shown to be dependent on the granule size, drug particle size, and drug loading in the tablets. Water-soluble polymers were demonstrated to be efficient release rate modifiers for this system.     

Properties of hot-melt extruded theophylline tablets containing poly(vinyl acetate)

The objectives of this study were to investigate the properties of poly(vinyl acetate) (PVAc) as a retardant polymer and to study the drug release mechanism of theophylline from matrix tablets prepared by hot-melt extrusion. A physical mixture of drug, polymer, and drug release modifiers was fed into the equipment and heated inside the barrel of the extruder. The cylindrical extrudates were either cut into tablets or ground into granules and compressed with other excipients into tablets. Due to the low glass transition temperature of the PVAc, the melt extrusion process was conducted at approximately 70°C. Theophylline was used as the model drug in this study. Theophylline was present in the extrudate in its crystalline form and was released from the tablets by diffusion. The Higuchi diffusion model and percolation theories were applied to the dissolution data to explain the drug release properties of the matrix systems. The release rate was shown to be dependent on the granule size, drug particle size, and drug loading in the tablets. Water-soluble polymers were demonstrated to be efficient release rate modifiers for this system.