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.     

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).     

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).     

Impact of roll compaction design,process parameters,and material deformation behaviour on ribbon relative density

Ribbons from microcrystalline cellulose (MCC), mannitol, and their 50:50% mixture were produced using the roll compactors AlexanderWerk BT120, Hosokawa Alpine Pharmapaktor C250, L.B. Bohle BRC 25, and Gerteis Mini-Pactor in the frame of multilevel full factorial experimental plans. The specific compaction force (SCF)/hydraulic pressure (HP), gap width (GW), roll speed, and fraction of MCC were analyzed as quantitative factors, whereas the roll surface and sealing system were examined as qualitative factors. Ribbon relative density was investigated as response of the models. The SCF/HP is found to be the most significant factor in each model. A significant inverse effect of the GW is obtained in the models of AlexanderWerk BT120, Pharmapaktor C250, and BRC 25 roll compactors, using smooth rolls. The principle of the establishment of a conversion factor (c_f) is introduced based on the obtained data sets of AlexanderWerk BT120 and Mini-Pactor. This can facilitate the transfer of a roll compaction process between different types of roll compactors.     

Investigation of the physical–mechanical properties of Eudragit® RS PO/RL PO and their mixtures with common pharmaceutical excipients

Ammonio methacrylate copolymers Eudragit^® RS PO and Eudragit® RL PO have found widespread use as key components in various types of extended release solid dosage forms. The deformation behavior of neat polymers and binary mixes was evaluated using Heckel Analysis, strain rate sensitivity, work of compaction and elastic recovery index. Additionally, the compact forming ability of neat materials and binary mixes were evaluated by analyzing their tabletability, compressibility and compactibility profiles. The Heckel analysis of both polymers exhibited a speed-sensitive deformation behavior typical to plastic materials. The yield values of the binary mixes of the polymers with microcrystalline cellulose revealed a linear relationship with the weight fractions of individual components. The yield values of binary mixes of both the polymers with dibasic calcium phosphate exhibited slight negative deviations from linearity. Both polymers exhibited axial relaxation after ejection typical of viscoelastic materials, as measured by the elastic recovery index values. The work of compaction and the elastic recovery index values of the binary mixtures were found to be linearly related to the weight fractions of the individual components thus, confirming ideal mixing behavior based on the composition. Addition of microcrystalline cellulose to both polymers significantly improved their tabletability and compactibility. The tensile strengths of the compacts prepared with neat materials and binary mixes with microcrystalline cellulose, dibasic calcium phosphate and lactose were the function of their solid fraction and independent of the tableting speeds tested; thus, validating compactibility as a reliable parameter in predicting acceptable tablet properties.     

Discontinuous metallic-glass ribbon reinforced glass-ceramic matrix composites

Discontinuous metallic-glass ribbons of varying lengths and widths were used to reinforce a brittle glass-ceramic matrix. The fracture strength and toughness of such composites as a function of ribbon volume fraction and geometry were measured by three-point bending. The mechanical properties were found to be relatively isotropic in the plane of compaction (without significant loss of strengthening achieved with unidirectional reinforcement). The higher composite strength exhibited in a direction perpendicular to the plane of compaction was attributed to the higher percentage of ribbons oriented with their short transverse faces perpendicular to the opening crack front.     

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.     

An investigation into the impact of magnesium stearate on powder feeding during roller compaction

A systematic evaluation on the effect of magnesium stearate on the transmission of a placebo formulation from the hopper to the rolls during screw fed roller compaction has been carried out. It is demonstrated that, for a system with two 'knurled' rollers, addition of 0.5% w/w magnesium stearate can lead to a significant increase in ribbon mass throughput, with a consequential increase in roll gap, compared to an unlubricated formulation (manufactured at equivalent process conditions). However, this effect is reduced if one of the rollers is smooth. Roller compaction of a lubricated formulation using two smooth rollers was found to be ineffective due to a reduction in friction at the powder/roll interface, i.e. powder was not drawn through the rollers leading to a blockage in the feeding system. An increase in ribbon mass throughput could also be achieved if the equipment surfaces were pre-lubricated. However this increase was found to be temporary suggesting that the residual magnesium stearate layer was removed from the equipment surfaces. Powder sticking to the equipment surfaces, which is common during pharmaceutical manufacturing, was prevented if magnesium stearate was present either in the blend, or at the roll surface. It is further demonstrated that the influence of the hopper stirrer, which is primarily used to prevent bridge formation in the hopper and help draw powder more evenly into the auger chamber, can lead to further mixing of the formulation, and could therefore affect a change in the lubricity of the carefully blended input material.     

Assessment of granulation technologies for an API with poor physical properties

Granulation technologies are widely used in solid oral dosage forms to improve the physical properties during manufacture. Wet, dry, and melt granulation techniques were assessed for Compound A, a BCS class II compound. Characterization techniques were used to quantify physical property limitations inherent for Compound A including hygroscopicity, low solubility and bulk density, and poor powder flowability. High shear aqueous wet granulation induced an undesirable water mediated phase transition of the solid form. A formulation and process for dry granulation by roller compaction was developed and scaled to 10 kg batch size. Roll force, and roll gap parameters were assessed. Porosity of compacted ribbons was analyzed by mercury intrusion porosimetry, and particle size distributions of milled ribbons by sieve analysis. A roll force of 15 kN/cm produced granules with higher density and improved flow properties compared to the pre-blend. Fines content (<75 µm) decreased from approximately 90% pre-granulation to 26% post-granulation. Cohesive properties of Compound A limited drug loading (API:excipient ratio) in roller compaction to 0.6:1 or less. Hot melt granulation by extrusion assessed with four polymers. A vast improvement in drug loading of 4:1 was achieved via melt processes using low molecular weight thermo-binders (glyceryl behenate and Polyethylene glycol 4000). Granules produced by melt processing contained less fines compared to wet and dry granulation. Both roller compaction and melt extrusion are viable granulation process alternatives for scale up to overcome the physical property limitations of Compound A.     

Acoustic Characterization of a Microcrystalline Cellulose Powder During and After Its Compression

Acoustic emissions were detected, both during the roller compaction of the microcrystalline cellulose powder and from single tablets after compaction by a single-punch tablet machine, via air using a microphone with a flat frequency response up to 20 kHz. Both of the compaction units were instrumented for the measurement of applied compressive force. The microcrystalline cellulose roller compacted using compressive forces below 30 kN showed a quite normal compaction behaviour but the product compacted at this force split into two and turned to yellow by its edges. This “capping” phenomenon was indicated by an enhancement of acoustic emission in the region of about 17-23 kHz. Acoustic emissions from single tablets after compaction by a single-punch tablet machine seemed to appear as wave packets consisting in very many frequency components that may, in addition, be time-varying. However, some small peaks were found probably being characteristic of these transient sounds.     

Water Vapour Interaction with Pharmaceutical Cellulose Powders

Since interaction between water and particulate solid is a major factor in formulation, processing and product performance of pharmaceuticals, the moisture sorption properties of four grades of microfine cellulose (MFC) and three grades of microcrystalline cellulose (MCC) were investigated.     

A THREE-DIMENSIONAL FINITE ELEMENT MODEL FOR POWDER COMPACTION—TIME-DEPENDENT FORMULATION AND VALIDATION

Many industrial powders have been documented to have time-dependent compression response. However, in the literature very few time-dependent formulations are reported for three-dimensional analysis of powder compaction. In the paper, a time-dependent constitutive model, based on the theory proposed by Adachi and Oka, was used in a three-dimensional finite element formulation suitable for PC or desktop environments. The finite element model (FEM) predicts both the stress and density distributions in the powder mass during compression, i.e., from no load to the maximum compression load. A user-friendly interactive GUI (graphical user interface) was developed for the 3-D FEM, making it easy to use. To validate the FEM, microcrystalline cellulose was compressed to form cylindrical pellets using a press. The pellet was used to obtain spatial density distribution using the sectioning method. Then, the measured density distribution was compared with the Adachi and Oka model-based FEM calculated values. The density distributions were predicted within the 95% confidence interval of measured values. In addition, the overall error between the measured and predicted density values throughout the pressed pellet was less than 10%     

超声波辅助纤维素系高吸水树脂的合成及表征

选用可生物降解的纤维素为基本骨架,利用硝酸铈铵作为引发剂处理纤维素,采用超声波辅助方法使其与丙烯酸发生接枝共聚反应,合成高吸水树脂.研究超声波功率、引发剂用量、丙烯酸与微晶纤维素的质量比、中和度、交联剂用量对树脂吸水倍率的影响,并对纤维素系高吸水树脂进行红外光谱和扫描电镜分析.结果表明,最佳工艺条件:超声波功率为500 W,引发剂用量为1.8 mL,丙烯酸与微晶纤维素的质量比为3.0:2.0,中和度为50％,交联剂质量分数为0.10％.此条件下制得的吸水树脂的吸蒸馏水倍率为486倍,吸自来水倍率为173倍.经红外光谱和扫描电子显微镜综合分析,证明超声波处理可以使得微晶纤维素表面发生变化,促进微晶纤维素与丙烯酸的固相接枝共聚,合成的纤维素系高吸水树脂保留了微晶纤维素分子骨架和聚丙烯酸各自的特性,在纤维素大分子表面和无定型区引发了接枝聚合.     

A THREE-DIMENSIONAL FINITE ELEMENT MODEL FOR POWDER COMPACTION—TIME-DEPENDENT FORMULATION AND VALIDATION

ABSTRACT

Many industrial powders have been documented to have time-dependent compression response. However, in the literature very few time-dependent formulations are reported for three-dimensional analysis of powder compaction. In the paper, a time-dependent constitutive model, based on the theory proposed by Adachi and Oka, was used in a three-dimensional finite element formulation suitable for PC or desktop environments. The finite element model (FEM) predicts both the stress and density distributions in the powder mass during compression, i.e., from no load to the maximum compression load. A user-friendly interactive GUI (graphical user interface) was developed for the 3-D FEM, making it easy to use. To validate the FEM, microcrystalline cellulose was compressed to form cylindrical pellets using a press. The pellet was used to obtain spatial density distribution using the sectioning method. Then, the measured density distribution was compared with the Adachi and Oka model-based FEM calculated values. The density distributions were predicted within the 95% confidence interval of measured values. In addition, the overall error between the measured and predicted density values throughout the pressed pellet was less than 10%     

Surface composition of scratched and sputtered Al–Cu ribbons prepared by melt-spinning

In this study, aluminium–copper ribbons of various compositions are prepared by melt-spinning and analysed by Auger electron spectroscopy. Rapidly solidified ribbons usually show a microcrystalline or featureless microstructure, especially in zones located near the surface solidified in direct contact with the rotating wheel. The composition of that surface of the ribbons was analysed by Auger electron spectroscopy. These measurements were performed in both scratched and also ion sputtered zones. After sputtering of the ribbon surface with argon ions, a surface enrichment in copper was observed. However scratching the surface of the ribbons produced a surface composition nearly identical to the bulk. The interest of rapidly solidified alloys in calibration applications is discussed.     

Compaction Properties of Spheronized Binary Granular Mixtures

Two spheronized granular formulations containing 20% anhydrous lactose/80% microcrystalline cellulose (MCC) and 80% anhydrous lactose/20% microcrystalline cellulose were blended in various proportions and compressed. Physical-mechanical properties of the resulting compacts were investigated using tableting indices and compared with powder mixtures of the same compositions. The compacts were compressed at a solid fraction of 0.80 for both powder and bead mixtures. An additional set of bead compacts were made at a solid fraction of 0.87. The thickness of the compacts was measured in the post-ejection stage to investigate their expansion behavior. The tensile strength with and without a stress concentrator and the dynamic indentation hardness of the compacts were determined. The brittle fracture index (BFI) and bonding index (BI) values were also calculated. The microstructure of the beads and compacts were investigated using scanning electron microscopy to observe the bonding phenomena. The results showed that the compacts made from beads underwent different compaction/consolidation behaviors than the powders of the same lactose/MCC compositions. For powdered compacts, the tensile strength with or without a stress concentrator increased with increasing MCC content while the compacts made from beads showed the opposite trend. However, this trend was not seen in the indentation hardness test. The resulting BFI values were all low due to the plastic nature of the materials selected. The BI values of the bead and powder compacts also exhibited opposite tendencies and reflected the divergent mechanical properties of the materials presented in granulated and powdered forms. Microstructure studies revealed the bonding states between the beads in the compacts. Discrepancies in mechanical properties were related to the compressibility, compactibility, and porosities of the excipients studied.     

Use of highly compressible Ceolus™ microcrystalline cellulose for improved dosage form properties containing a hydrophilic solid dispersion

The development of amorphous solid dispersions containing poorly soluble drug substances has been well-documented; however, little attention has been given to the development of the finished dosage form. The objective of this study was to investigate the use of Ceolus(?) microcrystalline cellulose, a highly compressible excipient, for the production of rapidly disintegrating tablets containing a hydrophilic solid dispersion of a poorly soluble drug, indomethacin. Solid dispersions of indomethacin and Kollidon(?) VA64 were prepared by hot melt extrusion and characterized for amorphous nature. Milled dispersion particles at 500 mg/g drug loading were shown to be amorphous by differential scanning calorimetry and provided rapid dissolution in sink conditions. Physical characterization of the milled extrudate showed that the particle size of the intermediate was comparable with Ceolus(?) PH-102 and larger than the high compressibility grades of microcrystalline cellulose selected for the trial (Ceolus(?) KG-802, Ceolus(?) UF-711). Preliminary tableting trials showed that dissolution performance was significantly reduced for formulations at dispersion loadings in excess of 50%. Using a mixture design of experiments (DOE), the levels of PH-102, KG-802, UF-711, and PH-301 were optimized. Trials revealed a synergistic relationship between conventional grades (PH-102 and PH-301) and highly compressible grades (KG-802 and UF-711) leading to improved compression characteristics and more rapid dissolution rates. The formulation and resulting compressibility were also shown to have an impact on in vitro supersaturation indicating tablet formulation could impact oral bioavailability. Through the use of highly compressible microcrystalline cellulose grades such as Ceolus(?) KG-802 and UF-711, it may be possible to maximize the bioavailability benefit of amorphous solid dispersions administered as tablet dosage forms.     

Effects of partial crystallinity and quenched-in defects on corrosion of a rapidly solidified Ti-Cu alloy

Rapid solidification by planar flow casting has been found to have introduced deficiencies, viz. partial crystallinity, air pockets and compositional difference in the ribbons of rapidly solidified Tiin42.9Cuin57.1 alloy. In order to investigate the effects of these deficiencies on the corrosion of rapidly solidified Tiin42.9Cuin57.1 alloy ribbons, electrochemical behaviour of alloy ribbons has been investigated in the acidic chloride environments at room temperature by taking into consideration each side of the alloy ribbon separately. The alloy displayed passivity followed by pitting corrosion. In the as- solidified condition, air pockets appear to be the most detrimental defect from the viewpoint of corrosion resistance of the alloy ribbons.     

The influence of API concentration on the roller compaction process: modeling and prediction of the post compacted ribbon,granule and tablet properties using multivariate data analysis

Objective: While previous research has demonstrated roller compaction operating parameters strongly influence the properties of the final product, a greater emphasis might be placed on the raw material attributes of the formulation. There were two main objectives to this study. First, to assess the effects of different process variables on the properties of the obtained ribbons and downstream granules produced from the rolled compacted ribbons. Second, was to establish if models obtained with formulations of one active pharmaceutical ingredient (API) could predict the properties of similar formulations in terms of the excipients used, but with a different API.

Materials and methods: Tolmetin and acetaminophen, chosen for their different compaction properties, were roller compacted on Fitzpatrick roller compactor using the same formulation. Models created using tolmetin and tested using acetaminophen. The physical properties of the blends, ribbon, granule and tablet were characterized. Multivariate analysis using partial least squares was used to analyze all data.

Results: Multivariate models showed that the operating parameters and raw material attributes were essential in the prediction of ribbon porosity and post-milled particle size. The post compacted ribbon and granule attributes also significantly contributed to the prediction of the tablet tensile strength.

Conclusions: Models derived using tolmetin could reasonably predict the ribbon porosity of a second API. After further processing, the post-milled ribbon and granules properties, rather than the physical attributes of the formulation were needed to predict downstream tablet properties. An understanding of the percolation threshold of the formulation significantly improved the predictive ability of the models.