The influence of direct compression powder blend transfer method from the container to the tablet press on product critical quality attributes: a case study

Objective: The aim of this article is to compare the gravitational powder blend loading method to the tablet press and manual loading in terms of their influence on tablets’ critical quality attributes (CQA).

Significance: The results of the study can be of practical relevance to the pharmaceutical industry in the area of direct compression of low-dose formulations, which could be prone to content uniformity (CU) issues.

Methods: In the preliminary study, particle size distribution (PSD) and surface energy of raw materials were determined using laser diffraction method and inverse gas chromatography, respectively. For trials purpose, a formulation containing two pharmaceutical ingredients (APIs) was used. Tablet samples were collected during the compression progress to analyze their CQAs, namely assay and CU.

Results: Results obtained during trials indicate that tested direct compression powder blend is sensitive to applied powder handling method. Mild increase in both APIs content was observed during manual scooping. Gravitational approach (based on discharge into the drum) resulted in a decrease in CU, which is connected to a more pronounced assay increase at the end of tableting than in the case of manual loading.

Conclusions: The correct design of blend transfer over single unit processes is an important issue and should be investigated during the development phase since it may influence the final product CQAs. The manual scooping method, although simplistic, can be a temporary solution to improve the results of API’s content and uniformity when compared to industrial gravitational transfer.     

Monitoring of the manufacturing process for ambroxol hydrochloride tablet using NIR-chemometric methods: compression effect on content uniformity model and relevant process parameters testing

This study aimed at using near-infrared (NIR) spectroscopy to monitor compaction pressure for simultaneously determining the tensile strength and content uniformity, as well as moisture and mean particle size of ambroxol hydrochloride tablets. The content uniformity, compression force and tensile strength of the laboratory samples were obtained by pressing a mixture of active principle and excipient components into tablets. To reduce the spectral baseline shift of the laboratory samples, the compaction pressure applied to the mixture was assessed by a variable pressure test. Production samples were added to the test and subjected to principal component analysis. The expanded partial least-squares (PLS) calibration model used to quantify the active content was more accurate than the model constructed from laboratory samples using the production tablets included in the calibration set. The model showed good predictability, with correlation coefficient (R) 0.9977. The validation and reliability of the content model were evaluated to determine trueness and reliability for the measurement of individual production tablets and the laboratory tablets with drug content ranging from 24 to 36?mg. The PLS calibration models for compression force and tensile strength were constructed using the same spectral set assuming both were highly related. These models yielded high R values (0.9955 and 0.9910). The R values of the moisture and mean particle size were 0.9994 and 0.9919, respectively. This study demonstrated that NIR spectroscopy combined with chemometric techniques can be successfully used to quantitatively monitor the tablet manufacturing process in the pharmaceutical industry.     

The effects of relative humidity and super-disintegrant concentrations on the mechanical properties of pharmaceutical compacts

The influence of the composition and the relative humidity on the properties of pharmaceutical compacts prepared from mixtures of three excipients and three super-disintegrants was evaluated. Various amounts of super-disintegrant and different conditions of relative humidity during the storage were used to study mechanistically the disintegration process and to connect it to compact's mechanical properties. Three point single beam test was used to measure tensile strength and Young's modulus of compacts containing various amount of disintegrant and stored under various relative humidity. The presence of moisture within pharmaceutical compacts containing a disintegrant influences drastically their mechanical properties. Then, the results are related to micro-cracks visualized by MEB.     

The effect of silicon dioxide content of natural stones on their strength properties,material removal rate and power consumption in diamond grinding

The paper addresses the influence of silicon dioxide content of natural stones on their Mohs hardness, ultimate uniaxial compression strength, microhardness as well as on the removal rate and power consumption in diamond grinding of these materials. An increase in the amount of this constituent in natural stones is demonstrated to have an effect on strength properties and power consumption in grinding and a considerable effect on removal rate in diamond grinding.     

CNTs含量对CNTs/Al微观组织及力学性能的影响

为增加碳纳米管(CNTs)在铝基体中的分散性,利用机械球磨-真空热压烧结工艺制备碳纳米管/铝(CNTs/Al)复合材料,采用扫描电子显微镜(SEM)、电子万能试验机和万能摩擦磨损实验机,研究了CNTs质量分数对CNTs/Al复合材料微观组织、力学性能及摩擦磨损性能的影响.结果表明:CNTs经超声波预先分散后分散性增加;当CNTs质量分数为2.0%时,复合材料中CNTs与Al粉之间表现出较好的相容性;随着CNTs含量进一步增加,CNTs团聚现象严重;热压烧结温度600℃时,随着CNTs添加量的增加,铝基复合材料的屈服强度和抗拉强度呈现出明显的先增大后降低的趋势,同时,CNTs/Al复合材料的摩擦因数和磨损率随CNTs含量的增大先减小后增加;CNTs质量分数为2.0%时,复合材料的屈服强度最大值为116 MPa,抗拉强度最大值为245 MPa,与纯Al基体相比,分别提高了78%和1.9倍.2.0%CNTs/Al复合材料可获得较好的摩擦磨损性能,其摩擦系数和磨损率呈现平缓趋势,复合材料的磨痕最浅.     

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.     

The effects of fabrication atmosphere condition on the microstructural and mechanical properties of laser direct manufactured stainless steel 17-4 PH

The effects of atmosphere conditions on microstructural and mechanical properties of stainless steel 17-4PH components fabricated by laser direct manufacturing (LDM) were investigated through measurements on phase constitution, porosity, tensile strength, fracture morphology, hardness and evolution of substrate temperature. Results showed that the samples produced in air atmosphere condition possessed higher tensile strength and hardness for both as-deposited and heat-treated states than that in Ar chamber condition, due to dispersion strengthening effect of amorphous oxide particles and nitrogen solution strengthening as a result of higher content of oxygen and nitrogen. The temperature of substrate heat accumulation was higher in Ar chamber condition, leading to dramatically lower porosity and more reverse austenite, which also contributed to the lower strength and hardness.     

High‐pressure processing effects on the mechanical,barrier and mass transfer properties of food packaging flexible structures: a critical review

Food products can be high‐pressure processed (HPP) either in bulk or prepackaged in flexible or semi‐rigid packaging materials. In the latter case the packaging material is subjected, together with the food, to high‐pressure treatment. A number of studies have been performed to quantify the effects of high‐pressure processing on the physical and barrier properties of the packaging material, since the integrity of the package during and after processing is of paramount importance to the safety and quality of the food product. This article reviews the results of published research concerning the effect of HPP on packaging materials. Copyright © 2004 John Wiley & Sons, Ltd.     

Chitosan tailor‐made films: the effects of additives on barrier and mechanical properties

With the aim of achieving ‘tailor‐made’ chitosan films, the effects of several variables on the properties of chitosan films were studied. These variables were chitosan concentration and molecular weight of thermally depolymerized chitosan, addition of lipids (palmitic acid, beeswax or carnauba wax) and plasticizer (glycerol). The water vapour transmission rate (WVTR) and mechanical properties of these films were measured. The innovative feature of this study is that it provides specific information to support the design of tailor‐made films. These can only be formulated when the effects of the important variables are well understood. It was found that WVTR was reduced by 57% in film made from chitosan that had been thermally treated for 7 h at 100°C (molecular mass 13.7 kDa), while in the emulsion films, the WVTR was increased by incorporation of palmitic acid, beeswax or carnauba wax incorporation. The mechanical properties (tensile strength and elongation at break) were improved when glycerol was used as plasticizer, resulting in more elastic films (increasing the elongation at break by 62%). Copyright © 2008 John Wiley & Sons, Ltd.     

Combining strategies to optimize a gel formulation containing miconazole: the influence of modified cyclodextrin on textural properties and drug release

Background: Miconazol, an antimycotic drug, is commonly formulated into semisolid formulations designed to be applied in the oral cavity to treat oral candidiasis. However, given its limited aqueous solubility, permeation through the biological membranes is low and therefore its activity is also limited. Cyclodextrins (CDs) have been widely used to increase the solubility and stability of poorly water-soluble drugs. Aim: The aim of this study is to formulate a gel containing an inclusion complex between a modified CD, methyl-β-cyclodextrin (MβCD), and miconazole (MCZ). The influence of the CD on the textural properties of the prepared gel and the drug release from formulation were evaluated. Methods: The gels were prepared using two polymers, Carbopol 71G and Pluronic F127, which were selected taking into account their bioadhesiveness and thermal-sensitive gelling properties, respectively. Texture profile analyses were performed at two different temperatures to ascertain the influence of the temperature on the gel texture properties. The in vitro MCZ release profiles from the prepared gel and the commercial gel formulations were evaluated and compared using modified Franz diffusion cells. Results: The addition of MβCD to the gel resulted in a decrease of the gel adhesiveness and firmness, and the MCZ release profile through f1 and f2 proved to be similar to the commercial product. Conclusions: A gel comprising miconazol in the form of an inclusion complex with MβCD showed suitable textural properties to be applied to the buccal mucosa. The MβCD enhanced the solubility of the MCZ in the gel formulation resulting in adequate in vitro drug release profiles.     

Effect of recycled content and rPET quality on the properties of PET bottles,part II: Migration

Polyethylene terephthalate (PET) bottles were produced from three types of recycled PET (rPET) with four levels of recycled content. The migration of substances from these bottles to water was studied. Several migrated substances were detected. The migrated amounts of acetaldehyde and ethylene glycol complied with the limits given in the food contact material (FCM) legislation. Migration of 2-methyl-1,3-dioxolane was below the limit of 10 μg·L⁻¹, which is conventionally applied for non-intentionally added substances (NIAS) not classified as ‘carcinogenic’, ‘mutagenic’ or ‘toxic to reproduction’ (CMR). Limonene, acetone, butanone and furan were also detected as migrants, of which limonene is a natural fragrant, and the other three are probably residues from solvents used to clean and protect the mould at the small-scale production facility. Finally, benzene and styrene were also found as migrants from rPET. These migrants appear to originate from heat-induced reactions within the PET matrix, which involve contaminants. The formation of benzene in rPET is attributed to polyvinylchloride as contaminant. The migrated amounts of benzene from the PET bottles with recycled content to the water simulant are relatively small (0.03–0.44 μg·L⁻¹) after 10 days at 40°C. Consequently, the margin of exposure is 3.10⁵–8.10⁶. Hence, the level of concern for the public health is low, and the migrated amount represents a low priority for risk management. The FCM legislation demands a risk assessment for migrating NIAS. Depending on the underlying data and exposure scenario, different threshold limits in the food can be derived which can still be considered as safe.     

Effects of temperature and clay content on water absorption characteristics of modified MMT clay/cyclic olefin copolymer nanocomposite films: Permeability,dynamic mechanical properties and the encapsulated organic device performance

In the present study, amino-silane modified layered organosilicates were used to reinforce cyclic olefin copolymer to enhance the thermal, mechanical and moisture impermeable barrier properties. The optimum clay loading (4%) in the nanocomposite increases the thermal stability of the film while further loading decreases film stability. Water absorption behavior at 62 °C was carried out and compared with the behavior at room temperature and 48 °C. The stiffness of the matrix increases with clay content and the recorded strain to failure for the composite films was lower than the neat film. Dynamic mechanical analysis show higher storage modulus and low loss modulus for 2.5–4 wt% clay loading. Calcium degradation test and device encapsulation also show the evidence of optimum clay loading of 4 wt% for improved low water vapor transmission rates compared to other nanocomposite films.     

High shear wet granulation: Improved understanding of the effects of process variables on granule and tablet properties of a high-dose,high-hydrophobicity API based on quality by design and multivariate analysis approaches

High shear wet granulation (HSWG), as a widely used granulation technology, has been studied extensively. However, for the HSWG of formulations containing hydrophobic components, the influence of process variables on the properties of granules and tablets has not been reported. In the present study, based on a combination of quality by design and multivariate analysis (MVA) approaches, quercetin with high-dose and high-hydrophobicity was used to study the relationship between process variables, granule properties, and tablet properties in HSWG systematically. Control and response variables were determined using risk assessment. The optimal fitting empirical models established by Box-Behnken design showed that the liquid to solid ratio and impeller speed were the most important factors, which affected all product properties except Carr’s index and yield pressure. Instead, the influence of wet massing time was relatively small (only the effects on yield, granule size, granule hardness, and compression ratio were significant). Then, the process design space was obtained by limiting the related critical quality attributes, which was verified effectively. Scanning electron microscope images showed that smooth granules were produced using higher process parameters, whereas rough and porous granules resulted at lower process parameters. Furthermore, the MVA results demonstrated that increasing the granule hardness led to an increase in the compression ratio and a decrease in tensile strength of the tablets. Tablet fragility and disintegration time were mainly affected by granule density and bulk density, respectively, and both were negatively correlated. The established research paradigm is not only conducive to the successful development of quercetin products, but also provides valuable guidance for improving HSWG–based product development with such formulation characteristics.