Mechanical properties of powders for compaction and tableting: an overview

This review provides an insight into mechanical properties that are critical to understanding powder processing for tableting. Various parameters that reflect these basic fundamental properties of powder and their evaluation by different techniques are described. Some recent examples in which these techniques are used in drug substance selection, formulation optimization or scale-up are also provided.     

Roller compaction of crude plant material: influence of process variables, polyvinylpyrrolidone, and co-milling

Roller compaction of a milled botanical (Baphicacanthus cusia) with and without a binder, polyvinylpyrrolidone (PVP) was conducted. Effects of co-milling on binder function and flowability of the powder blend was also investigated. Flakes were comminuted, and the size and size distribution, friability, Hausner ratio, and Carr index of the granulations were determined. Crude herb should be reduced to a suitable size for it to be successfully roller compacted. Larger-sized and less friable granules were obtained with decreasing roller speed. Addition of PVP affected the flowability and binding capacity of the herbal powder blend, which influenced size and friability of the granules. Co-milling of PVP with the herbal powder enhanced the flow of the blends and the effectiveness of the binder, which contributed favorably to the roller-compacted product. Roller compaction is a convenient and cost-effective granulating technique suitable for milled botanicals. Co-milling can be used to improve the properties of roller-compacted products.     

Preparation of controlled porosity osmotic pump tablets for salvianolic acid and optimization of the formulation using an artificial neural network method

In this paper controlled porosity osmotic pump tablets (CPOPT) for salvianolic acid (SA) were prepared and optimized with experimental design methods including an artificial neutral network (ANN) method. Three causal factors, i.e., drug, osmotic pressure promoting agent rate, PEG400 content in coating solution and coating weight, were evaluated based on their effects on drug release rate. The linear correlation coefficient of the accumulative amount of drug release and the time of 12 h, r(Y₁), and the sum of the absolute value between measured and projected values, Y₂, were used as outputs to optimize the formulation. The weight expression Y=(1?Y₁)²+Y₂² was used in the calculation. Furthermore, the ANN and uniform design gave similar optimization results, but ANN projected the outputs better than the uniform design. This paper showed that the release rate of salvianolic acid B and that of the total salvianolic acid was consistent in the optimized formulation.     

Facile radiolabeling optimization process via design of experiments and an intelligent optimization algorithm: Application for omeprazole radioiodination

The major uses of radiopharmaceuticals (RP) in clinical areas are diagnosis and/or therapy. The present study aimed to utilize the application of fractional factorial design analysis (FFDA) coupled with particle swarm optimization algorithm (PSO) to assess the optimization of RP production process. In this regard, omeprazole (OMP), which is gastric parietal cell proton pump inhibitor (PPI), was radiolabeled with iodine‐125 (¹²⁵I) isotope in order to be used as a radiotracer for stomach imaging. Different factors that affect radiolabeling process were studied. According to the proposed design, just 16 experimental runs of radiolabeling process were performed using the extremes of each factor. In addition, one run was executed at the mean point of each factor. Undesirable maximum radiolabeling yield (RY) of radioiodinated omeprazole (¹²⁵I‐OMP) was deduced from application of FFDA (88.4%). Furthermore, after applying PSO with changing limits of one factor, the maximum RY of ¹²⁵I‐OMP was found to be 93.78%. Moreover, the practically verification from optimum conditions, which obtained from PSO, was found to give an RY of 93.99%. Overall, the findings of this study confirmed the potential use of that hybrid design for optimization of radiolabeling processes.     

Roll compaction/dry granulation: effect of raw material particle size on granule and tablet properties

The influence of particle size of MCC, as a binder, and theophylline, as an active pharmaceutical ingredient on the process of roll compaction/dry granulation was investigated using a D-optimal design of experiments. Examined parameters were particle size of both starting materials, fraction of theophylline and ribbon porosity. Therefore, different binary mixtures were roll compacted, dry granulated and compressed into tablets. Flowability of powders and granules and tensile strength of tablets made from powders or granules were the focus of this study. This study showed that a decrease in particle size of MCC or theophylline resulted in an increase of tensile strength even after roll compaction/dry granulation. Comparing tensile strength of tablets made from powder using large size MCC with ones made from granules with small sized MCC revealed that the tensile strength of tablets produced from granules was equal or even higher than tensile strength from direct compressed tablets. Furthermore, using small sized MCC instead of large sized MCC led to larger granules with better flowability. It is shown that the fraction of binder can be reduced without a loss of tensile strength of the final tablets by size reduction of MCC.     

舒乐颗粒制备工艺的优化研究

目的探讨舒乐颗粒的处方配伍及制备工艺。方法采用正交试验设计,考察乙醇体积分数、乙醇用量、提取时间、提取次数对三七提取结果的影响,优选出最佳工艺;同时比较水煎煮法、甲醇冷浸法和95%乙醇回流3次法提取豨莶草奇壬醇;比较乙醇回流提取、超声提取和超声加乙醇回流提取法提取绞股蓝皂苷;混合各提取物与其余各药的水提物、炮甲珠粉来制备舒乐颗粒。结果优化三七提取工艺为:乙醇体积分数70%,乙醇用量6倍,提取时间30 min,提取1次;甲醇冷浸法提取豨莶草优于水提法;绞股蓝较佳提取法是75%乙醇超声提取。结论按最优组合的三七提取液中总皂苷含量较高,乙醇超声提取绞股蓝皂苷效果好,甲醇冷浸提豨莶草简便快捷,适用于大生产。     

Roller compaction and tabletting of St. John's wort plant dry extract using a gap width and force controlled roller compactor. II. Study of roller compaction variables on granule and tablet properties by a 3(3) factorial design

The purpose of this study was to investigate the influence of roller compaction parameters and the amount of magnesium stearate used in dry granulation on granule and tablet properties of a dry herbal extract from St. John's wort (Hypericum perforatum L.). Two different extract batches were blended with magnesium stearate and compacted using a gap width and force controlled roller compactor. A 3(3) factorial design was used to evaluate the influence of the three independent variables, the amount of magnesium stearate, the roller compaction force, and the granulating sieve size on the mean particle size of granulated extracts and on the disintegration time of tablets containing these granulated extracts. The evaluation was done by multilinear stepwise regression analysis. The mean particle size d50 (R2 > 0.9) of both compacted extracts increased with increasing compaction force and with granulating sieve size. The disintegration time of the tablets was mostly in the range 5-15 min and increased slightly with increasing magnesium stearate concentration in the compacted extract and with decreasing compaction force of the roller compaction. The incorporation of magnesium stearate into the granulated extract reduced its potential negative influence on the disintegration time, while maintaining its functionality as a lubricant.     

A comparative study of the influence of alpha-lactose monohydrate particle morphology on granule and tablet properties after roll compaction/dry granulation

The influence of particle morphology and size of alpha-lactose monohydrate on dry granules and tablets was studied. Four different morphologies were investigated: Two grades of primary crystals, which differed in their particle size and structure (compact crystals vs. agglomerates). The materials were roll compacted at different specific compaction forces and changes in the particle size distribution and the specific surface area were measured. Afterwards, two fractions of granules were pressed to tablets and the tensile strength was compared to that from tablets compressed from the raw materials. The specific surface area was increased induced by roll compaction/dry granulation for all materials. At increased specific compaction forces, the materials showed sufficient size enlargement. The morphology of lactose determined the strength of direct compressed tablets. In contrast, the strength of granule tablets was leveled by the previous compression step during roll compaction/dry granulation. Thus, the tensile strength of tablets compressed directly from the powder mixtures determined whether materials exhibited a loss in tabletability after roll compaction/dry granulation or not. The granule size had only a slight influence on the strength of produced tablets. In some cases, the fraction of smaller granules showed a higher tensile strength compared to the larger fraction.     

Determination of content uniformity and distribution characteristics of an investigational drug in its tablets dosage form and granule by ICP-AES

An investigational drug (A) in its calcium salt form has been developed as the tablet dosage form. Monitoring drug distribution and uniformity in granules and tablets during early stage formulation/process development is critical for drug product quality control and process robustness. In this report, an efficient and reliable analytical method for monitoring drug compound A uniformity and distribution has been developed by analyzing calcium, the counter ion of the drug substance, by Inductively Coupled Plasma Atomic Emission Spectrometer (ICP-AES). In this method, calcium in compound A granule and tablet samples was digested with 1 M hydrochloric acid by heating at 90 °C for 2 h. The resulting suspension was centrifuged, and the supernatant was directly aspirated into an ICP-AES. This method has been validated to demonstrate satisfactory precision, accuracy, specificity and sensitivity. Finally, this method has been used to analyze sieve fraction granules and tablets of drug compound A. The data generated were highly comparable to those by validated HPLC methods (UV method can not be applicable due to significant bias). In comparison with HPLC methods, this method demonstrates a significantly improved efficiency with very short analysis time (1 min per sample), and can be used as an excellent alternative for UV and HPLC methods to support formulation screening.     

火花型合成射流激励器流动特性及其激励参数数值研究

利用能量方程中的源项模拟电火花能量的输入,数值模拟了火花型合成射流激发器的流场,获得了激励器的能量蓄积、喷射和吸入过程。结果表明,电火花瞬间能量的输入产生了腔体内的高温、高压环境,从而诱发合成射流的形成;在周期性激励下,合成射流在3个周期后稳定,喷口处的速度呈现非正弦的周期性变化,射流喷射过程时间极短,吸入外界环境气体的过程时间较长,与压电式合成射流明显不同;喷口下游周期性出现的涡对强度大、卷吸能力强。在输入能量和腔体体积不变时,喷口速度随激发频率的增加,先增加后减小,存在最佳激发频率。激发频率的增加缩短了腔体内气体的冷却时间,实验时对激发频率的选取要考虑腔体的耐温能力。     

Some compaction characteristics of the hot water leaf extract og Nauclea latifiola: a potential antimalarial agent

This study aims to develop a suitable tablet dosage form of Nauclea latifolia, a potential antimalarial agent. The compaction characteristics of the oven dried water extract were studied using the Heckel equation. The mechanical properties of the compacts were also determined. This preliminary information will be useful in developing a suitable dosage form of the extract for use in the management of malaria. The results showed that N. latifolia extract exhibited high densification due to dye filling while the subsequent rearrangement of the granules did not contribute, significantly, to their densification. The granules had enhanced plasticity as shown by the low yield point, Py. The tablets produced from the extract had good mechanical properties, with hardness increasing via compression pressure while the friability decreased. However, the tablets had poor disintegration properties; it is concluded that while tablets of suitable physical properties can be produced from the extract, a disintegrant would need to be included in the formulation to ensure adequate drug release.     

An investigation into the erosion behaviour of a high drug-load (85%) particulate system designed for an extended-release matrix tablet. Analysis of erosion kinetics in conjunction with variations in lubrication, porosity and compaction rate

The effects of the amounts of lubricants (magnesium stearate 0-5% and talc 0-3%) and changes in compaction rate and tablet porosity on the mechanism of drug release from high drug-load controlled-release theophylline tablets have been examined. Drug release was satisfactorily described by a surface-erosion model that takes into account the geometry of the tablet, differential radial and axial erosion rates, and the initial burst effect (r2 > 0.99 for all formulations). The axial and radial erosion rate constants were inversely proportional to the amount of magnesium stearate in the formulation (P < 0.0001). The most dramatic reductions in erosion rate occurred between 0 and 1% magnesium stearate content. For magnesium stearate concentrations > or =2.5% the ratio of radial to axial erosion rate constants was essentially constant at 3 (approx.); however, for formulations with magnesium stearate < or =1% the ratio tended toward unity. Reducing matrix porosity over the range 26 to 14% resulted in reduced erosion rates. However, a threshold of 17% (approx.) porosity was identified below which further reductions in porosity resulted in only incremental changes in release rates. The rate of erosion and drug release was insensitive to changes in machine speed over the range 20 to 100 rev min(-1). For highly loaded matrix tablets containing sparingly soluble drugs, such as theophylline, magnesium stearate at appropriate levels can modulate the erosion rate constants and act as an effective release-controlling excipient. Drug-release profiles are predictable and relatively robust in terms of changes in compaction rate and applied force routinely encountered in large-scale tablet manufacturing.     

Co-existence of GABA and Glu in the hippocampal granule cells: implications for epilepsy

The granule cells of the Dentate Gyrus are one of the most exciting and intriguing cells in the central nervous system. Besides containing and releasing Glu, they have been shown to contain and release peptides (somatostatin, neuropeptide Y, neurokinin B, cholecystokinin, dynorphin, enkephalin), Zn(++) ion, and brain-derived neurotrophic factor (BDNF). The recent addition of GABA to this list suggests that these cells can also function as inhibitory cells. Indeed, evidence has been presented of co-localization of all markers of the GABAergic phenotype in granule cells: GABA, the enzyme for its synthesis (Glu decarboxylase) and the membrane and vesicular transporters of GABA. These markers of the GABAergic phenotype are up-regulated after epileptic seizures. When this occurs, monosynaptic GABA receptor-mediated transmission emerges in the mossy fiber synapse thus restraining excitation and mediating antiepileptic and neuroprotective actions.     

A material-sparing method for simultaneous determination of true density and powder compaction properties--aspartame as an example

True density results for a batch of commercial aspartame are highly variable when helium pycnometry is used. Alternatively, the true density of the problematic aspartame lot was obtained by fitting tablet density versus pressure data. The fitted true density was in excellent agreement with that predicted from single crystal structure. Tablet porosity was calculated from the true density and tablet apparent density. After making the necessary measurements for calculating tablet apparent density, the breaking force of each intact tablet was measured and tensile strength was calculated. With the knowledge of compaction pressure, tablet porosity and tensile strength, powder compaction properties were characterized using tabletability (tensile strength versus pressure), compactibility (tensile strength versus porosity), compressibility (porosity versus pressure) and Heckel analysis. Thus, a wealth of additional information on the compaction properties of the powder was obtained through little added work. A total of approximately 4 g of powder was used in this study. Depending on the size of tablet tooling, tablet thickness and true density, 2-10 g of powder would be sufficient for characterizing most pharmaceutical powders.     

A study of the residual fermentation sugars influence on an alternative downstream process for first and second-generation lactic acid

Lactic acid is an important biomolecule with a substantial market share. Currently, investments in the area are concentrated on new substrates and technologies, in order to boost production and separation performance. Molecular distillation has been recognized as a promising technology in the separation, purification, and concentration of natural products and hence with potential for application in the lactic acid production process. In this study, lactic acid was produced by fermentation using first (1G) and second-generation (2G) substrates, producing a complex mixture of lactic acid and residual sugars. The influence of the residual sugars, such as glucose, sucrose, and xylose, was investigated. For the 1G process, the results showed that the highest lactic acid concentration (99.51 g/L) can be obtained using the feed stream with the lowest sugars composition. For the 2G process, the highest lactic acid concentration reached (75.87 g/L) was lower than that observed for 1G experiments. The concentration of lactic acid using 1G or 2G lactic acid were, respectively, 2.73 times and 2.12 times higher than the initial raw material concentration, without the use of any extra solvent. The final process analysis showed that the use of molecular distillation for lactic acid downstream has different challenges to defeat for the separation of 1G and 2G lactic acid, which is relevant since many different feedstocks may be used in the lactic acid production.