Evaluation of selected micronized poloxamers as tablet lubricants

The primary objective of this study was to compare the lubrication properties of micronized poloxamer 188 (Lμ trol micro 68^®) and micronized poloxamer 407 (Lμ trol micro 127^®) with certain conventional lubricants such as magnesium stearate and stearic acid. The secondary objective was to use these micronized poloxamers as water-soluble tablet lubricants in preparation of effervecsent tablets. The results showed that these micronized poloxamers have superior lubrication properties compared with stearic acid, with no negative effect on tablet hardness, friability, disintegration, or dissolution. Moreover, lubricant mixing time had no significant effect on tablet properties when poloxamers were used as lubricants. Effervescent tablets also were produced successfully using micronized poloxamers as lubricants. The micronized poloxamers had a better lubrication effect in compariason with that of water-soluble lubricant l-leucine.     

Hexagonal boron nitride as a tablet lubricant and a comparison with conventional lubricants

The objective of this study was to investigate the lubrication properties of hexagonal boron nitride (HBN) as a new tablet lubricant and compare it with conventional lubricants such as magnesium stearate (MGST), stearic acid (STAC), and glyceryl behenate (COMP). Tablets were manufactured on an instrumented single-station tablet press to monitor lower punch ejection force (LPEF) containing varied lubricants in different ratio (0.5, 1, 2%). Tablet crushing strength, disintegration time and thickness were measured. Tensile strength of compacted tablets were measured by applying a diametrical load across the edge of tablets to determine mechanical strength. The deformation mechanism of tablets was studied during compression from the Heckel plots with or without lubricants. MGST was found to be the most effective lubricant based on LPEF-lubrication concentration profile and LPEF of HBN was found very close to that of MGST. HBN was better than both STAC and COMP. A good lubrication was obtained at 0.5% for MGST and HBN (189 and 195N, respectively). Where COMP and STAC showed 20 and 35% more LPEF compare to that of MGST (239 and 288N, respectively). Even at the concentration of 2% COMP and STAC did not decrease LPEF as much as 0.5% of MGST and HBN. Like all conventional lubricants the higher the concentration of HBN the lower the mechanical properties of tablets because of its hydrophobic character. However, this deterioration was not as pronounced as MGST. HBN had no significant effect on tablet properties. Based on the Heckel plots, it was observed that after the addition of 1% lubricant granules showed less plastic deformation.     

Evaluation of hexagonal boron nitride as a new tablet lubricant

In this study, hexagonal boron nitride (HBN) was evaluated as a new lubricant for pharmaceutical tablet manufacturing. The other conventional lubricants such as magnesium stearate (MGST), stearic acid (STAC), and glyceryl behenate (COMP) were also tested along with HBN. Tablets were manufactured on an instrumented single-station tablet press to monitor and quantify the lower punch ejection force (LPEF). The force ratio, tablet crushing strength, disintegration time, and thickness were measured. The lubricant film formation and lubricant distribution in tablets were studied using the scanning electron microscopy (SEM) and electron probe micro analyzer (EPMA). Based on the force ratio, a good lubrication was obtained at 1% for MGST and HBN; in contrast, STAC and COMP did not show a good lubrication. After 1%, all lubricants performed well. MGST was found to be the most effective lubricant based on LPEF-lubricant concentration profile. HBN provided a 50% decrease in LPEF at 2% lubricant concentration and was rated as an effective tablet lubricant. HBN was better than either STAC or COMP. Unlike MGST, HBN had no significant prolongation effect on tablet disintegration times.     

Effects of hexagonal boron nitride on dry compression mixture of Avicel DG and Starch 1500

The objective of this study was to investigate the lubrication properties of hexagonal boron nitride (HBN) on a (1:1) binary mixture of Avicel DG and Starch 1500 after using the dry granulation–slugging method and compare it with conventional lubricants, such as magnesium stearate (MGST), glyceryl behenate (COMP) and stearic acid (STAC). MGST is one of the most commonly used lubricants in the pharmaceutical industry. However, it has several adverse effects on tablet properties. In our current study, we employed various methods to eradicate the work hardening phenomenon in dry granulation, and used HBN as a new lubricant to overcome the adverse effects of other lubricants on tablet properties. HBN was found to be as effective as MGST and did not show any significant adverse effects on the crushing strength or work hardening. From the scanning electron microscope (SEM) images, it was concluded that HBN distributed better than MGST. As well as showing better distribution, HBN’s effect on disintegration was the least pronounced. Semi-quantitative weight percent distribution of B and N elements in the tablets was obtained using EDS (energy dispersive spectroscopy). Based on atomic force microscope (AFM) surface roughness images, formulations prepared with 1% HBN showed better plastic character than those prepared with MGST.     

Tablet lubricants I. Theory and modes of action

Tablet lubricants are essential components of all tablet formulations, since they prevent sticking of the tablets in the dies. Without tablet lubricants, tablets cannot be produced. A lubricant may be defined as a suitable material, a small amount of which interposed between two rubbing surfaces will reduce friction arising at the interface (Strickland et al., 1960; Komarek, 1967).A lubricant should also be capable of reducing wear on the rubbing surfaces (Silversher, 1969). To perform this function the lubricant must provide a film that will prevent solid-to-solid contact, and is easily sheared (Jentgen, 1971). Lubricants are added to tablet formulations primarily to reduce friction between the die wall and granules as the tablet is formed and ejected (Sprowl, 1974; Lachman et al., 1970). The other main activities attributed to a lubricant are: (a) prevention of sticking of granules to the tooling—anti-adherent; and (b) improvement of granule flow properties—glidant (Lachman et al., 1970). A given lubricant may provide one or more of these actions to varying degrees but no one material is highly efficient in all categories (Sperandeo and De Machi, 1976; Strickland, 1959; Sprowl, 1974). Accordingly combinations of lubricants are often selected to provide the necessary total lubricant effect (Maly, 1963; Munzel and Kogi, 1954). Careful selection is necessary since some lubricants may interact adversely when in combinations; for example, magnesium stearate and talc (De Blaey, 1972), although some authors have found that these two lubricants are compatible (Rubio, 1957; Esnaud et al., 1973). Although tablet lubricants have been used in practice for many decades it is only in the last 15 years that the lubrication process has been studied fundamentally.     

Combination of a hot-melt subcoating and an enteric coating for moisture protection of hygroscopic Sennae fructus tablets

The objective of this study was to investigate the efficiency of moisture protection of hot-melt coatings solely and in combination with an enteric coating on hygroscopic tablet cores containing a spray-dried Sennae fructus extract. Tablet cores were subcoated with different hot-melt coating materials: medium chain tryglycerides, stearic acid, Precirol^® ATO 5, and Compritol^® 888 ATO, at varying amounts and coated with Eudragit^® L 30D-55 for enteric resistance. Subcoating penetration, tablet disintegration, dissolution times, tablet hygroscopicity, and tablet properties such as weight, height, diameter, and hardness were analyzed. 3?mg/cm² of tablet surface seemed to be sufficient if sustained release is not required. Thereby, hot-melt coating did not adversely affect the tablet properties with regard to subsequent processing steps. Compared to the tablet cores it was possible to reduce the moisture uptake by 85% at 75% relative humidity with tablets coated with a combination of Precirol^® ATO 5 and Eudragit^® L 30D-55. This combination was more efficient than high amounts of Eudragit^® L 30D-55. Hot-melt coating proved to be a suitable technique for the application of subcoating material to tablet cores serving as a barrier against water permeation into hygroscopic tablet cores without exceeding the required disintegration times.     

Effects of disintegration-promoting agent, lubricants and moisture treatment on optimized fast disintegrating tablets

Effects of calcium silicate (disintegration-promoting agent) and various lubricants on an optimized beta-cyclodextrin-based fast-disintegrating tablet formulation were investigated. Effects of moisture treatment were also evaluated at 75, 85 and 95% relative humidities. A two factor, three levels (3(2)) full factorial design was used to optimize concentrations of calcium silicate and lubricant. Magnesium stearate, being commonly used lubricant, was used to optimize lubricant concentration in optimization study. Other lubricants were evaluated at an obtained optimum concentration. Desiccator with saturated salt solutions was used to analyze effects of moisture treatments. Results of multiple linear regression analysis revealed that concentration of calcium silicate had no effect; however concentration of lubricant was found to be important for tablet disintegration and hardness. An optimized value of 1.5% of magnesium stearate gave disintegration time of 23.4 s and hardness of 1.42 kg. At an optimized concentration, glycerol dibehenate and L-leucine significantly affected disintegration time, while talc and stearic acid had no significant effect. Tablet hardness was significantly affected with L-leucine, while other lubricants had no significant effect. Hardness was not affected at 75% moisture treatment. Moisture treatment at 85 and 95% increased hardness of the tablets; however at the same time it negatively affected the disintegration time.     

三元固体分散体提高利多卡因溶解度研究（英文）

使用熔融法制备利多卡因-泊洛沙姆固体分散体以提高利多卡因的溶解度及溶出度。以利多卡因(LIC)作为模型药物,分别使用泊洛沙姆188 (P188)和泊洛沙姆407 (P407)作为单一及混合载体,制备三元及二元固体分散体并进行比较。使用DSC、XRD、SEM及FTIR进行一系列表征,通过溶出度试验研究固体分散体的溶出特性,药物以晶体形式存在于载体中,药物溶出度及溶解度结果较原料药均有明显提高。相溶解度研究显示出药物与载体呈AL型曲线,有分子相互作用的存在。此外,还考察了固体分散体在不同相对湿度下的长期稳定性,稳定性测试结果表明三元及二元利多卡因-泊洛沙姆固体分散体在不同湿度下,6个月内保持稳定。研究结果表明,混合泊洛沙姆三元固体分散体可以显著提高难溶性利多卡因的溶出度和溶解度。     

Solubility enhancement of desloratadine by solid dispersion in poloxamers

The present study investigates the possibility of using poloxamers as solubility and dissolution rate enhancing agents of the poorly water soluble drug substance desloratadine that can be used for the preparation of immediate release tablet formulation. Two commercially available poloxamer grades (poloxamer P 188 and poloxamer P 407) were selected, and solid dispersions (SDs) containing different weight ratio of poloxamers and desloratadine were prepared by a low temperature melting method. All SDs were subjected to basic physicochemical characterization by thermal and vibrational spectroscopy methods in order to evaluate the efficiency of poloxamers as solubility enhancers. Immediate release tablets were prepared by direct compression of powdered solid dispersions according to a General Factorial Design, in order to evaluate the statistical significance of two formulation (X(1) - type of poloxamer in SD and X(2) - poloxamer ratio in SD) and one process variable (X(3) - compression force) on the drug dissolution rate. It was found that desloratadine in SDs existed in the amorphous state, and that can be largely responsible for the enhanced intrinsic solubility, which was more pronounced in SDs containing poloxamer 188. Statistical analysis of the factorial design revealed that both investigated formulation variables exert a significant effect on the drug dissolution rate. Increased poloxamer ratio in SDs resulted in increased drug dissolution rate, with poloxamer 188 contributing to a faster dissolution rate than poloxamer 407, in accordance with the results of intrinsic dissolution tests. Moreover, there is a significant interaction between poloxamer ratio in SD and compression force. Higher poloxamer ratio in SDs and higher compression force results in a significant decrease of the drug dissolution rate, which can be attributed to the lower porosity of the tablets and more pronounced bonding between poloxamer particles.     

Cellactose® a Co-processed Excipient: A Comparison Study

This article describes the differences in compaction properties between microcrystalline cellulose (MCC) and α-lactose monohydrate physical mixture, and microcrystalline cellulose co-processed with α-lactose monohydrate (Cellactose®). The different compaction parameters are not only compared for the pure materials but also for the lubricated powders with magnesium stearate. Magnesium stearate does not facilitate the densification of either the physical mixture or Cellactose during compaction. The difference in tablet relaxation of the physical mixture and Cellactose indicates that the negative effect of the lubricant on the interparticle bonding of Cellactose particles is smaller than the physical mixture particles because after compaction, the structure in the Cellactose tablet is completely different from that in the physical mixture tablet. However, a larger increase in tablet relaxation at a high compression speed was found for both Cellactose and the physical mixture at different lubricant concentrations: 1.0% and 0.0%. Accordingly, the decrease in tablet strength was larger for the physical mixture tablets than for the Cellactose tablets when lubrication was applied. The examination of the tablet strengths of tablets compressed from physical mixtures of different ratios of α-lactose monohydrate and MCC proved the positive effect of cellulose on the tensile strength of tablets. Co-processing of MCC with α-lactose monohydrate showed extra contribution on the tablet strength of a physical mixture with the same mixing ratio. This extra contribution of Cellactose was attributed only to the interfacial attraction of the particles.     

Effect of poloxamer on the dissolution of felodipine and preparation of controlled release matrix tablets containing felodipine

The effects of poloxamer and HPMC on the dissolution rate of felodipine were investigated and a felodipine controlled release tablet was developed by increasing the water solubility of felodipine and using swelling polymer to control release rate. Milling of felodipine slightly increased the dissolution rate of felodipine when compared with physical mixture. XRD results indicated that felodipine remained in the crystalline form even after co-milling with poloxamer. Improved dissolution rates after co-milling with HPMC and poloxamer were due to both solubilization effect of polymer and milling. The effect of poloxamer on dissolution rate was more significant than that of HPMC. Based on increased solubility of felodipine in the presence of poloxamer, it was concluded that the improved dissolution rate of felodipine was mainly due to a high local concentration of poloxamer around felodipine. Controlled release felodipine tablets were prepared using poloxamer as a solubilizing agent and Carbopol as a controlled release matrix.     

Effect of the type of lubricant on the characteristics of orally disintegrating tablets manufactured using the phase transition of sugar alcohol.

The aim of this study was to evaluate the effect of lubricants on the characteristics of orally disintegrating (OD) tablets manufactured using the phase transition of sugar alcohol. OD tablets were produced by directly compressing a mixture containing lactose-xylitol granules, disintegrant, glidant and lubricant, and subsequent heating. The effect of the type of lubricant on the tablet characteristics was evaluated using magnesium stearate (Mg-St), sodium stearyl fumarate (SSF), and talc as lubricants. The hardness of the tablets increased to ca. 6kp as a result of heating, regardless of the kind of lubricant. The oral disintegration time of the tablets containing Mg-St or SSF increased with an increase in the hardness. In contrast, the oral disintegration time of the tablets containing talc was not changed despite of an increase in hardness. The water absorption rate of the tablets containing talc was much faster than that of the tablets containing other lubricants. The surface free energy measurement showed that the polarity of the tablet components containing talc was remarkably increased by heating. The water absorption rate of the tablets containing talc was also increased by heating. These results indicate that a more hydrophilic surface might be attained by heating the talc. Consequently, talc was demonstrated to be the most desirable lubricant for the preparation of OD tablets based on the principle of the phase transition of sugar alcohol.     

Glycerin fatty acid esters as a new lubricant of tablets

Lubrication properties were compared among glycerin fatty acid esters (Poem TR-FB and Poem TR-HB), magnesium stearate (Mg-St), and a sucrose fatty acid ester (RYOTO SUGAR ESTER S-370F: SSE). Granules containing 50% acetaminophen were prepared, and improvements in their fluidity by the lubricants were compared. The lubricant effects of TR-FB and HB during tablet punching (pressure transmission ratio, ejection force) were similar to those of Mg-St and were better than those of SSE. When the lubricant content, mixing time, and tabletting pressure were changed, TR-FB and TR-HB provided better tablet hardness than Mg-St. TR-FB and TR-HB made tablets more disintegratable than Mg-St. When the effects of these lubricants on the stability of acetylsalicylic acid (ASA) were compared, Mg-St promoted its hydrolysis, but TR-FB or TR-HB did not affect its stability.     

Influence of the granulation technique and starting material properties on the lubricating effect of granular magnesium stearate

Magnesium stearate has been granulated in four ways to produce lubricant granulations with different properties. The lubricating properties, as well as the tablet properties with the granulated lubricant, were evaluated on tablets prepared from a mixture of dicalcium phosphate, corn starch and microcrystalline cellulose. The lubricating effect of the magnesium stearate granulations showed a similar pattern regardless of the granulation technique used except for a granulation with providone. Increasing the particle size of the magnesium stearate granulation increased the amount of lubricant required to obtain lubrication similar to powdered magnesium stearate. Variations in the specific surface area of the starting materials could be masked by using them in granular form.     

Effect of lubricant type and concentration on the punch tip adherence of model ibuprofen formulations

A model formulation, comprising ibuprofen and direct compression lactose (Tablettose 80) was used to assess the influence of two lubricants, magnesium stearate and stearic acid, on punch tip adherence. Lubricant concentrations were varied from 0.25% to 2% w/w. Formulations in the presence and absence of 0.5% w/w colloidal silica (Aerosil 200) were examined, to assess the influence of the glidant on the anti-adherent effects of the lubricants. Differential scanning calorimetry (DSC) was used to examine the effect of the lubricants on the melting temperature of ibuprofen. Tablets were compacted using a single punch tablet press at 10 kN using hard chrome-plated punches or at 40 kN using uncoated steel punches, tooling was 12.5-mm diameter in each case. The upper punch faces were characterized by obtaining Taylor Hobson Talysurf surface profiles. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. At low concentrations of each lubricant, the levels of sticking observed were similar. Whilst sticking increased at magnesium stearate concentrations above 1%, sticking with stearic acid remained relatively constant at all concentrations. DSC revealed that the melting temperature of ibuprofen was lowered by the formation of eutectic mixtures with both lubricants. However, the onset temperature of melting and melting point were lowered to a greater extent with magnesium stearate compared with stearic acid. When using uncoated tooling at 40 kN, the deleterious effects of magnesium stearate on the tensile strength of the tablets also contributed to sticking. When using chrome-plated punches at 10 kN, the tensile strength reduction by the presence of magnesium stearate was less pronounced, as was the level of sticking.     

Variations in the friction coefficients of tablet lubricants and relationship to their physicochemical properties

A previously described modified annular shear cell (MASC) has been used to measure the friction coefficients of some powdered tablet lubricants on a steel surface. Commonly used lubricants, as well as others belonging to the stearate group, differed in their friction coefficients at equivalent sample sizes and in the degree of their ability to reduce friction with increasing amounts when evaluated by the apparatus. In all comparisons, magnesium stearate had the lowest friction coefficient. Divalent salts of stearic acid appeared to be better than the other lubricants tested, and among themselves differed only in the extent of their ability to decrease friction. The lubricants also differed in their physical and chemical properties. On evaluation by stepwise regression analysis, such physical properties as projected surface area of lubricant particles, Martin's diameter and bulk density accounted for most of the variation in friction coefficients of the lubricants rather than moisture content or melting point. It could therefore be suggested that particle size and/or surface area parameters be incorporated in product specifications to ensure reproducible functionality.     

A study of a novel coprocessed dry binder composed of α-lactose monohydrate,microcrystalline cellulose and corn starch

This paper deals with a study of the novel coprocessed dry binder Combilac®, which contains 70% of α-lactose monohydrate, 20% of microcrystalline cellulose and 10% of native corn starch. These tests include flow properties, compressibility, lubricant sensitivity, tensile strength and disintegration time of tablets. Compressibility is evaluated by means of the energy profile of compression process, test of stress relaxation and tablet strength. The above-mentioned parameters are also evaluated in the physical mixture of α-lactose monohydrate, microcrystalline cellulose and native corn starch and compared with Combilac. Combilac shows much better flowability than the physical mixture of the used dry binders. Its compressibility is better, tablets possess a higher tensile strength. Neither Combilac, nor the physical mixture can be compressed without lubricants due to high friction and sticking to the matrix. Combilac has a higher lubricant sensitivity than the physical mixture of the dry binders. Disintegration time of Combilac tablets is comparable with the disintegration time of tablets made from the physical mixture.     

Cellactose a co-processed excipient: a comparison study

This article describes the differences in compaction properties between microcrystalline cellulose (MCC) and alpha-lactose monohydrate physical mixture, and microcrystalline cellulose co-processed with alpha-lactose monohydrate (Cellactose). The different compaction parameters are not only compared for the pure materials but also for the lubricated powders with magnesium stearate. Magnesium stearate does not facilitate the densification of either the physical mixture or Cellactose during compaction. The difference in tablet relaxation of the physical mixture and Cellactose indicates that the negative effect of the lubricant on the interparticle bonding of Cellactose particles is smaller than the physical mixture particles because after compaction, the structure in the Cellactose tablet is completely different from that in the physical mixture tablet. However, a larger increase in tablet relaxation at a high compression speed was found for both Cellactose and the physical mixture at different lubricant concentrations: 1.0% and 0.0%. Accordingly, the decrease in tablet strength was larger for the physical mixture tablets than for the Cellactose tablets when lubrication was applied. The examination of the tablet strengths of tablets compressed from physical mixtures of different ratios of alpha-lactose monohydrate and MCC proved the positive effect of cellulose on the tensile strength of tablets. Co-processing of MCC with alpha-lactose monohydrate showed extra contribution on the tablet strength of a physical mixture with the same mixing ratio. This extra contribution of Cellactose was attributed only to the interfacial attraction of the particles.     

Quantitation of poloxamers in pharmaceutical formulations using size exclusion chromatography and colorimetric methods

Poloxamers have been used as functional excipients in pharmaceutical products. They function as surfactants, emulsifying agents, solubilizing agents, dispersing agents, and in vivo absorbance enhancer. Despite their wide range of applications, limited analytical techniques have been reported in literature for characterizing poloxamers and few are targeted to quantify poloxamer contents in formulations with desired sensitivity and accuracy. In this paper, two distinct analytical methods for quantifying low levels of poloxamers in pharmaceutical formulations have been developed and optimized: a colorimetric method and a size exclusion chromatography method. The colorimetric method is based on the formation of a colored complex between poloxamers and cobalt(II) thiocyanate in aqueous medium, which has a maximum UV absorbance at 624 nm. The feasibility of this method is product specific. In this report, adequate specificity and sensitivity was demonstrated for only one of the several products tested. The size exclusion chromatography (SEC) method utilizes size exclusion columns with THF as mobile phase and refractive index detection. The SEC method provides a limit of quantitation (LOQ) of 0.005 mg/mL (0.0005%, w/w) and at least three orders of magnitudes of linear range. We applied the SEC method to pharmaceutical products containing 0.3–10% poloxamer 188 or poloxamer 407, such as Avapro, Neurontin, Sudafed and other developmental formulations. The results obtained with the SEC method agreed very well with literature and theoretical values with 97–102% recovery. The SEC method was proven to be widely applicable, accurate, precise and simple to use.     

温脾补肾片的成型工艺研究

目的 研究温脾补肾片的最佳成型工艺.方法 通过单因素重复试验,考察填充剂、润湿剂和润滑剂的种类及用量对本制剂成型性能的影响,以颗粒的吸湿性、片剂的外观、颗粒的流动性、片剂的硬度、片剂的崩解度等为指标,优选出最佳成型工艺.结果 最佳成型工艺为选用淀粉为填充剂(浸膏粉与淀粉的配比为5:1),以90%乙醇(20%)为润湿剂制软材,并用硬脂酸镁(0.5%)为润滑剂.结论 制得的片剂符合<中国药典>2010版有关项下的规定.