Characterization of Synthesized and Commercial Forms of Magnesium Stearate Using Differential Scanning Calorimetry,Thermogravimetric Analysis,Powder X-Ray Diffraction,and Solid-State NMR Spectroscopy

Magnesium stearate is the salt of a complex mixture of fatty acids, with the majority being stearate and palmitate. It has multiple crystalline forms and, potentially, an amorphous form. Magnesium stearate is used in the pharmaceutical manufacturing industry as a powder lubricant, and typically is added at low levels (～1%) during the manufacturing process and blended for a relatively short time (～5 min). Proper levels and mixing times are needed, as too short a mixing time or too small a quantity will result in improper lubrication, and too much can negatively impact dissolution rates. The complex mixture of multiple fatty acids and crystalline forms in magnesium stearate leads to variability between commercial sources, and switching between sources can impact both the amount of lubricant and mixing time needed for proper lubrication. In order to better understand the complex nature of magnesium stearate, a variety of analytical techniques were used to characterize both synthesized and commercial magnesium stearate samples. The results show that correlation among differential scanning calorimetry, thermogravimetric analysis, solid-state NMR spectroscopy, and other techniques provides a unique insight into the forms of magnesium stearate. Finally, the ability to monitor form changes of magnesium stearate in an intact tablet using solid-state NMR spectroscopy is shown.     

Physical and lubrication properties of magnesium stearate.

The lubrication properties of two commercial-grade magnesium stearates were studied. Their moisture contents and crystal structures were similar. There were minor differences in their fatty acid composition, but the differences did not affect the lubrication properties. The lubrication properties correlated with particle size distributions and specific surface area. The effect of these parameters was further studied with unmilled and milled chemically pure magnesium stearate. Milling decreased the particle size and increased the specific surface area. In both cases, the batch with a smaller particle size and larger specific surface area had considerably better lubricity.     

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.     

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.     

硬脂酸镁和香精物料属性及其润滑性能相关性研究

润滑剂是口服固体制剂中常用的一类药用辅料，可以有效提高物料流动性、减小物料和机械摩擦系数等。然而，由于不同厂家采用的原料、工艺、质控要求等存在差异，可能导致“虽然润滑剂通用名一致，但不同来源润滑剂物料属性不一致”的情形，进而导致润滑性能存在差异。本研究征集了不同厂家来源的硬脂酸镁（Magnesium stearate, MgSt）和香精作为研究对象，全面考察了其堆密度、振实密度、粒度分布、比表面积等粉体学性质和玻璃化转变温度、熔点等热力学性质，并研究其在压片时的出片力表现，明确了影响其润滑性能的关键物料属性，为相关辅料的质量控制和功能性相关指标研究提供参考。     

Application of external lubrication during the roller compaction of adhesive pharmaceutical formulations

A novel use of external lubrication has been investigated in which magnesium stearate was applied directly to the roll surface during roller compaction. A scalable parameter; travelling roll distance per shot (D_pS), has been defined which ensures that an equal amount of magnesium stearate is applied to the roll surface per rotation at any roll speed. It was found that a formulation containing 20% w/w of either the API Pravastatin or Ibipinabant required a smaller D_pS than a placebo formulation in order to prevent roll adherence. The inherent adhesiveness, and hence the required amount of external magnesium stearate to prevent roll adhesion, will depend on the material properties of the formulation. The amount of magnesium stearate transferred from the roll surface to the ribbon was measured using inductively coupled plasma optical emission spectroscopy and was found to be less than 0.01% w/w. This is a significant reduction in magnesium stearate compared to the normal manufacturing procedure of blending 0.25–2.0% w/w within the formulation.The advantage of external lubrication during roller compaction is the significant reduction in magnesium stearate from the formulation which could lead to the production of tablets with superior mechanical properties and faster dissolution times.     

Formulation and process optimization to eliminate picking from market image tablets

A tablet formulation when compressed using market image tooling may cause picking of powder. A D-optimal statistical experiment was designed to optimize the direct compression formulation and the process to alleviate picking of powder. The effects of levels of magnesium stearate, colloidal silicon dioxide (CSD), and lubrication time on picking were investigated using original compression tooling. These optimization results provided a small robust manufacturing region, hence a change in the cut angles of embossed letters and numbers from 70 degrees to 90 degrees in the modified compression tooling was evaluated. A statistical analysis of the data identified a robust manufacturing region that included formulations containing magnesium stearate 1-1.25% w/w, CSD 0.1-0.3% w/w, with a lubrication time of 5-10 min when compressed using modified compression tooling. The results indicate a significant reduction in picking by increasing the cut angles of embossed letters and numbers in the modified compression tooling. By evaluating interactions between various variables, we demonstrate a concentration dependent effect of CSD on the lubrication efficiency of magnesium stearate and compactability of microcrystalline cellulose containing formulation. In addition, the lubrication efficiency of magnesium stearate is maintained by blending CSD with powder blend prior to lubrication with magnesium stearate.     

硬脂酸镁在直接压片工艺中产生的软化效应

脂酸镁又名十八酸镁,在粉末直接压片工艺中具有重要作用,但是硬脂酸镁的使用,往往会对片剂产生一定的软化效应.从直压辅料的分类、物料粒径大小、辅料与硬脂酸镁的混合时间以及硬脂酸镁使用浓度等方面,简要分析产生此种软化效应的原因以及影响其大小的因素,以期为实际生产中提高粉末直接压片工艺有所借鉴和帮助.     

The influence of magnesium stearate on the characteristics of mucoadhesive microspheres

Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, x-ray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential scanning calorimetry. No differences were observed in the physical state of pipemidic acid and in microsphere shape and surface between different size fractions of microspheres, prepared with different amounts of magnesium stearate. Additionally, no correlation between the physical state of the drug in different microspheres and their biopharmaceutical properties was found.     

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.     

Stress relaxation studies of granules as a function of different lubricants.

Viscoelastic properties of granules may be studied using stress relaxation. The effect of viscoelastic properties of different lubricants, namely magnesium stearate (Mgst), talc and precirol, on granule compaction properties was examined using texture analyzer TA-XT2i at low pressure. Normalized compact curves of stress relaxation have been discussed in relation to some parameters (flowability, porosity, viscoelasticity as well as particle size). The literature shows that viscoelasticity is always present and it produces an accompanying plastic deformation.This study revealed that bonding in compacted granules lubricated with Mgst was higher than those in compacts lubricated with the other two lubricants being studied. When studying the partial porosity of granule beds, we see that this is the result of stored energy, like the tablet case and the problem of its capping. The small stress relaxation due to talc or precirol suggested that these materials deformed principally by energy storage. However, a qualitative characterization of Mgst as tablet lubricant would be that it avoids the accumulation of stress in the compact that causes the problem of capping due to the entrapped air and therefore facilitates the optimization of pharmaceutical manufacturing. It has been possible to normalize stress relaxation using the Wischert model, represented by the sum of several exponentials, according to the nature of the lubricant.The use of texture analyzer TA-XT2i was considered to be a good technique for the evaluation of the stress relaxation of solid particles in the compression process at low pressure. It permitted the observation that viscoelasticity is influenced by the lubricant used. The brittle fracture index, like Carr's index values, has been correlated with the viscoelastic characteristics of granules.     

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.     

Application of Multivariate Methods to Evaluate the Functionality of Bovine- and Vegetable-Derived Magnesium Stearate

This work distinguishes and quantifies the effects of bovine- and vegetable-derived magnesium stearate (MgSt) molecular and macroscopic properties on lubrication efficiency using multivariate analysis. Principal component analysis (PCA) and partial least-square regression (PLS) were used to evaluate and quantify the lubricant effectiveness on a model tablet formulation. PCA score and loading plots showed a separation of model formulations based on the MgSt sources, which indicated different bovine- and vegetable-derived MgSt lubrication potential. PLS quantified the MgSt molecular [enthalpy of dehydration (ΔHd), enthalpy of melting (ΔHm), percent crystallinity, and moisture content] and macroscopic [particle size (d₅₀), specific surface area (SSA-MgSt), and MgSt Hausner ratio (HF-MgSt)] properties, their interactions, and square effects on formulation powder flow and tableting properties relating to MgSt's lubrication effectiveness. For crystalline MgSt, moisture content, HF-MgSt, d₅₀, and SSA-MgSt showed a major influence on the lubrication efficiency compared with the other MgSt molecular properties (percent crystallinity, ΔHm, and ΔHd). Amorphous MgSt showed poor lubrication, and none of its molecular or macroscopic properties showed significant effects on lubrication efficiency. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.     

Investigation of the film formation of magnesium stearate by applying a flow-through dissolution technique

The film formation of magnesium stearate on the surface of acetylsalicylic acid was investigated by applying a flow-through dissolution technique. The effect of mixing time, lubricant surface area, and the addition of colloidal silica was studied. The film formation increased by increasing mixing time. The final level reached was independent of the specific surface area of the lubricants, but granular magnesium stearate gave a lower surface coverage than the powdered lubricants. The lubricating effect was independent of the mixing time and specific surface area of the lubricants. Colloidal silica was found to interact primarily with the free fraction of magnesium stearate.     

Interaction of lubricants with microcrystalline cellulose and anhydrous lactose — a solubility parameter approach

Based on a model involving the integrating of the Lennard-Jones pair potential function to predict the properties of a single and two component system it has been possible to predict the intensity of the molecular interactions between the excipients microcrystalline cellulose and anhydrous lactose and the lubricants magnesium stearate, stearic acid and polytetrafluoroethylene using literature values of their partial solubility parameters. In the case of magnesium stearate the lubricant-excipient interactions are higher than those of lubricant-lubricant while in the case of polytetrafluoroethylene the reverse is true. This is consistent with the generally held belief that magnesium stearate forms a monomolecular film around the excipient causing a decrease in tablet strength.     

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.     

The influence of magnesium stearate on the characteristics of mucoadhesive microspheres

Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, xray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential     

硬脂酸镁过度润滑作用对盐酸二甲双胍缓释片的影响

目的 考察硬脂酸镁过度润滑作用对盐酸二甲双胍缓释片的影响。方法 通过改变硬脂酸镁的用量、改变硬脂酸镁的混合时间、改变加料器转速,制备不同盐酸二甲双胍缓释片。通过对比总混颗粒的粉体性质、片剂的溶出。综合评价硬脂酸镁过度润滑对盐酸二甲双胍缓释片的影响。结果 增加硬脂酸镁的用量、延长总混时间、加快加料器的转速均会导致硬脂酸镁过度润滑。表现为颗粒流动性并未明显改善,但可压性显著下降,盐酸二甲双胍缓释片溶出无明显减缓。结论 盐酸二甲双胍缓释片的可压性对硬脂酸镁的润滑作用敏感,需控制硬脂酸镁的用量、混合的时间以及加料器的转述,防止过度润滑,造成可压性变差的现象产生。     

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.     

Functionality of magnesium stearate derived from bovine and vegetable sources: dry granulated tablets

Magnesium stearate is a functional excipient used to ensure efficient ejection of tablets. This study compares the functionality of a vegetable and bovine grade of magnesium stearate. Tablets were prepared by direct compression and dry granulation of a model formulation. Physical and chemical tests were performed on bulk powders, granule intermediates, and finished tablets to provide a comprehensive comparison of the two grades of magnesium stearates. Raw material characterization of the two grades showed no difference in particle size, surface area, true density, and total moisture content. However, significant differences in fatty acid composition, surface tension, and zeta potential were detected. Tablet ejection force for the physical mixture formulations was variable, showing similar ejection force for the two grades of magnesium stearate at some concentrations and different ejection forces at other concentrations. The dry granulated formulation containing vegetable-based magnesium stearate showed a lower ejection force than the formulation containing bovine-based magnesium stearate. There was no difference between the dissolution profiles of the tablets containing the two grades of magnesium stearate prepared by both methods. The results indicated that magnesium stearate interchangeability with respect to lubricant efficiency depends upon the level in which it is used and the manufacturing method.