The Influence of Magnesium Stearate on the Hiestand Tableting Indices and Other Related Mechanical Properties of Maltodextrins

Magnesium stearate is widely used as a lubricant in pharmaceutical dosage forms. A film of magnesium stearate, or other lubricant, around individual granules is generally considered to cause the softening of tablets. Maltodextrins were chosen as model excipients since maltodextrins possessing a series of molecular weights showed systematically changing consolidation mechanisms. As maltodextrin molecular weight increases, the plasticity of the material increases. The Hiestand Tableting Indices and other related mechanical properties were used to study the effect of magnesium stearate addition on the mechanical properties and consolidation mechanisms of single component maltodextrins. Magnesium stearate was shown to lower the tensile strengths of maltodextrin compacts. Additionally, magnesium stearate addition lowered both the Hiestand Bonding Index and the Hiestand Brittle Fracture Index. The lower values of the Hiestand Brittle Fracture Index indicate that magnesium stearate promotes greater plastic behavior in maltodextrin compacts.     

The Effect of Binary Mixture Composition and Magnesium Stearate Concentration on the Hiestand Tableting Indices and Other Related Mechanical Properties

Maltodextrins were chosen as model excipients because maltodextrins possess a series of molecular weights that showed systematically changing consolidation mechanisms. As maltodextrin molecular weight increases, the plasticity of the material increases. Three commercial grades of Maltrin® (M040, M100, and M150) were used to prepare binary powder mixtures (M040-M150 and M040-M100). For each mixture, magnesium stearate was added at concentrations of 0%, 0.16%, 0.32%, 0.48%, and 0.64%. The Hiestand Tableting Indices and other related mechanical properties were used to quantify the effects of magnesium stearate addition on the compaction properties of the binary mixtures. Linear relationships were observed between the Hiestand Bonding Indices and the compositions of the compacts in the absence of magnesium stearate. However, the Hiestand Bonding Indices were related to compact compositions in polynomial fashion when magnesium stearate was present in the binary mixtures. The Hiestand Brittle Fracture Indices varied with compact compositions in polynomial fashion with and without magnesium stearate.     

The effect of binary mixture composition and magnesium stearate concentration on the Hiestand Tableting Indices and other related mechanical properties

Maltodextrins were chosen as model excipients because maltodextrins possess a series of molecular weights that showed systematically changing consolidation mechanisms. As maltodextrin molecular weight increases, the plasticity of the material increases. Three commercial grades of Maltrin (M040, M100, and M150) were used to prepare binary powder mixtures (M040-M150 and M040-M100). For each mixture, magnesium stearate was added at concentrations of 0%, 0.16%, 0.32%, 0.48%, and 0.64%. The Hiestand Tableting Indices and other related mechanical properties were used to quantify the effects of magnesium stearate addition on the compaction properties of the binary mixtures. Linear relationships were observed between the Hiestand Bonding Indices and the compositions of the compacts in the absence of magnesium stearate. However, the Hiestand Bonding Indices were related to compact compositions in polynomial fashion when magnesium stearate was present in the binary mixtures. The Hiestand Brittle Fracture Indices varied with compact compositions in polynomial fashion with and without magnesium stearate.     

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.     

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.     

A novel multifunctional pharmaceutical excipient: modification of the permeability of starch by processing with magnesium silicate

A directly compressible excipient has been developed by co-processing starch with magnesium silicate. The foregoing was achieved either by co-precipitation of magnesium silicate onto different types of starch or by dry granulation of maize starch with magnesium silicate. A variety of techniques (permeability, water retention/swelling, compression analysis, scanning electron microscopy, tensile strength and disintegration/dissolution studies) were used to characterize these systems. The permeability of the formulations produced using the two methods was evaluated experimentally using Darcy's permeability law. Magnesium silicate, as an anti-adhering agent, increases the permeability of both maize and partially pregelatinized starch, resulting in compacts of high mechanical strength, short disintegration time and low lubricant sensitivity. Such advantages are evident when the properties of the physical mixture of maize starch with magnesium silicate are compared with the co-precipitation and dry granulation techniques. Formulation with this novel excipient system, using paracetamol as a model drug, indicated its suitability as a single multifunctional excipient.     

Tensile strength of some pharmaceutical compacts and their relation to surface free energy

The time-dependent nature of plastic flow, of 7 pharmaceutical powders, and its effect on the tensile strength of their compacts after consolidation is reported. Magnesium stearate compact showed no change in strength with time. For plastic materials a In-In plot of tensile strength versus time resulted in a straight line. The obtained visco-elastic slope, v, is a measure of plasticity. The more pronounced the plastic flow the greater the slope.After 30 min from compaction, the values of tensile strength obtained were correlated quantitatively to the surface free energy of the materials studied. High surface free energies were associated with higher tensile strength. A constant, k, which relates the surface free energy of materials to the tensile strength of compacts is defined. Plastic materials exhibit the same k value which was greater than that obtained for magnesium stearate.     

Powder and capsule filling properties of lubricated granulated cellulose powder

Granulated powdered cellulose was studied in terms of powder bulk properties and capsule filling performance on a tamp-filling machine with and without the addition of various concentrations of magnesium stearate. Carr's compressibility reached its minimum value at 0.4% magnesium stearate suggesting an improvement of powder flow compared to the unlubricated material. However, shear cell measurements and the use of a powder rheometer indicated that the addition of 0.2% magnesium stearate and more impairs powder flow and does not reduce interparticulate friction. When capsules were filled into hard gelatine capsules at a zero-compression setting, the fill weight and plug density could be predicted from Carr's compressibility index and from the maximum bulk density. The decrease in one and simultaneous increase in the other bulk property with increasing magnesium stearate concentration caused both fill weight and plug density to go through a minimum at a lubricant concentration of 0.4%. When the capsules were filled at maximum compression, however, the addition of lubricant increased the coefficient of fill weight variation significantly, and the plug density remained constant for any added concentration of magnesium stearate. These findings were in agreement with the shear cell and powder rheometer results. However, the optimum lubricant concentration in terms of ease of machine function, which was identified from tamping pressure measurements, was found to be 0.8% magnesium stearate, which was not an optimal concentration for the powder bulk properties.     

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.     

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.     

Ultrasonic approach for viscoelastic and microstructure characterization of granular pharmaceutical tablets

The mechanical properties of a solid dosage, defined by its granular micro-structure and geometry, play a key role in its dissolution profile and performance. An ultrasonic method for extracting the viscoelastic material properties and granular structure of drug tablet compacts is introduced and its utility is demonstrated for tablet compacts made of microcrystalline cellulose (MCC), lactose monohydrate, and sodium starch glycolate as well as magnesium stearate as lubricant. The approach is based on the effect of viscoelasticity and internal micro-structures on the frequency-dependent attenuation of an ultrasonic wave propagating in a granular medium. The models for viscoelastic (a two-parameter Zener model) and scattering attenuation (Rayleigh model) mechanisms are employed. The material parameters including viscoelastic and scattering parameters (average Young's modulus, stress and strain relaxation time constants, and the Rayleigh scattering material parameter) and grain size distribution with a known distribution profile are extracted by an optimization algorithm based on the least square method. The results also indicate good agreement between experimentally and computationally determined phase and group velocities in compacted samples. It is found that the effects of both attenuation mechanisms are present and the extracted grain size distribution parameters are in good agreement with the optically determined values.     

Impact of solid-state properties on lubrication efficacy of magnesium stearate

The advent of high-speed tableting and slug capsule-filling machines has ushered in an increasingly important role for the lubricants to enact during manufacturing of dosage forms. Although lubricants help in processing, they can also adversely affect the flow properties and dissolution profile of the drug. It is thus critical to maintain a balance between these two behaviors, by understanding the underlying mechanisms and using their optimum concentration in the formulation. The source and manufacturing process inculcate different solid-state properties to magnesium stearate, the most commonly used lubricant, leading to variations in its lubrication efficacy. However, there has been no complete study relating the lubrication efficacy of magnesium stearate to various levels of solid state. Hence, this study was aimed at comprehensively scrutinizing the role of molecular, particle, and bulk level properties of solid state on the lubrication efficacy of magnesium stearate. A method based on net work done during compression using texture analyzer, was developed and validated to analyze its performance. Particle and bulk-level properties were studied using microscopy, particle size analysis, and particle surface area determination, and molecular level was characterized using thermal, spectroscopic, and crystallographic methods. Interplay of solid-state characteristics such as particle size, degree of agglomeration, and crystal habit were found to markedly influence the lubrication potential of magnesium stearate.     

Comparative evaluation of powder and tableting properties of low and high degree of polymerization cellulose I and cellulose II excipients

Low and high degree of polymerization (DP) cellulose II powders have been prepared from Avicel PH-102 and Solka Floc 40NF (low and high DP cellulose I powders, respectively), respectively, by treatment with sodium hydroxide (5N) for 24h and their powder and tableting properties investigated. Cellulose II powders, compared to the respective cellulose I counterpart, exhibited lower crystallinity, true density, and specific surface area. They were denser and showed higher moisture uptake. The Heckel analyses revealed both low and high DP cellulose II powders to be less ductile than the low DP cellulose I powder and more ductile compared to the high DP cellulose I powder. The crushing strengths of low and high DP cellulose II powders were comparable to that of the high DP cellulose I powder but lower than the low DP cellulose I powder. When compressed to comparable crushing strengths, the low and high DP cellulose II compacts disintegrated faster in comparison to the corresponding cellulose I compacts. Low DP cellulose I and II powders, compared to the high DP cellulose I counterparts were more sensitive to magnesium stearate. Magnesium stearate decreased the disintegration times of low DP cellulose I compacts but had no effect on the low and high DP cellulose II and high DP cellulose I compacts. In conclusion, low and high DP cellulose II powders, despite their different powder properties, show similar tableting properties, leading to the formation of rapidly disintegrating compacts. The low and high DP cellulose I excipients, in contrast, differ in their powder properties as well as tableting characteristics.     

几种直压辅料的可压性及其对硬脂酸镁的敏感性

目的比较不同类型的直压辅料,微晶纤维素、预胶化淀粉、山梨醇、乳糖和3种二元混合辅料的可压性以及对硬脂酸镁的敏感性。方法采用压实性和压缩度的测定方法比较辅料的压片性质差异,分别采用不同浓度的硬脂酸镁含量,不同的物料混合时间。不同的辅料粒径大小比较辅料对硬脂酸镁的敏感率。结果含有塑性物料微晶纤维素类的辅料具有较好的可压性,而直压辅料对硬脂酸镁的敏感性强弱为：弹性辅料〉塑性辅料〉脆性辅料。结论不同类型辅料压片性质差异较大,可选择塑性辅料和脆性辅料组合的方式作为填充剂。     

The Effect of Moisture on the Mechanical and Powder Flow Properties of Microcrystalline Cellulose

Purpose. This study determined the effects of moisture on the mechanical and powder flow properties of microcrystalline cellulose. Methods. A variety of mechanical properties were determined as a function of solid fraction at moisture levels ranging from 0 to 12.2% and included: compaction pressure required to form a compact, dynamic indentation hardness, quasi-static indentation hardness, tensile strength, best case and worst case Bonding Index, Brittle Fracture Index, Strain Index, Compressibility Index and shear cell index. Results. Significant changes were observed as the moisture level of microcrystalline cellulose increased. The compaction pressure required to produce a compact at a solid fraction of 0.6 decreased with increasing moisture content. The permanent deformation pressure and tensile strength of compacts were observed to be relatively independent of moisture content below about 5% moisture and then decrease as the moisture content increased further. The best case Bonding Index was also observed to be independent of moisture content below 5% and then increase with increasing moisture. The Brittle Fracture Index and worst case Bonding Index, however, did not appear to be affected by changes in moisture content. Powder flow was shown to decrease with increasing moisture content. Conclusions. These mechanical property data are consistent with the hypothesis that water acts as a plasticizer and influences the mechanical properties of microcrystalline cellulose. At moisture levels above about 5%, the material exhibits significant changes consistent with a transition from the glassy state to the rubbery state.     

Formulating Weakly Basic HCl Salts: Relative Ability of Common Excipients to Induce Disproportionation and the Unique Deleterious Effects of Magnesium Stearate

Purpose

Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular structure. Such a correlation enables a general, simple excipient selection process.

Methods

Binary compacts and “pseudo formulations” are studied after stressing at 40°C/75%RH and 40°C/35% RH for up to 28 days. Near-Infrared (NIR) and X-Ray powder diffraction (XRPD) measurements monitored the conversion of the HCl salt to the free base.

Results

The excipients which induced measureable disproportionation were magnesium stearate, sodium croscarmellose, and sodium stearyl fumarate. Magnesium stearate induced the most extensive and rapid disproportionation at 40°C/75%RH and 40°C/35%RH. Samples containing magnesium stearate showed a unique and significant water uptake above 31%RH.

Conclusions

The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pK_a’s higher than the pH_max of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride.     

Effect of magnesium stearate on bonding and porosity expansion of tablets produced from materials with different consolidation properties

The negative effect of magnesium stearate on tablet strength is widely known. This strength reduction is always considered to be the result of reduction of interparticle bonding. It is also known that interparticle bonding affects relaxation of tablets. Relaxation increases with decreasing bonding. Microcrystalline cellulose is an example of a material with a high lubricant sensitivity, which effect is caused by its plastic deformation behavior during compression. This paper shows for microcrystalline cellulose that the porosity under pressure was equal for unlubricated tablets and for tablets containing 0.5% magnesium stearate. This points to equal densification properties. The lubricated tablets show, however, a much larger relaxation than the tablets without magnesium stearate. This difference can be ascribed to the reduction of interparticle bonding by the lubricant, because a strong interparticle bonding counteracts tablet relaxation. In contrast to microcrystalline cellulose, aggregated gamma-sorbitol (Karion Instant) has a low lubricant sensitivity. Both porosity under pressure and tablet relaxation were found to be equal for lubricated and unlubricated sorbitol tablets. This phenomenon is caused by the particle structure of gamma-sorbitol. During compression, a lubricant film will be destroyed by fragmentation of the sorbitol aggregates. For this reason, magnesium stearate will hardly affect the interparticle bonding between sorbitol particles and hence have only a small or no effect on tablet relaxation.Copyright     

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.     

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.     

Evaluation of cocoa butter as potential lubricant for coprocessing in pharmaceutical tablets

The lubricant activity of cocoa butter coprocessed with magnesium stearate plus talc (CMT) was compared with magnesium stearate plus talc (MT) using flow and compressional characteristics of paracetamol granules and mechanical properties of their tablets as assessment parameters. The flow of the granules quantified as Hausner's ratio, Carr's index, and angle of repose showed that CMT has a higher ability than MT to reduce densification of granules due to vibration. Compressional characteristics analyzed using density measurements and the Heckel and Kawakita plots revealed that CMT did not facilitate the increase in the densification of the granules during the filling and at low pressures, D(b). Also, CMT reduced the plastic deformation of the granules measured by the P(y)-yield pressure at onset of plastic deformation and P(k)-yield pressure of deformation under compression. The mechanical properties determined by the tensile strength, T, and brittle fracture index, BFI, of the tablets produced were affected by CMT. The T and BFI of tablets with CMT were lower than those of MT. The results suggest that though CMT lowered the plasticity of the granules, it improved their flow rate and assisted in producing tablets with fewer tendencies to cap or laminate. This work concluded that cocoa butter, an inexpensive and easily available lipid, is an effective and viable lubricant that can be co-processed with magnesium stearate/talc mixture for an efficient lubrication of granules and may be useful in reducing lamination and capping in formulations that are susceptible to these 2 defects of tablets.