Swaminathan V, Kildsig DO. Effect of Magnesium Stearate on the Content Uniformity of Active Ingredient in Pharmaceutical Powder Mixtures. AAPS PharmSciTech. 2002; 3(3): article 19.

Effect of Magnesium Stearate on the Content Uniformity of Active Ingredient in Pharmaceutical Powder Mixtures
Vidya Swaminathan,¹  and Dane O. Kildsig² 

¹Pfizer Global R&D Groton Laboratories, Eastern Point Road, Groton, CT 06340
²Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN 47906

Correspondence to:
Vidya Swaminathan
Tel: (860) 686-1890
Fax: (860) 441-3972
Email: vidya_swaminathan@groton.pfizer.com

Submitted: March 21, 2002; Accepted: July 19, 2002; Published:

Keywords:  magnesium stearate, content uniformity, powder mixtures

Abstract

The objective of this study was to determine the effect of magnesium stearate on the physical stability of polydisperse powder mixtures. The effects of concentration of magnesium stearate and the time of lubrication of mixtures with magnesium stearate on the content uniformity of the active ingredient in the mixtures were evaluated in a model mixture of lactose and aspirin. These effects were compared in a random mixture of non-interacting components and a mixture based on particle interaction. A statistical model that adequately described the relationship between the factors examined and the response was generated. The model indicated the presence of an interaction between magnesium stearate concentration and lubrication time. At a given concentration of magnesium stearate, there was a significant reduction in the content uniformity of aspirin as the time of lubrication of the mixture with magnesium stearate was increased. This effect was larger in mixtures based on particle interaction than in random mixtures of non-interacting components.

Introduction

Magnesium stearate is widely used as a lubricant in the manufacture of pharmaceutical solid dosage forms. While the effect of magnesium stearate on the disintegration and dissolution of tablets and capsules has been extensively studied and documented, its effect on the physical stability of mixtures has received little attention to date. It has been shown that magnesium stearate can displace _fine_ active ingredient from coarse monodisperse carriers in mixtures based on particle interactions.^1,2 In practice, most mixtures are polydisperse. The objective of this study was to determine the effect of magnesium stearate on the physical stability of polydisperse powder mixtures. Specifically, the effects of concentration of magnesium stearate and the time of lubrication of mixtures comprising a drug and inert carrier with magnesium stearate on the content uniformity of the active ingredient were determined in a model mixture of lactose and aspirin. The coefficient of variation (CV) of aspirin in the mixture was used as a measure of content uniformity. These effects were compared in two types of mixtures—a random mixture of non-interacting components and a mixture based on particle interaction.

Materials and Methods

Spray-dried lactose of 100-µm median volume diameter was obtained from Foremost Wisconsin Dairies (Foremost Farms, Baraboo, WI). Commercial aspirin powder having a median volume diameter of 100 μm was obtained from Miles Laboratories, Elkhart, IN. Micronized aspirin of 8-μm median volume diameter was obtained by milling the commercial powder in a fluid-energy mill (Gem-T Model, Trost Equipment Corporation, Newton, PA). The temperature of the processing environment was 20 ± 5°C, and the relative humidity was 40% ± 5%.

The size distribution of powders was measured by laser diffraction using the Microtrac particle size analyzer (Leeds & Northrup, Clearwater, FL). Absolute ethanol (High performance liquid chromatography [HPLC] grade) was used as the dispersion medium for lactose; micronized aspirin and magnesium stearate were dispersed in double-distilled water with the aid of 2% wt/vol polysorbate 80.

A premix of aspirin and lactose, prepared by sieving aspirin and ten parts of lactose on a 250μm mesh screen, was mixed with bulk lactose in a stainless steel tumbling V-mixer for 20 minutes. The optimum mixing time was determined from preliminary experiments. Each mixture was lubricated with magnesium stearate; the concentration of magnesium stearate and time of lubrication in each series of experiments are listed in the following section. Fifteen samples (200 mg each) were removed from each mixture with a stainless steel thief sampler prior to and following lubrication with magnesium stearate. The samples were assayed for aspirin by measuring the UV absorbance of chloroform extracts at 277.5 nm (Beckman spectrophotometer, Beckman Instruments, Schaumburg, IL).The CV of aspirin in the mixture was calculated from the mean and standard deviation of the aspirin content in the samples.

The effects of magnesium stearate concentration and lubrication time on the CV of aspirin in mixtures of 1% micronized aspirin and lactose were evaluated in a full factorial design. We used 0.25%, 0.5%, and 2% of magnesium stearate and lubrication times of 2, 5, and 15 minutes corresponding to low, intermediate, and high levels of the factors. The experimental runs were fully randomized. JMP Statistical Analysis Software (SAS Institute, Version 3.1, Research Triangle Park, NC) was used in experimental design and data analysis.

For this study, a mixture of lactose and 1% micronized aspirin was used as a model mixture of interacting components, and that of lactose and polydisperse aspirin (20% wt/wt) was assumed to represent a random mixture of noninteracting components.³ The effect of magnesium stearate concentration on the content uniformity of aspirin in these mixtures was evaluated at a fixed lubrication time in a mixed-level factorial design. Mixtures were prepared as described previously and lubricated with magnesium stearate (in concentrations of 0%, 0.5%, and 1%) for 5 minutes. The CV of aspirin was calculated from the assay of aspirin in samples of the mixtures. The experimental runs were randomized.

Effects of magnesium stearate concentration and lubrication time on the CV of aspirin in mixtures of lactose and 1% micronized aspirin.

The whole model and effect tests are listed in Table 1. The parameters, the degrees of freedom associated with the effect, the sum of squares for the hypothesis that the listed effect is zero, the F statistic for testing that the effect is zero, and the significance probability for the F ratio for each effect are listed. The least squares means (LSM) were compared in testing the effects. The measured response was adequately accounted for by the factors in the statistical model, as indicated by the whole model test. The leverage plot for the whole model test shown in Figure 1 is a display of how the fit carries the data. The confidence curve crosses the sample mean (represented by the horizontal line) if the F test is significant at some alpha level, 0.05 in this instance. The P>F value of <.0001 (Table 1) indicates that the line of fit carries the points significantly better than the sample mean of a partially constrained model.

The difference in response among magnesium stearate concentrations at the various lubrication times indicated the presence of an interaction between the factors. The interaction is represented by the non-parallel lines in the plots of the response among the three levels of magnesium stearate concentration at different lubrication times (Figure 2). To draw inferences about main effects in the presence of the interaction, the concentration of magnesium stearate was fixed at 0.5% and the effect of varying the lubrication time on the CV of aspirin content was determined.⁴ The mean response was compared using the Tukey-Kramer test for multiple comparisons of the means at a significance level of 5%. Figure 3 is a plot of the effect of lubrication time on the CV of aspirin in the mixtures. Data at zero time represent the CV of aspirin in samples removed from the mixture before it was blended with magnesium stearate. There was an increase in the CV of aspirin in the mixture as lubrication time was increased, indicating a decrease in the homogeneity of the mixture. The CV of aspirin in mixtures that were blended with magnesium stearate for over 5 minutes was significantly larger than that measured at lubrication times of 5 minutes or less (P>F: .0001). Further increase in the lubrication time resulted in only a small increase in the CV of aspirin in the mixture. Since lubrication times of over 5 minutes are rarely exceeded in practice, data corresponding to the time period of 0 to 5 minutes were compared by the same test. The difference in the CV of aspirin between the control (ie, mixture sampled prior to blending with magnesium stearate) and the mixture blended with magnesium stearate for 2.5 minutes was not significant. The CV of aspirin in mixtures lubricated for 2.5 and 5 minutes was significantly larger than that measured in mixtures lubricated for 2.5 minutes. The practical implication of this observation is that lubrication time can have a significant effect on the content uniformity of drug in low-dose mixtures. The extent of its impact on mixture homogeneity is dependent upon the composition of the mixture and the concentration of magnesium stearate.

Comparison of the effect of magnesium stearate on the CV of aspirin in random mixtures and mixtures based on particle interaction.

Mixtures comprising a coarse carrier and a small concentration of a ‘fine’ component, such as microfine drug, are widely held to be stabilized by interactions between the components. Such mixtures have been referred to as ordered mixtures in the literature.³ It has previously been shown that under similar processing conditions, when the size distribution of the minor component and inert carrier are similar and the powders are largely non-cohesive (ie, having a median particle size larger than 70 µm), the resulting mixtures generally behave like random mixtures of noninteracting components, assuming the absence of other surface effects.⁵ Mixtures of (1) lactose and micronized aspirin of 8-µm volume median diameter and (2) lactose and polydisperse aspirin of 100-µm volume median diameter were assumed to represent ordered and random mixtures respectively in this study, and the effect of magnesium stearate on the content uniformity of these mixtures was compared.

The whole model and effect tests are given in Figure 4 and Table 2. The model adequately described the response at various levels of the factors. The concentration of magnesium stearate and type of mixture (ordered vs random) were main effects for the CV of aspirin content. There was no significant interaction between the 2 main effects (P>F = .1028). The overall effect of the addition of magnesium stearate to the mixture was a decrease in homogeneity of the mixture, as indicated by the large CV of aspirin content. The CV of aspirin was larger in mixtures lubricated with magnesium stearate than in the control (mixture prior to addition of magnesium stearate). The addition of magnesium stearate to a mixture of micronized aspirin and lactose resulted in a larger CV (9%) than that measured in a mixture of lactose and polydisperse aspirin (5.4%). In the latter, the CV of aspirin in mixtures lubricated with 0.5% and 1% magnesium stearate was comparable (Figure 5).

The mixture of polydisperse lactose and aspirin of 100-μm median diameter can be considered (roughly) to be a system of noninteracting components. Adhesion of the fine fraction of the components is expected to be minimal, given the size distribution of the minor component. The effect of magnesium stearate on the content uniformity of such a mixture appears to be significantly smaller than that in a mixture of coarse lactose and micronized aspirin, where there is considerable adhesion of the fine component to the carrier.^2,3

It has been shown that magnesium stearate can displace drug from the surface of the carrier.^1,2 A likely mechanism for this has been postulated to be due to dissipation of electrostatic charge of the components of the mixture by magnesium stearate.^6,7 The dry process environment (20°C, 40% relative humidity) is conducive to electrostatic charge effects. The tendency of magnesium stearate particles to delaminate under shear can result in its rapid dispersion in the mixture at mixing times that are a fraction of those used in dispersing active ingredient in the bulk. While no direct evidence of adhesion of magnesium stearate to the surface of the carrier was obtained in this study, the large dispersion component of the surface energy of magnesium stearate relative to that of aspirin⁸ can facilitate its adhesion on the carrier surface.

The concentration of magnesium stearate and time of lubrication of mixtures with magnesium stearate can affect the content uniformity of active ingredient in mixtures that are based on particle interactions, as determined in model mixtures of lactose and micronized aspirin in this study. By comparison, this effect was significantly smaller in mixtures of noninteracting components. Translated into practical terms, the effect of magnesium stearate on the content uniformity of active ingredient in coarse powder mixtures such as granules for encapsulation or compaction into tablets, is not likely to be as significant as that in ordered mixtures containing low-dose active ingredient and diluent. In the latter, lubrication time can have a significant effect on the content uniformity of active ingredient. The extent of the impact of lubrication time depends on the composition of the mixture and on the concentration of magnesium stearate in the mixture.

Acknowledgements

The authors gratefully acknowledge the financial support provided by the Purdue Research Foundation.

1.    Stewart PJ. Influence of magnesium stearate on the homogeneity of a prednisone-granule ordered mix. Drug Dev Ind Pharm. 1981;7(5):485-495.
 

2.    Swaminathan V, Kildsig DO. Effect of particle morphology on the physical stability of pharmaceutical powder mixtures: effect of surface roughness of carrier on the stability of ordered mixtures. Drug Dev Ind Pharm. 2000;26(4):356-373.
PubMed  

3.    Hersey JA. Ordered mixing: a new concept in powder mixing practice. Powder Technol. 1975;11:41-44.
 

4.    Montgomery DC. Design and Analysis of Experiments. 3rd ed. New York, NY: John Wiley & Sons, Inc; 1991.
 

5.    Swaminathan V, Kildsig DO. Polydisperse powder mixtures: effect of particle size and shape on mixture stability. Drug Dev Ind Pharm. 2002;28(1):41-48.
PubMed  

6.    Staniforth JN, Rees JE. Electrostatic charge interactions in ordered powder mixes. J Pharm Pharmacol. 1982;34(2):69-76.
PubMed  

7.    Staniforth JN, Rees JE, Lai FK, Hersey JA. Interparticle forces in binary and ternary ordered powder mixes. J Pharm Pharmacol. 1982;34(3):141-145.
PubMed  

8.    Zografi G, Tam S. Wettability of pharmaceutical solids: estimates of solid surface polarity. J Pharm Sci. 1976;65:1145-1149.
PubMed