(83e) Analysis of the Effects of Shearing Conditions On the Distribution of MgSt Using Laser-Induced-Breakdown-Spectroscopy (LIBS) and near Infrared Spectroscopy (NIR)

The development of new analytical validation techniques in addition to sampling procedures that are well understood are some of the main topics discussed in the industry guidance (FDA, 2003). In this work we have used model formulations of Magnesium Stearate (MgSt), Lactose, and micro-crystalline cellulose exposed to different shear conditions. The operating parameters studied include total shear and strain rate. The effect of varying the MgSt percentage was also studied, considering the effect lubricants have on powder flow can greatly facilitate processing steps such as mixing and tableting (Faqih et al., 2007).

Samples from each formulation were retrieved and analyzed for MgSt content in order to determine the composition uniformity within the samples. The powder samples are initially scanned using NIR, and than compressed into tablets using a Carver Press with the intention to ensure a constant compression force on each tablet. This is crucial because the effect compression has on hardness is also studied since different hardness levels will affect the NIR and LIBS results for the acquisitions. NIR acquisition is also performed on tablets, with the intention to compare the variability in the prediction models between the powder samples and tablets using NIR. One of the disadvantages of NIR is that at low percentages of one of the components, NIR performance worsens, thus finding alternatives as well as other techniques that can validate the analysis results is greatly desired. Once the tablets have been analyzed using NIR, they are subsequently examined using LIBS.

LIBS has been used to determine the content of MgSt (Green et al., 2005), interestingly they found that increasing the number of shots and including additional sites did not improve there quantitative results. Considering there are several parameters to set when operating the process, in this work we will discuss the statistical significance of these effects. In addition to compare the statistical significance between the analysis methods (LIB, NIR) in terms of concentration and homogeneity predictions. An Analysis of Variance (ANOVA) will be used to examine the different sources (ie. MgSt %, Analysis Method, Shear Rate, Total Shear) and varying levels for each source.

In terms of predicting the concentration of MgSt within samples, the findings show that there is a statistically significant distinction between the analysis methods. Interestingly at no or low MgSt the effect of varying RPM on the predicted concentration is not significant for both methods. The effect of RPM becomes significant on the quantitative concentration predictions at high levels of MgSt. In terms of relative variance between the formulations at a 2 % MgSt level, the variability between the methods is not statistically significant. The effect of RPM also is considered to be statistically insignificant for a majority of the studies. Total shear (strain) has been shown to be an important parameter affecting flow index, MgSt micro-distribution, and tablet hardness (Mehrotra et al., 2007). Characterizing physical effects using fast analytical tools such as LIBS and NIR measurements was performed on the tablets made from blends exposed to different levels of strain. Homogeneity improved for powder and tablets when the strain was increased, but this effect diminished by increasing the MgSt concentration. NIR calibration models have been developed for powder and tablet samples. The effect of strain on the LIBS signal has been shown to be significant. Thus, applicability of LIBS and NIR for characterizing lubrication will be demonstrated.

References

FDA, Guidance for Industry, Powder Blends and Finished Dosage Units ? Stratified In-Process Dosage Unit Sampling and Assessment, Pharmaceutical CGMP's, October 2003.

Faqih A. M., Mehrotra A., Hammond S. V., Muzzio F. J., 2007, Effect of moisture and magnesium stearate concentration on flow properties of cohesive granular materials, International Journal of Pharmaceutics, 336, 2, 338-345.

Green R., Mowery M., Good J., Higgins J., Arrivo S., McColough K., Mateos A., Reed R., 2005, Comparison of Near-Infrared and Laser-Induced Breakdown Spectroscopy for Determination of Magnesium Stearate in Pharmaceutical Powders and Solid Dosage Forms, Applied Spectroscopy, 59, 2, 2005, 340-347.

Mehrotra A., Llusa M., Faqih A., Levin M., Muzzio F. J., Influence of shear intensity and total shear on properties of blends and tablets of lactose and cellulose lubricated with magnesium stearate, International Journal of Pharmaceutics, 2007, 336, 284-291.