Rodolpho J. Romanach

Analytical methods are needed to acquire process knowledge even after a product is approved and in commercial production. A recent product quality research institute (PQRI)/FDA report acknowledged: "Information is learned about a process during the first year of commercial production that could only come from manufacture in a routine environment. This information is critical to providing better control of the process and quality of the resulting product."

  Some of the post-approval information will be gained by simply observing the manufacturing process and evaluating results received from the quality control (QC) laboratory in an effort to identify trends in the data. However, process knowledge would be increased exponentially with the use of analytical methods to monitor raw material attributes and critical process parameters.   

FDA's process analytical technology (PAT) initiative emphasizes the need to improve pharmaceutical manufacturing through process knowledge, and the inverse relationship between process knowledge and risk of manufacturing a poor quality product.

  Information gained during the development process is useful, but process knowledge obtained during routine production is necessary to improve pharmaceutical manufacturing. The authors envision that as a result of PAT efforts, technical support groups in pharmaceutical manufacturing will develop laboratories with small-scale production equipment and analytical instrumentation to increase their understanding of pharmaceutical processes.         

 Table 1 Excipients lubricated with magnesium stearate.			

Technical support groups and pharmaceutical manufacturing often face problems related to lubrication. The lubrication of pharmaceutical formulations has been the subject of many studies for over 30 years.

  Magnesium stearate, the most commonly used lubricant, reduces the friction between the die wall and tablet to facilitate tablet ejection. It may also lead to a series of problems such as high disintegration times, low dissolution and low tablet hardness. Recent studies have involved the use of near infrared (NIR) spectroscopy and laser induced breakdown spectroscopy (LIBS) to determine magnesium concentration on tablet surfaces, and atomic force microscopy for studying the adhesion of magnesium stearate.

  This report presents initial results with a Raman spectroscopic method to study lubrication. 

In Raman spectroscopy (RS) radiation from a laser interacts with the electron cloud, creating a short-lived virtual state that is not stable and, consequently, the radiation is quickly reradiated.

  The majority of the radiation is elastically scattered and only one in every 10

  photons is scattered at optical frequencies different from that of the incident radiation. The weak Raman scattering effect does not make the technique insensitive because of the high power density of the lasers used. The Raman spectrum is obtained by subtracting the scattered energy from the laser energy and is expressed as a shift in energy from that of the exciting radiation. The difference in energy corresponds to frequencies in the infrared region providing an information-rich Raman spectrum that may be used to understand intramolecular and crystal lattice vibrations, and is a useful tool in structure elucidation studies. Several recent publications have demonstrated the use of RS in monitoring pharmaceutical processes.

The experiments described in this study show that RS may be used to detect low levels of magnesium stearate in lubricated materials. RS provides a direct measurement of the CH

 hydrophobic groups in magnesium stearate. This report presents the initial results in a project to develop useful Raman spectroscopic methods for the evaluation of lubrication in pharmaceutical manufacturing.    

 Magnesium stearate was received from several suppliers:  					

 Impalpable Powder 2255 and Kosher Passover code 6504 (Mallinckrodt; Hazelwood, MO, USA). 

 Magnesium stearate lot # EU4149 (Witco Corp.; Chicago, IL, USA). 

 Magnesium stearate NF Bulky PW (Chemtura; Middlebury, CT, USA).  

 Magnesium stearate Kosher (Peter Greven Fett-Chemie GmbH & Co. KG; Venlo, The Netherlands).  

Excipients were obtained from various manufacturers/suppliers: 					

 Hydrous lactose United States Pharmacopeia (USP) grade, spray-dried for direct compression (DMV International; Veghel, The Netherlands). 

 Mannitol (Roquette; Lestrem Cedex, France). 

 Calcium phosphate dibasic anhydrous and calcium phosphate dibasic dehydrate (Solutia; Saint Louis, MO, USA). 

 Vivapur-type 101 microcrystalline cellulose (JRS Pharma; Rosenburg, Germany). 

 Pregelatined starch NF (Starch 1500 [Colorcon; West Point, PA, USA]). 

 Croscarmellose sodium NF (FMC; Philadelphia, PA, USA). 

 Povidone, Kollidon 30 (BASF; Mount Olive, NJ, USA). 

An API Ibuprofen USP 70 grade produced by Albemarle Corp. (Baton Rouge, LA, USA) and donated by Pharmacia and Upjohn Caribe (Barceloneta, PR, USA) was also used. 

The excipients and a pharmaceutical blend described in Table 1 were lubricated for 2 min in a 4-quart acrylic shell powered by P.K. Blend Master (model B, Patterson-Kelley Co.; East Stroudsburg, PA, USA). 

Raman spectra were acquired using a Raman RXN1–RA–785 system (Kaiser Optical Systems; Ann Arbor, MI, USA), which has an immersion probe accessory that was installed in the vertical position in contact with powder and tablet from the same formulation. The laser wavelength in the system is 785 nm, with spectral coverage from 150–3450 cm

 . The spectra obtained were the result of five accumulations and an exposure time of 10 s. Powder samples were placed in glass covered with aluminum foil and the immersion flask was placed into the powder in vertical position. The system's non-contact probe may also be used to obtain spectra of powders and tablets, but the immersion probe was used in this study. Raman spectra were collected for the excipients before and after lubrication, and for tablets from the formulation described in Table 1.    

The spectral noise was estimated in accordance with the International Conference on Harmonization (ICH) and the EMEA guidelines by computing the standard deviation for 30 spectra of dibasic calcium phosphate (used as a blank sample) over the 2950–2825 cm

  spectral region, and then taking the average standard deviation as an estimate of the noise.

  The standard deviation was also calculated in the same spectral area for the dibasic calcium phosphate lubricated with 0.15, 0.25 and 0.5% (w/w) magnesium stearate. The limit of detection was then calculated as the signal with three times the noise (average standard deviation), and on the basis of the standard deviation of the lubricated samples.  

All spectral transformations were performed using the Pirouette 3.11 software (Infometrix Inc.; Bothell, WA, USA). First, derivative spectra were obtained using five point segments. The spectra were exported to Excel 2003 (Microsoft Corp.; Seattle, WA, USA) for preparation of figures.    

Table 2 Peak ratio for the 2883 and 2848 cm -1 bands. 			

Figure 1 shows Raman spectra of magnesium stearate received from three different suppliers. Samples were received from five different suppliers, but only three spectra are shown to preserve the clarity of Figure 1. The spectra include a number of bands in the 3000–2800 cm

  spectral region that are assigned to C–H stretching modes.

 antisymmetric or out-of-phase stretching vibration. The wide band near 2934 cm

 antisymmetric stretch. The strongest band observed was that at 2883 cm

  band shown in Figure 1a was assigned to the in-phase or symmetric stretch of the CH

  is clearly distinguishable in the spectra of lubricated materials described in Table 1. The intensity of this band varies according to the magnesium stearate concentration as shown in Figure 2. The band 2883 cm

  is also strengthened as the magnesium stearate is increased, but tends to overlap with bands in the spectra of the excipients listed in Table 1, with the exception of the inorganic materials.  

The magnesium stearate spectra are similar, but not identical as subtle differences are observed in the spectra. One of the subtle spectral differences is in the ratio of the peak intensity for bands at 2883 cm

 , which may be used as an indication of the presence of methyl and methylene groups in the materials as shown in Table 2. This simple check may be useful in cursory evaluations of magnesium stearate as this material is known to vary in its chemical composition and physical properties.

  USP currently defines magnesium stearate as: "A compound of magnesium with a mixture of solid organic acids, and consists chiefly of variable proportions of magnesium stearate and magnesium palmitate. The fatty acids are derived from edible sources. It contains between 4.0% and 5.0% of magnesium, calculated on the dried basis," — a definition that provides significant leeway in the composition of this excipient.

  peak ratio varied from 1.41–1.60 as indicated in Table 2. The peak ratios do not indicate 1.41 or 1.60 methyl groups per methylene group, as the Raman scattering of these groups differ significantly. However, they indicate subtle differences in the composition of the materials. 

Table 1 lists several common excipients and a pharmaceutical formulation that were lubricated with magnesium stearate. The magnesium stearate bands at 2848 cm

  are easily distinguishable in the lubricated calcium phosphate as this is an inorganic material. The other excipients show C–H stretch bands in the 2800–3000 cm

  region. However, first derivative spectra clearly differentiate between the magnesium stearate and the organic excipients listed in Table 1. Figure 3 shows first derivative spectra of lubricated lactose samples where the level of magnesium stearate used was varied from 0.5–5% (w/w). Differences in spectra are evident as the magnesium stearate concentration is varied.    

In the fingerprint region magnesium stearate bands at 1460 cm

 asymmetrical bending modes, and the weak band at 1373 cm

 bending mode. The C–H bending bands overlap with similar bands from organic excipients. Magnesium stearate also has a band at 1060 cm

 rocking vibration. This band is not observed in the spectra of the organic excipients evaluated in this study. The 1060 cm

  band is easily observed in the spectra of the different magnesium stearate samples, but was only observable in the lubricated materials with more than 1% (w/w) magnesium stearate. A recently introduced Raman system provides greater sensitivity in the fingerprint region, and will be thoroughly evaluated in future studies.

The Raman spectroscopic method may also be used to obtain spectra of tablets and detect the magnesium stearate on the surface of tablets. Figure 4 shows spectra of tablets compressed without magnesium stearate and with 3% (w/w) magnesium stearate.  

Many formulations are lubricated at a level of 0.5% (w/w) magnesium stearate or less. Figure 5 shows that magnesium stearate is easily determined at the 0.5% (w/w) level. The method's detection limit was calculated to be about 0.093% (w/w) by determining the noise in 30 spectra of unlubricated dibasic calcium phosphate, and the signal to noise (S/N) ratio in lubricated samples as described in the experimental section.  

The method's detection limit was confirmed by obtaining the spectra of lubricated dibasic calcium phosphate at 0.13% (w/w) and 0.25% (w/w) as shown in Figure 5. Thus, the detection limit for the magnesium stearate band at 2848 cm

  is about 0.1% (w/w). The detection limit is not a definitive figure of merit; it is an estimate and may be slightly higher or lower in another instrument.    

These initial results indicate that RS could be used to detect magnesium stearate on the surface of tablets and powder blends. The potential advantage of using RS is that it provides a direct measure of the CH

 groups that are directly responsible for the hydrophobic effects of the magnesium stearate. A Raman spectroscopic method could be used to investigate possible relationships between the magnesium stearate distribution and dissolution or tabletting properties of a formulation. RS could provide a potential map of hydrophobic areas on the tablet surface. Further development of Raman methods would complement LIBS methods that provide a measure of the magnesium stearate based on the magnesium concentration. Future studies will also involve the use of RS in the quantitative determination of magnesium stearate in powder blends and tablets. 

Mutchler Chemical and Excipientfest are thanked for their help in obtaining excipients and partial funding of this research. INDUNIV (Puerto Rico Industry University and Government) research consortium provided the funding for the acquisition of the Raman system.  

1. "A Drug Quality System for the 21st Century," PQRI/FDA Report on the Workshop from 22–24 April 2003, Washington, DC, USA, prepared 16 June 2003. 

2. "PAT — A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance." 

Articles

A new Raman spectroscopic method to detect magnesium stearate in powder blends and tablets is described. High-volume pharmaceutical manufacturing requires the use of lubricants to facilitate tablet ejection from compressing machines. However, lubricants may also bring a number of undesired problems that have been widely documented in pharmaceutical scientific literature. New analytical methods are needed to understand lubrication and provide process knowledge in support of FDA's process analytical technology initiative. The detection of magnesium stearate in lactose, mannitol, corn starch and other commercially important excipients is reported. The Raman spectroscopic method has a detection limit of about 0.1% (w/w) based on the 2848 cm-1 band that corresponds to the symmetric stretch of the methylene group in magnesium stearate.