Effect of temperature and humidity on vegetable grade magnesium stearate

Powder Technology 147 (2004) 79 85 www.elsevier.com/locate/powtec Effect of temperature and humidity on vegetable grade magnesium stearate Mikko Koivisto a, *, Hannu Jalonen b, Vesa-Pekka Lehto a a Department of Physics, University of Turku, FIN-20014 Turku, Finland b Orion Corporation, ORION PHARMA, P.O. Box 425, FIN-20101 Turku, Finland Received 13 August 2003; received in revised form 19 March 2004; accepted 15 September 2004 Available online 10 November 2004 Abstract Thermal and physical properties of vegetable grade magnesium stearate monohydrate, dihydrate and trihydrate have been studied. The samples have been studied as received, after moisture treatment (3 and 6 weeks at 96%RH) and after degassing (2 h in vacuum at 40 and 105 8C). The specific surface area, average pore size, thermal properties and crystal structure were dependent on the hydration state of the samples. All of the studied properties changed crucially after the samples were degassed at 105 8C. The biggest changes were in magnesium stearate trihydrate whose specific surface area after degassing at 105 8C was only a fifth of the area of the as-received sample. The results of the thermal analysis and X-ray diffraction measurements show that all of the studied magnesium stearates changed to the anhydrate after degassing in vacuum at 105 8C. A gravimetric method was used to examine the water sorption behavior of the samples and results show that part of the water absorbed at room temperature remains in the structure of magnesium stearate. No changes in the hydration states were observed, whereas properties were different compared to the as-received samples. The monohydrate sample changed most in the moisture treatment. All of the measured nitrogen adsorption desorption isotherms except the isotherms measured from the anhydrated samples did not fit properly to any known theory, which might be a result of interaction of nitrogen and water. D 2004 Elsevier B.V. All rights reserved. Keywords: Magnesium stearate; Moisture treatment; Degassing; Specific surface area 1. Introduction Magnesium stearate is widely used as a lubricant in pharmaceutical tablet formulations. The main reason for its good lubricating properties is its hydrophobic nature and an ability to reduce friction between tablets and die wall during the ejection process [1]. The physical properties of magnesium stearate have been studied intensively but no good correlation or no correlation at all [2,3] between its lubricating properties and physical parameters such as specific surface area, particle size and moisture content have been found. The specific surface area is a parameter apparently affecting the lubricating properties of magnesium stearate. Several authors have reported surface area values based on * Corresponding author. Tel.: +358 2 333 5672; fax: +358 2 333 5993. E-mail address: mikjuko@utu.fi (M. Koivisto). both single- and multi-point BET methods. Results show that values can vary significantly. Many authors have suggested that one reason for the different physical properties is the moisture content and the hydration state of the magnesium stearate samples [4 6]. Since all samples are usually degassed before BET analysis, the other reason may be the degassing temperature. Magnesium stearate samples have been degassed at high temperatures without questioning its effects on the properties of the magnesium stearate samples. Commonly used temperatures are 40, 50 and 105 8C. The USP recommendation is 2 h at 40 8C. Ertel and Carstensen [1] have reported that heating at 105 8C not only removed water from the crystals but also changed the structure of the crystals. Andrès et al. [6] presented the complete nitrogen and krypton adsorption and desorption isotherms and stated that the shape of the isotherms does not agree to any known theory. They also calculated the value of the constant C in 0032-5910/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2004.09.041

80 M. Koivisto et al. / Powder Technology 147 (2004) 79 85 the BET formula and noticed that for some samples the C value was very low. The constant C in the BET theory is related to the difference of adsorption energy and heat of liquefaction of adsorption gas. This means that the BET theory does not describe the adsorption process properly if the value of C is low [7]. Some authors [5,6,8] have studied the properties of moisture treated magnesium stearate. In spite of the hydrophobic nature of magnesium stearate some physical properties were found to change in these studies. Andrès [6] reported the increase of specific surface area and density with increasing moisture content. Rajala and Laine [5] obtained results indicating a change of the crystal structure after the moisture treatment. The study performed by Barra and Somma [8] showed similar results. Therefore it is obvious that the properties of magnesium stearate change especially when treating samples at high relative humidity conditions. Magnesium stearate as a lubricant is not ideal but it is shown to be better than any other lubricating agent, being a very good compromise in most cases [9]. It has been suggested that the lubricating properties of magnesium stearate correlate with the initial water content and the pseudopolymorphic form of the samples. Wada and Matsubara [10] reported that the addition of water resulted in better lubrication properties. They also suggested that the water molecules act like ball-bearings between stearate the molecules. According to Ertel and Carstensen [2] there is a weak correlation between the crystal structure and the lubricating properties of bovine magnesium stearate. They stated that the structure of magnesium stearate depends on its moisture content. Many earlier studies [8,11] have reported that the properties of magnesium stearate from different manufacturers can vary considerably. The new vegetable source magnesium stearates have not yet been studied intensively. According to the European Pharmacopeia, the commercially available magnesium stearates are mixtures of salts of different fatty acids consisting mainly of stearic acid and palmitic acid. The fatty acid fraction contains not less than 40% stearic acid and the sum of stearic acid and palmitic acid is not less than 90%. The rest consists of other fatty acids and magnesium, which amounts are between 4% and 5%. There is a possibility that the variation in the amounts of the components affects physical and lubricating properties of magnesium stearate. This should always be remembered when investigating magnesium stearate. In the present paper the specific surface area, crystal structure, water content and thermal properties as a function of degassing temperature and duration of moisture treatment of some vegetable grade magnesium stearate samples is discussed. Especially the nitrogen vapor adsorption on the surface of the samples is being addressed. 2. Materials and methods 2.1. Samples and sample preparation Three vegetable magnesium stearate batches were obtained from different manufacturers as specified in Table 1. They represent three different hydration states. As-received (AR) samples were not treated before measurements. The moisture treatments were made in a dessicator containing saturated K 2 SO 4 salt solution at room temperature, thus giving a relative humidity in the desiccator of approximately 96%. Two different samples from each magnesium stearate batch were prepared for the moisture treatment. The first sample was kept 3 weeks and the second for 6 weeks in the desiccator in open containers. The degassing was done using a Micromeritics VacPrep 061. The temperatures used were 40 and 105 8C. The degassing time was 2 h and the pressure during degassing was below 25 Pa. The degassing was done with the as-received samples. The moisture treated samples were not degassed. All samples were measured instantly after treatments. The moisture treated samples were named after the duration of the treatment (3 and 6) and the degassed samples after the degassing temperature (40 and 105). All measurements were done at least in duplicate and the given numerical results are average values of these measurements. 2.2. Thermal analysis Thermal analyses were carried out using Pyris Diamond, DSC-7 and TGA-7 from PerkinElmer. Both differential scanning calorimeter (DSC) and thermogravimetric (TG) measurements were performed in nitrogen atmosphere. Sample size was approximately 1 mg. Temperature was scanned from 25 to 150 8C at a heating rate of 10 8C min 1. Aluminum pans with holes were used in DSC measurements. TG measurements were carried out using an open platinum pan. Total weight losses were determined from TG curves. 2.3. Gas adsorption measurements Nitrogen adsorption and desorption isotherms at liquid nitrogen temperature were measured using TriStar 3000 from Micromeritics. The specific surface areas were determined using the BET theory [7]. Eight points of the adsorption isotherm between relative pressure values of 0.06 Table 1 Designation, manufacturer and hydration state of investigated magnesium stearates Sample Manufacturer Hydration state ms1 Faci monohydrate ms2 Mallinckrodt dihydrate ms3 Peter Greven trihydrate

M. Koivisto et al. / Powder Technology 147 (2004) 79 85 81 Fig. 1. The DSC (left) and derivated TG (right) curves of magnesium stearate sample ms1. Moisture treatment was 6 weeks at 96%RH. Degassing was done under vacuum and the degassing time was 2 h. and 0.20 were used in these calculations. Average pore sizes were calculated using the BJH theory [12] and the desorption branch of the isotherms. 2.4. X-ray diffraction The X-ray powder diffraction analysis was performed in ambient conditions with a Philips powder diffractometer with the following conditions: Ni-filtered CuKa radiation (k=0.154 nm); generator 45 kv, 35 ma; diffraction angle range 3.00 35.008; step 0.02 s 1. 2.5. Moisture sorption behavior The moisture sorption behavior of the samples was examined gravimetrically using an HMA analyzer from PuuMan. The HMA equipment is a dynamic on-line measurement system for determination of mass changes of samples under controlled humidity and temperature conditions. The set-up of the system makes it possible to monitor as much as eight samples simultaneously. The measurement temperature was 23.5F0.5 8C. After the samples were placed in the analyzer, the relative humidity of the chamber was lowered using silica gel. After drying the relative humidity was raised to 96% for 10 days. To examine whether the moisture was absorbed or adsorbed on the samples the relative moisture was lowered to 42%, which corresponds to the normal ambient conditions. Finally, silica gel was used to dry the samples. 3. Results 3.1. Thermal analysis The DSC thermographs and derivated TG curves of the as-received (untreated), moisture treated (6 weeks at 96%RH) and degassed (in vacuum at 105 8C) samples are presented in Figs. 1, 2 and 3. The as-received magnesium stearate monohydrate sample ms1 has three discrete endotherms in the DSC curve (Fig. 1). The different peaks are explained as follows: The first peak is caused by the free moisture. The second peak around 100 8C is due to the hydrate water. Finally, there is a melting endotherm. The DTG curves support this conclusion. After the as-received sample is degassed at 105 8C, all peaks related to water have disappeared. Moreover, the melting peak has shifted towards higher temperature values. After the moisture treatment a new peak has appeared at 70 8C and the peak of the hydrate water has grown. Similar trends were seen also in the DTG curve of moisturized sample. The different treatments have only minor effects on the magnesium stearate dihydrate sample ms2 (Fig. 2). Fig. 2. The DSC (left) and derivated TG (right) curves of magnesium stearate sample ms2. Moisture treatment was 6 weeks at 96%RH. Degassing was done under vacuum and the degassing time was 2 h.

82 M. Koivisto et al. / Powder Technology 147 (2004) 79 85 Fig. 3. The DSC (left) and derivated TG (right) curves of magnesium stearate sample ms3. Moisture treatment was 6 weeks at 96%RH. Degassing was done under vacuum and the degassing time was 2 h. The as-received sample has a dehydration endotherm around 100 8C and a narrow melting endotherm at 125 8C. The degassing at 105 8C removes the hydrate water but the moisture treatment has changed the dihydrate sample very little. However, the melting endotherm has shifted towards higher temperature values after the degassing treatment. The weight loss of the moisturized sample is still slightly higher than the weight loss of the as-received sample. The as-received magnesium stearate trihydrate has two dehydration endotherms at 85 and 110 8C (Fig. 3). Once again the hydrate water has been removed as a result of the degassing treatment at 105 8C. The DSC curve of the degassed sample shows a two-stage endotherm starting at 115 8C. The endotherm is probably a result of the different melting temperatures of the sample components. After the moisture treatment a new peak is observed at 60 8C, with the thermograph being otherwise almost identical to the DSC curve of the as-received sample. The new peak is probably due to the water, which has been absorbed by the structure of the sample during the moisture treatment. The DTG curves support the observations and conclusions from the DSC curves well. According to the DSC and TG measurements all the studied magnesium stearates change to anhydrates after they have been degassed under vacuum at 105 8C. 3.2. Gas adsorption measurements Specific surface area, average pore size and TG weight loss as a function of moisture treatment time and degassing temperature are presented in Table 2. The data in Table 2 suggest that all the parameters are dependent on the treatment. The impact of the treatment is most significant for magnesium stearate trihydrate sample ms3 and least significant for magnesium stearate monohydrate ms1. Major changes are observed after the samples are degassed at 105 8C. The specific surface area was for all samples found to decrease with increasing degassing temperature. The specific surface area of ms1 and ms2 was found to decrease due to the moisture treatment. However, the specific surface area of ms3 increased when the moisture treatment time was prolonged. Especially the BET surface area values measured from as-received samples are totally different from the values obtained from the samples that are degassed at 105 8C. The BET C values were very small when specific surface area of magnesium stearate was over 10 m 2 /g. Also, the reproducibility of the surface area values was found to be poor. The average standard deviations of the specific surface area measurements were approximately 10% (data not shown). This indicates that the BET theory is not appropriate for analysis of as-received di- and trihydrates of magnesium stearate. The average pore sizes obtained from the BJH calculations from the desorption branches of the isotherms increased significantly after the samples were degassed at 105 8C. This kind of behavior indicates that the average pore size is somehow dependent on the presence of hydrate water. Perhaps the hydrate water is situated mainly in the Table 2 Various parameters of magnesium stearate samples after different treatments Sample Treatment Surface area a (m 2 /g) Average pore diameter b (nm) TG weight loss (%) ms1 6 2.4 (18) 8.1 4.5 3 2.8 (15) 8.7 3.7 AR c 2.7 (19) 12.1 2.7 40 2.7 (17) 14.0 1.5 105 2.1 (39) 26.1 0.6 ms2 6 10.1 (5.8) 9.9 4.1 3 10.6 (6.4) 10.3 3.8 AR c 13.2 (4.9) 10.0 3.3 40 12.5 (5.1) 9.7 3.4 105 4.4 (25) 18.5 0.6 ms3 6 29.3 (3.1) 8.6 4.0 3 28.0 (3.7) 7.9 4.0 AR c 27.6 (4.3) 7.9 4.1 40 26.3 (3.5) 7.8 3.9 105 5.0 (24) 23.6 0.5 The numbers represent the moisture treatment time (3 and 6 weeks at 96%RH) or the vacuum degassing temperature (40 and 105 8C) used. a Eight-point BET-method, the BET C values in parentheses. b BJH method. c As received (untreated).

M. Koivisto et al. / Powder Technology 147 (2004) 79 85 83 Fig. 4. Various nitrogen adsorption desorption isotherms of magnesium stearate sample ms1. Degassing time was 2 h and the pressure during degassing was below 25 Pa. pores and the pore walls. Another explanation could be that the nitrogen molecules used in the adsorption measurements interact with the hydrate water, distorting the results. The complete adsorption desorption isotherms of moisture treated (6 weeks at 96%RH), as-received and degassed (at 40 and 105 8C) samples are presented in Figs. 4, 5 and 6. The first observation is that the samples having hydrate and/or adsorbed water show significant hysteresis. Moreover, the shape of these isotherms does not obey any of the standard isotherms by Brunauer [13]. The second observation is that the samples degassed at 105 8C have type II isotherms with no hysteresis. Furthermore, an anomalous behavior as a small step around the relative pressure value 0.5 is observed in the desorption isotherms of samples containing water. This kind of step could indicate the presence of inkbottle-type pores or the condensation of measuring gas (N 2 ) between the parallel plate-like crystals [13]. The anomalous behavior of the isotherms is enhanced as the water content in the samples increases. One possible explanation for that could be the dissolving of nitrogen in Fig. 6. Various nitrogen adsorption desorption isotherms of magnesium stearate sample ms3. Degassing time was 2 h and the pressure during degassing was below 25 Pa. water. If the water is held in the pores nitrogen could dissolve in water after it has been condensated in the pores. It may also be possible that the affinity of nitrogen to water is more extensive than the affinity to the magnesium stearate. The behavior of the isotherms could be a result of these two different mechanisms. 3.3. X-ray diffraction The X-ray powder diffraction patterns of as-received, moisturized (6 weeks at 96%RH) and degassed (2 h in vacuum at 105 8C) are presented in Fig. 7. They indicate distinct changes. The higher the hydration state, the more changes are observed after degassing. After the moisturizing treatment peaks around 3, 5 and 98 have increased and narrowed. The peaks of the degassed samples are wider and smoother. The greatest changes have happened at the wide peak around 228. The fine structure of the di- and trihydrate samples has vanished when the samples have been changed Fig. 5. Various nitrogen adsorption desorption isotherms of magnesium stearate sample ms2. Degassing time was 2 h and the pressure during degassing was below 25 Pa. Fig. 7. Changing of the X-ray diffraction patterns of magnesium stearate samples after degassing and moisture treatment. (Note: The curves are shifted from another. 6=six week moisture treatment at 96%RH. 105=2 h vacuum degassing at 105 8C.)

84 M. Koivisto et al. / Powder Technology 147 (2004) 79 85 Fig. 8. Gravimetrically measured weight increase profiles of the magnesium stearate samples at the different humidity conditions as a function of time. (Note: The symbols are drawn only to guide the eye). to anhydrate. After the moisture treatment the trihydrate and dihydrate samples have changed only slightly. However, some new small peaks have appeared in the diffractographs around 13 and 188. The changes affected by the moisture treatment are clearest in the magnesium stearate monohydrate sample ms1. Some new peaks have appeared in the wide peak in the region near 218. Those peaks are most certainly caused by the absorbed water and the results of the X-ray measurements indicate that the moisture and the hydrate water are shown in diffractographs in that region. 3.4. Moisture sorption behavior Although magnesium stearate is known to be hydrophobic [9], the results show that the studied samples are slightly hydrophilic. As can be seen in Fig. 8, the moisture uptakes vary from 1% to 3%. Moreover, the weight of the magnesium stearate monohydrate sample still increases after 10 days. When the relative moisture of the measuring chamber is lowered, a part of the adsorbed water remains in the sample. This indicates that the properties of the moisturized samples are not similar to properties of the asreceived samples. The phenomenon is observed also with the dihydrate and trihydrate sample. These samples tend to adsorb moisture rapidly and most of the adsorbed water is desorbed after the samples are dried. When the samples were dried at 42%RH, the final weight increase is 0.7 1.9% depending on the sample. When the samples were dried with silica gel the final weight increase is 0.2 0.7%. 4. Discussion and conclusions The physical properties of the studied magnesium stearate samples varied widely depending on the hydration state and the initial water content of the samples. Furthermore, all of the studied properties changed crucially after the samples were degassed at 105 8C. According to the results of this study magnesium stearate cannot be degassed under high temperatures without changing the properties markedly because degassing will remove the hydrate water and change the crystal structure of magnesium stearate. Moreover, the nitrogen vapor adsorption desorption isotherms seem to collapse after the degassing. Also, according to the DSC measurements, the melting endotherms will shift towards higher temperature values after this treatment. This might be an indication that the physical structure of the samples would also collapse as a result of degassing. The suitable degassing temperature for the magnesium stearate samples prior to the adsorption measurements should thus not exceed 40 8C. The results show that water affects the studied physical properties of the magnesium stearate most. Although moisture treatment was not observed to change the hydration states of the samples, the other properties were different after the moisture treatment used. The treatments used were 3 and 6 weeks at 96%RH, with most of the changes having occurred after 3 weeks. Magnesium stearate monohydrate changed most and dihydrate least after the moisture treatment. The pore size determinations indicated that water is located in pores and according to the results of the HMA measurement, the irreversibly adsorbed water is partly chemisorbed after the moisture treatment. However, water was not observed to chemisorb in the magnesium stearate dihydrate sample. So there is a possibility that water does not react with magnesium stearate but some other component presented in the commercial magnesium stearate batches [9]. The additional studies of water and for example its interactions with magnesium palmitate and other known components of commercial magnesium stearate could clarify this phenomenon. The problems having arisen when measuring the specific surface area of magnesium stearate are partially explained by the disagreement with the BET theory. The detected anomalous hysteresis loop in the nitrogen vapor adsorption desorption isotherms of magnesium stearate is manifestation of this. It describes that the adsorbed nitrogen does not desorb completely even when the sample is kept in vacuum. Thus the nitrogen might react with the sample. Due to this fact nitrogen is perhaps not the most suitable gas to use in surface area measurements with magnesium stearate. Because the hysteresis loops are more significant in the moisture treated samples the nitrogen probably reacts somehow with water. Another problem especially when comparing surface areas measured in different laboratories is the degassing temperature used. The mentioned problems could be one reason why the previous studies for determining the correlation between physical and lubricating properties of the magnesium stearate have not shown good and reproducible results. Specific surface area is certainly a parameter having an effect on the lubricating properties of the magnesium stearate. However, due to the problems mentioned above it should not be the primary parameter in the

M. Koivisto et al. / Powder Technology 147 (2004) 79 85 85 studies. The better parameter could be the initial water content or the hydration state of the magnesium stearate that can be measured more reliably than the specific surface area. However, the adsorption mechanisms should be carefully examined in order to obtain reliable results from the adsorption measurements. The lubricating properties of studied magnesium stearate samples were not investigated in this study. The previous studies showed that the lubricating properties correlated with the water content of the samples [2,10]. In the study described here, it was demonstrated that the physical properties of the magnesium stearate samples changed after moisture treatment. As a result, the lubricating properties of the moisture treated samples would be different from the asreceived samples. Acknowledgement We wish to thank Orion, ORION PHARMA, Finland, for providing magnesium stearate samples. References [1] K.D. Ertel, J.T. Carstensen, An examination of the physical properties of pure magnesium stearate, Int. J. Pharm. 42 (1988) 171 180. [2] K.D. Ertel, J.T. Carstensen, Chemical, physical, and lubricant properties of magnesium stearate, J. Pharm. Sci. 77 (1988) 625 629. [3] U.I. Leinonen, H.U. Jalonen, P.A. Vihervaara, E.S.U. Laine, Physical and lubrication properties of magnesium strearate, J. Pharm. Sci. 81 (1992) 1194 1198. [4] T.A. Miller, P. York, Physical and chemical characteristics of some high purity magnesium stearate and palmitate powders, Int. J. Pharm. 23 (1985) 55 67. [5] R. Rajala, E. Laine, The effect of moisture on the structure of magnesium stearate, Thermochim. Acta 248 (1995) 177 188. [6] C. Andrès, P. Bracconi, Y. Pourcelot, On the difficulty of assessing the specific surface area of magnesium stearate, Int. J. Pharm. 218 (2001) 153 163. [7] S. Brunauer, P.H. Emmet, E. Teller, Adsorption of gases in multimolecular layers, J. Am. Chem. Soc. 40 (1938) 1361 1403. [8] J. Barra, R. Somma, Influence of the physicochemical variability of magnesium stearate on its lubricant properties: possible solutions, Drug Dev. Ind. Pharm. 22 (1996) 1105 1120. [9] T.A. Miller, P. York, Pharmaceutical tablet lubrication, Int. J. Pharm. 41 (1988) 1 19. [10] Y. Wada, T. Matsubara, Pseudopolymorphism and lubricating properties of magnesium stearate, Powder Technol. 78 (1994) 109 114. [11] R. Dansereau, G.E. Peck, The effect of the variability in the physical and chemical properties of magnesium stearate on the properties of compressed tablets, Drug Dev. Ind. Pharm. 13 (1987) 975 999. [12] E.P. Barret, L.G. Joyner, P.P. Halenda, The determination of pore volume and area distributions in porous substances, J. Am. Chem. Soc. 73 (1951) 373 380. [13] S. Lowell, J.E. Shields, Powder Surface Area and Porosity, third ed., Chapman & Hall, Cornwall, 1991.