A Basis For Understanding the Effects of Residual Water on the Mechanical Properties of Solids. George Zografi University of Wisconsin-Madison

Transcription

1 A Basis For Understanding the Effects of Residual Water on the Mechanical Properties of Solids George Zografi University of Wisconsin-Madison Possible Roles of Water in Affecting Mechanical Properties Alteration of surface energetics by water vapor adsorption or by the formation of a crystal hydrate Attraction due to capillary forces caused by condensed water (capillary condensation) Dissolution and softening due to deliquescence Plasticization of disordered (noncrystalline) structure leading to less viscosity, reduced relaxation times, greater diffusivity, and, therefore, greater molecular mobility. 1

2 Hiestand proposed that the ability of a formulation to exhibit good tablet bond depends on : viscoelastic responses that are sufficient to provide an increase in true area of contact upon compaction, and; the ability of the resultant intermolecular interactions to offset elastic rebound upon removal of the stress. E.N.Hiestand, Powders : Particle-Particle Interactions, J.Pharm. Sci. 55 (1966) 1325 Such Desirable Viscoelasticity in Organic Solids Requires a Certain Level of Molecular Disorder Wet Granulation amorphous structure introduced primarily by the presence of polymeric binders such as PVP and HPC Direct Compaction - useful excipients need to have a significant amount of amorphous components microcrystalline cellulose 37% amorphous Spray-dried lactose 10-15% amorphous DiPac 97% crystalline sucrose/ 3% amorphous maltodextrin 2

3 Plasticization by Water of Amorphous Regions in a Solid Can Directly Affect Bulk Mechanical Properties Upon Compaction To Produce Greater Molecular Mobility Effects of Water On the Mechanical Properties of Amorphous Nylon 6,6 Closed circles Dynamic modulus (ε ) Energy loss factor, tan δ moles of Water absorbed Open circles Energy loss (e =ηω) relative humidity Quistwater and Dunell, J.Polym.Sci.28 (1958) 309 3

4 Absorbed Water Reduces the Glass Transition Temperature Glassy state RT W g Super-cooled liquid Oksanen and Zografi, Pharm. Res. 7 (1990) 654 Water Vapor Absorption Isotherms For Amorphous Solids May Suggest a Second Critical Water Content, the BET Constant, W m Corn Starch BET W m GAB GAB Equation 4

5 Water Vapor Absorption By Poly (Vinylpyrrolidone) MW = 50kDa MW = 1500kDa W g W m Oksanen, PhD Thesis, University of Wisconsin-Madison, 1992 Is There Any Physical Significance of W m for The Effects of Water on Mechanical Properties of Amorphous Solids? 5

6 Water Vapor Absorption of PVP Relationship Between W m and W g T( o C) W m W g W m /W g W g = amount of water absorbed at Tg = T Oksanen and Zografi, Pharm. Res. 7 (1990) 654 What Are The States of An Amorphous Solid At Water Contents Just Below and Above W m That Might Influence Mechanical Properties? 6

7 Model For Water Vapor Sorption By Amorphous Nylon 6 DRY Saturated water vapor pressure Puffr and Sebenda, J.Polym. Sci. C 16 (1967) 79 Hole Free Volume For Nylon 6 As a Function of Temperature and RH From Positron Annihilation Lifetimes Dlubek, et al., J.Appl. Polymer Sci. 84 (2004) 244 7

8 Effects of Absorbed Water On Free Volume of Nylon 6 At Tg, Relative To That Under Dry Conditions, W m V g = V humid,g V dry,g Dlubek, et al., J.Appl. Polymer Sci. 84 (2004) 244 Below W m, Water Acts As An Antiplasticizer Reducing the Free Volume of the Polymer Above W m, The Free Volume Increase Due To the Presence of Water Begins To Dominate 8

9 Water Vapor Sorption by Microcrystalline Cellulose At 298K BET W m = 0.03g/g GAB Data : Hollenbeck,et al., J.Pharm.Sci. 67 (1978) 1599 Relationships Between W m and W g For Cellulose Batzer and Kreibach, Polym. Bull. 5(1981) 585 9

10 Elastic Modulus of MCC Compacts Radebaugh, et al., Int. J. Pharm. 57 (1989) 95 Mechanical Properties of MCC Worst case hardness Best case hardness Tensile strength G.E. Amidon, et al., Pharm. Res. 12 (1995)

11 Tablet Bonding Indices for MCC Best Case Worst Case G.E. Amidon,et al, Pharm.Res. 12 (1995) 923 Direct Compaction Properties of DiPac* and MCC Have Been Shown To Depend on a Critical Water Content Sample W m Corr.W m Minimum Required.Water (g/g) (g/g) (g/g) DiPac* ** *97% crystalline sucrose + 3% maltodextrin MCC ** ** Tabibi,S.E., PhD Thesis, University of Maryland,

12 General Proposal For the Role of Water In the Compaction Process Dynamic properties of formulations under compaction are governed in large part by the non crystallinity of various components, and by the water absorbed in these regions that promotes viscoelasticity by its plasticizing effects The water content must be above W m and below W g Magnesium Stearate As a Tabletting Lubricant What factors have been shown to influence the lubricity of magnesium stearate? Non-adhesive hydrophobic fatty acid chains Proportion of stearate and palmitate Crystal Structure plates vs. needles Level of non-crystallinity Particle size and specific surface area Amount, location and state of the residual water 12

13 What is the Influence of Sorbed Water on the Tablet Lubricant Properties of Magnesium Stearate? Moisture Content and Die Wall Friction* For Various Commercial Magnesium Stearates Sample Moisture Die-Wall Friction Content (%) (kp/cm 2 ) A B C D E F G H Mueller, Zbl. 116 (1977) 1262 *Lactose + 0.1% MgSt 13

14 Lubricating Properties of Magnesium Stearate As a Function of Water Content r = Wada and Matsubara, Powder Tech. 78 (1994) 109 Location of Waters of Hydration in Pure Magnesium Stearate plates 5.7% w/w water needles 8.4% w/w water Sharpe, et al., Structural Chem. 8 (1997) 73 14

15 Water Situated Between Oriented Fatty Acid Layers, Primarily As the Dihydrate Appears To Be Able To Facilitate Shear Wada and Matsubara, Powder Tech. 78 (1994) 109 Ertel and Carstensen, J.Pharm. Sci. 77 (1988) 625 XRPD Patterns For Magnesium Stearate COMMERCIAL SAMPLES PURE SAMPLES Leinonen, et al., J. Pharm. Sci. 81 (1992)

16 Thermogravimetric Analysis of Magnesium Stearate Samples a) and b) are Commercial samples Pure dihydrate Rajala and Laine Thermchimica Acta 248 (1995) 177 XRPD OF Three Commercial Sources of Magnesium Stearate Faci Witco Mallinckrodt Swaminathan and Kildsig, AAPS PharmSciTech 2001, 2(4) article 28 16

17 Effect of Increasing RH on XRPD of Noncrystalline Magnesium Stearate RH 100% 92.5% 84.3% 79.1% 54.4% 11.3% 0.0% Swaminathan and Kildsig, AAPS PharmSciTech 2001, 2(4) article 28 This Suggests That Commercial Magnesium Stearate Contains A High Degree of Non-crystallinity and That This Can Vary From Sample to Sample Depending, To Some Extent, on Water Content What Is the Nature of This Noncrystallinity? 17

18 A Variety of Structurally Disordered Solid Systems Can Exist Super-cooled liquids and glasses Liquid Crystals Glassy Crystal Mesophases, e.g. glassy plastic crystals, and conformationally disordered crystals B. Wunderlich, Thermochimica Acta, , (1999) Liquid Crystals Only Retain Two- Dimensional Order 18

19 PXRD Patterns for Various Solid Forms of Cyclosporine Liquid crystalline Lechuga-Ballesteros,et al., J. Pharm. Sci. 92 (2003) 1821 X Ray Diffraction of Liquid Crystalline Polyguanidines Kim,et al., Macromol. 37 (2004)

20 Various Possible Phase Transitions for Liquid Crystalline Systems T g T g Two Types of Liquid Crystals 20

21 Dimyristoylphosphatidyl Choline Dihydrate Represents A Crystalline Bilayered Structure Like Magnesium Stearate 2 H 2 O s Per lipid Pearson and Pascher, Nature 281 (1979) 499 Phase Behavior of Dimyrisitoylphosphatidyl Choline Crystal Gel Tilted Ripple Liquid Crystalline HI HII T s T p T m T h Lc L β P β (P β ) L α HI or HII Low Transition Temperature High Transition Temperature Low Molecular Mobility High Molecular Mobility ABSORBED WATER LOWERS TRANSITION TEMPERATURES 21

22 Magnesium Stearate is A Heavy Metal Soap That Should Be Capable of Forming Lyotropic Liquid Crystals Is There Any Evidence That Liquid Crystalline Behavior of Magnesium Stearate May Be Important For Its Lubricant Properties? Mueller has presented evidence to show that lubricating properties are lost when the proportion of crystalline lamellar structure ( monoclinic or orthorhombic) is reduced relative to a non-lamellar hexagonal nematic liquid crystalline structure B.W. Mueller, Seifen Ole -Fette - Wachse 102 (1976)

23 Possible Role of Water in Magnesium Stearate Water may maintain lamellar crystalline and/or lamellar liquid crystalline structure, thus, providing ease of shear between layers of magnesium stearate bilayers Processing of commercial samples may lead to disordered glassy liquid crystals, or to nonlamellar nematic structures, with different hydration characteristics and the loss of the lubricating lamellar structure, explaining in part, the variability in commercial samples Acknowledgements Many former graduate students and postdoctoral fellows who worked on surface chemical and solid-state problems in my laboratory over the past 44 years Steve Byrn, Ken Morris, Joe Stowell, and Ralph Pfeiffer at Purdue University For Patiently Educating Me About Crystalline Solids This Presentation Is Dedicated to Dr. Everett N. Hiestand, My Friend, Colleague and Mentor for Forty Years 23