Studies on the Interaction between Water and (Hydroxypropyl)methylcellulose ALI NOKHODCHI,JAMES L. FORD X , AND MICHAEL H. RUBINSTEIN Received July 5, 1996, from the Pharmaceutical Technology and Drug Delivery Group, School of Pharmacy and Chemistry, Liverpool John Moores University, Byrom St., Liverpool, L3 3AF, UK. Final revised manuscript received December 20, 1996. Accepted for publication February 24, 1997 X . Abstract 0 The moisture sorption and desorption profiles of four different viscosity grades of (hydroxypropyl)methylcellulose (HPMC) 2208 (HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M) of different particle size fractions were analyzed according to the Young and Nelson equations. These equations describe three locations of the sorbed moisture: monolayer adsorption, externally adsorbed moisture, and internally absorbed moisture. The effects of particle size and viscosity grade of HPMC on the three locations of moisture showed that an increase in particle size generally resulted in a reduction in the amount of internal absorption and an increase in the amount of external adsorption. These changes were more apparant for HPMC K100 and HPMC K4M than for the higher viscosity grades. The lowest values of internally absorbed moisture were obtained for HPMC K100M. Changes in tensile strengths, mean yield pressures, and elastic recoveries of HPMC K4M tablets were explained in terms of the changes produced in the internally absorbed moisture and the externally adsorbed moisture. The amounts of nonfreezing and freezing water in samples exposed to moisture were determined from melting endotherms obtained by differential scanning calorimetry. Increases in the water:HPMC ratio resulted in increases in the enthalpies of water melting for the four viscosity grades of HPMC for the <45 and 250-350 µm particle size fractions. The amount of nonfreezable water was unaffected by change in viscosity grade or particle size. Introduction Residual water, associated with polymers in the solid state, may have significant effects on their physical, chemical, and pharmaceutical properties, e.g., glass transition temperature, stability, powder flow, compaction, and dissolution rate. 1-3 This residual water may exist because of prolonged exposure to an atmosphere containing water vapor or as a result of processing that involves the use of water, e.g., lyophilization, spray drying, aqueous film coating, wet granulation, or crystallization. The effects of moisture depend on the amount of water sorbed or desorbed. For instance, the presence of moisture may either increase or reduce the mechanical strengths of different powders. 4-7 These findings have been ascribed to moisture being present as different physical states. 8,9 Thus, the water can form an adsorbed monomo- lecular layer or an adsorbed multilayer which produces pendular, funicular or capillary bonds between particles, or it can be absorbed into the interior of particles. At low moisture contents particles are wetted and a liquid film will be formed on their surface and may combine to produce discrete liquid bridges at points of contact. The surface tension and negative capillary pressure in such bridges provide the cohesive forces that result in the pendular state. As the liquid content increases, several bridges may coalesce, giving rise to the funicular state. Eventually, as more liquid is added and the void spaces are eliminated, bonding is affected by interfacial forces at the surface of the particles by negative capillary pressure throughout the interior liquid. This is a condition referred to as the capillary state. 10 To characterize the water associated with a solid, moisture sorption isotherms, i.e., the mass of moisture taken up per unit mass of dry solid plotted against the relative humidity at constant temperature, may be determined. Brunauer, Emmet, and Teller 11 successfully developed a model describing a multilayer adsorption isotherm. Their method (the BET method) was modified to be applicable to wider ranges of relative humidities, 12,13 with further assumptions. For in- stance, the presence of intermediate adsorbed layers having heats of adsorption different from the heat of liquefaction of the adsorbate or the presence of a finite number of layers of adsorption have been described. The GAB equation was developed by Guggenheium, Anderson and DeBoer 14 and was successfully applied to sorption of water by celluloses. 14-16 It was noted that the mechanism of water sorption on the solid powders was different from the physical adsorption proposed by the BET treatment and the sorbed water could be described as three states, i.e. tightly bound, less tightly bound, and bulk water due to capillary condensation. 16 It was further hypoth- esized 8 that the condensed phase of water on the surface of sorbent could develop a driving force to cause the water to diffuse into the sorbent bulk. Young and Nelson 8,9 also developed a technique to determine separately the proposed states of water. The technique later was applied to sorption to maize starch by some pharmaceuticals. 17 This study examines the effect of viscosity grade on the moisture distribution in (hydroxypropyl)methylcellulose (HPMC) 2208 to determine which type(s) of moisture is (are) responsibile for improvement in the compaction properties of HPMC K4M. Nokhodchi et al. 18 have shown that, when the moisture content of HPMC K4M was increased from 0 to 14.9% w/w, the tensile strength of its tablets increased from 2.15 to 8.54 MPa. Therefore, the present study aims to explain the inter-relationship between bound water and the mechanical properties of HPMC K4M. This study examines also the effects of particle size and water content on the distribution of moisture in other viscosity grades of HPMC 2208. Experimental Section MaterialssFour different viscosity grades of (hydroxypropyl)- methylcellulose 2208 (HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M, manufactured by Dow Chemicals) were used. Two particle size fractions (<45 and 250-350 µm) of each viscosity grade were obtained by sieving using test sieves (Endecott) on a mechanical vibrator (Pascal Engineering). Moisture Sorption and Desorption IsothermssEach sample of HPMC 2208 was dried at 70 °C for 5 days. The dried samples were then placed in tared, 5 cm diameter Petri dishes and exposed to different relative humidities using dessicators which had been pre- equilibrated and stored at 22 ( 3 °C. Saturated salt solutions of lithium chloride, potassium chloride, magnesium chloride, potassium carbonate, sodium bromide, sodium chloride, potassium chloride, or X Abstract published in Advance ACS Abstracts, April 1, 1997. S0022-3549(96)00279-1 CCC: $14.00 608 / Journal of Pharmaceutical Sciences © 1997, American Chemical Society and Vol. 86, No. 5, May 1997 American Pharmaceutical Association