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Pharmaceutical solids as raw materials or as dosage forms most often come in contact with water during processing and storage. This may occur (1) during crystallization, lyophilization, wet granulation, or spray drying, and (2) because of exposure upon handling and storage to an atmosphere containing water vapor or exposure to other materials in a dosage form that contains water capable of distributing to other ingredients. Some properties known to be altered by the association of solids with water include rates of chemical degradation in the “solid-state,” crystal growth and dissolution, dispersibility and wetting, powder flow, lubricity, powder compactibility, and compact hardness.
Water can associate with solids in two ways. It can interact only at the surface (adsorption), and it can penetrate the bulk solid structure (absorption). When both adsorption and absorption occur, the term sorption is often used. Adsorption is particularly critical in affecting the properties of solids when the specific surface area is large. Large values of specific surface area are seen with solids having very small particles, as well as with solids having a high degree of intraparticle porosity.
Absorption is characterized by an association of water per g of solid that is much greater than that which can form a monomolecular layer on the available surface, and an amount that is generally independent of the specific surface area. Most crystalline solids will not absorb water into their bulk structures because of the close packing and high degree of order of the crystal lattice. Indeed, it has been shown that the degree of absorption into solids exhibiting partial crystallinity and partial amorphous structure is often inversely proportional to the degree of crystallinity. With some crystalline solids, however, crystal hydrates may form. These hydrates may exhibit a stoichiometric relationship, in terms of water molecules bound per solid molecule, or they may be nonstoichiometric. Upon dehydration, crystal hydrates may (1) retain their original crystal structure, (2) lose their crystallinity and become amorphous, or (3) transform to a new anhydrous or less hydrated crystal form.
Amorphous or partially amorphous solids are capable of taking up significant amounts of water when there is sufficient molecular disorder in the solid to permit penetration and dissolution of the water molecule. Such behavior is observed with most amorphous polymers and with small-molecular-weight solids rendered amorphous during preparation, e.g., lyophilization, or after milling. The introduction of defects into highly crystalline solids will also produce this behavior. The greater the chemical affinity of water for the solid, the greater the total amount that can be absorbed. When water is absorbed by amorphous solids, the bulk properties of the solid can be significantly altered. It is well established, for example, that amorphous solids, depending on the temperature, can exist in at least one of two states, “glassy” or “fluid”; the temperature at which one state transforms into the other is the glass transition temperature, Tg. Water absorbed into the bulk solid structure, by virtue of its effect on the free volume of the solid, can act as an efficient plasticizer and reduce the value of Tg. Since the rheological properties of “fluid” and “glassy” states are quite different, i.e., the “fluid” state exhibits much less viscosity as one goes increasingly above the glass transition temperature, it is not surprising that a number of important bulk properties dependent on the rheology of the solid are affected by moisture content. Since amorphous solids are metastable relative to the crystalline form of the material, with small-molecular-weight materials, it is possible for absorbed moisture to initiate reversion of the solid to the crystalline form, particularly if the solid is transformed by the sorbed water to a fluid state. This is the basis of “cake collapse,” often observed during the lyophilization process. An additional phenomenon noted specifically with water-soluble solids is their tendency to deliquesce, i.e., to dissolve in their own sorbed water, at relative humidities, RHi, in excess of the relative humidity of a saturated solution of the solid, RHo. Deliquescence arises because of the high water solubility of the solid and the significant effect it has on the colligative properties of water. It is a dynamic process that continues to occur as long as RHi is greater than RHo.
Although precautions can be taken when water is perceived to be a problem, i.e., eliminate all moisture, reduce contact with the atmosphere, or control the relative humidity of the atmosphere, such precautions generally add expense to the process with no guarantee that during the life of the product further problems associated with moisture will be avoided. It is also important to recognize that in many situations a certain level of water in a solid is required for proper performance, e.g., powder compaction. It is essential for both reasons, therefore, that as much as possible be known about the effects of moisture on solids before strategies are developed for their handling, storage, and use. Some of the more critical pieces of required information concerning water-solid interactions are (1) total amount of water present, (2) the extent to which adsorption and absorption occur, (3) whether or not crystal hydrates form, (4) specific surface area of the solid, as well as such properties as degree of crystallinity, degree of porosity, and glass transition and melting temperatures, (5) site of water interaction, the extent of binding, and the degree of molecular mobility, (6) effects of temperature and relative humidity, (7) various factors that might influence the rate at which water vapor can be taken up by a solid, and (8) for water-soluble solids capable of being solubilized by the sorbed water, under what conditions dissolution will take place.

Determination of Sorption-Desorption Isotherms—
The tendency to take up water vapor is best assessed by measuring sorption or desorption as a function of relative humidity, at constant temperature, and under conditions where sorption or desorption is essentially occurring independently of time, i.e., equilibrium. Relative humidity, RH, is defined as:
RH = (Pc) / (Po) × 100,
where Pc is the pressure of water vapor in the system and Po is the vapor pressure of pure water under the same conditions. The ratio Pc / Po is referred to as the relative pressure. It is usually varied by the use of saturated salt solutions in a closed system. Sorption or water uptake is best assessed starting with dried samples and subjecting them to a known relative humidity. Desorption is studied by beginning with a system already containing sorbed water and reducing the relative humidity. Ordinarily, if we are at equilibrium, moisture content at a particular relative humidity should be the same, whether determined from sorption or desorption measurements. However, it is common to see sorption-desorption hysteresis for certain types of systems, particularly those with microporous solids and amorphous solids, both capable of sorbing large amounts of water vapor. Here, the amount of water associated with the solid as relative humidity is decreased is greater than the amount that originally sorbed as the relative humidity is increased.
For microporous solids, vapor adsorption-desorption hysteresis is an equilibrium phenomenon associated with the process of capillary condensation. This takes place because of the high degree of irregular curvature of the micropores and the fact that they “fill” (adsorbtion) and “empty” (desorbtion) under different equilibrium conditions. For nonporous solids capable of absorbing water, hysteresis occurs because of a change in the degree of vapor–solid interaction due to a change in the equilibrium state of the solid, e.g., conformation of polymer chains, or because the time scale for structural equilibrium is longer than the time scale for water desorption.
In measuring sorption-desorption isotherms, it is important to establish that indeed something close to an equilibrium state has been reached. Particularly with hydrophilic polymers at high relative humidities, the establishment of water sorption or desorption values independent of time is quite difficult, since one is usually dealing with a polymer plasticized into its “fluid” state, in which the solid is undergoing significant change. Storing samples in chambers at various relative humidities and removing them to measure weight gained or lost is most commonly carried out. The major advantage of this method is convenience; the major disadvantages are the slow rate of reaching constant weight, particularly at high relative humidities, and the error introduced in opening and closing the chamber for weighing. Studies under vacuum in a closed system, using an electrobalance to measure weight change, avoid these problems but reduce the number of samples that can be concurrently run. It is also possible to measure amounts of water uptake not detectable gravimetrically by using volumetric techniques. In adsorption, to improve sensitivity, one can increase the specific surface area of the sample by reducing particle size or by using larger samples to increase the total area. It is important, however, that such comminution of the solid not alter the surface structure of the solid or render it more amorphous or otherwise less ordered in crystallinity. For absorption, where water uptake is independent of specific surface area, only increasing sample size will help. Increasing sample size, however, will increase the time to establish some type of equilibrium. To establish accurate values, it is important to dry the sample as thoroughly as possible. Higher temperatures and lower pressures (vacuum) facilitate this process; however, one must be aware of any adverse effects this might have on the solid, such as chemical degradation or sublimation. Using higher temperatures to induce desorption, as in a thermogravimetric apparatus, likewise must be carefully carried out with these possible pitfalls in mind. In some cases, direct analysis of water content by methods such as Karl Fischer titration or inverse gas chromatography may be advantageous. Sorption is usually expressed as weight of water taken up per unit weight of solid and plotted versus relative humidity. In most cases, the shape of the curve obtained resembles that normally seen for gas adsorption fitted to the Langmuir or Brunauer, Emmett, and Teller equations. Since crystal hydrate formation involving a phase change is usually a distinct first-order phase transition, the plot of water uptake versus pressure or relative humidity will in these cases exhibit a sharp increase in uptake at a particular pressure, and the amount of water taken up will usually exhibit a stoichiometric mole: mole ratio of water to solid. In some cases, however, crystal hydrates will not appear to undergo a phase change or the anhydrous form will appear amorphous. Consequently, water sorption or desorption may appear more like that seen with adsorption processes. X-ray crystallographic analysis and thermal analysis are particularly useful for the study of such systems. For situations where water vapor adsorption occurs predominantly, it is helpful to measure the specific surface area of the solid by an independent method and to express adsorption as weight of water sorbed per unit area of solid surface. This can be useful in assessing the possible importance of water sorption in affecting solid properties. For example, 0.5% w/w uptake of water could hardly cover the bare surface of 100 m2/g, while for 1.0 m2/g this amounts to 100 times more surface coverage. Since we generally find that pharmaceutical solids are in the range of 0.01 to 10 m2/g in specific surface area, what appears to be a low water content could represent a significant amount of water for the surface available.
Since the “dry surface area” is not a factor in absorption, sorption of water with amorphous or partially amorphous solids is best expressed on the basis of unit mass corrected for crystallinity when the crystal form does not sorb significant amounts of water relative to the amorphous regions.

Rates of Water Uptake—
The rate at which solids exposed to the atmosphere might either sorb or desorb water vapor can be a critical factor in the handling of solids. Even the simple act of weighing out samples of solid on an analytical balance and the exposure, therefore, of a thin layer of powder to the atmosphere for a few minutes can lead to significant error in, for example, the estimation of loss on drying values. It is well established that water-soluble solids exposed to relative humidities above that exhibited by a saturated solution of that solid will spontaneously dissolve via deliquescence and continue to dissolve over a long time period. The rate of water uptake in general depends on a number of parameters not found to be critical in equilibrium measurements because rates of sorption are primarily mass-transfer controlled, with some contributions from heat-transfer mechanisms. Thus, factors such as vapor diffusion coefficients in air and in the solid, convective airflow, and the surface area and geometry of the solid bed and surrounding environment, can play an important role. Indeed, the method used to take such measurements can often be the rate-determining factor because of these environmental and geometric factors.

Physical States of Sorbed Water—
The key to understanding the effects water can have on the properties of solids, and vice versa, rests with an understanding of the location of the water molecule and its physical state. More specifically, water associated with solids can exist in a highly immobile state, as well as in a state of mobility approaching that of bulk water. This difference in mobility has been observed through such measurements as heats of sorption, freezing point, nuclear magnetic resonance, dielectric properties, and diffusion. Such changes in mobility have been interpreted as arising because of changes in the thermodynamic state of water as more and more water is sorbed. Thus, water bound directly to a solid is often thought of as “tightly” bound and unavailable to affect the properties of the solid, whereas larger amounts of sorbed water tend to become more clustered and form water more like that exhibiting solvent properties. In the case of crystal hydrates, the combination of intermolecular forces (hydrogen bonding) and crystal packing can produce very strong water–solid interactions. However, there are reported situations where hydration and dehydration of crystals occur quite easily at low temperatures. More recently, the concept of “tightly” bound water in amorphous systems has been questioned. Recognizing that the presence of water in an amorphous solid can affect the glass transition temperature and hence the physical state of the solid, it is argued that at low levels of water, most polar amorphous solids are in a highly viscous glassy state because of their high values of Tg. Hence, water is “frozen” into the solid structure and is rendered immobile by the high viscosity, e.g., 1014 poise. As the amount of water sorbed increases and Tg decreases and approaches ambient temperatures, the glassy state approaches that of a “fluid” state, and water mobility along with the solid itself increases significantly. At high RH, the degree of water plasticization of the solid can be sufficiently high that water and the solid now can assume significant amounts of mobility. In general, therefore, this picture of the nature of sorbed water helps to explain the rather significant effect moisture can have on a number of bulk properties of solids such as chemical reactivity and mechanical deformation. It suggests strongly that methods of evaluating chemical and physical stability of solids and solid dosage forms should take into account the effects water can have on the solid when it is sorbed, particularly when it enters the solid structure and acts as a plasticizer. Much research still remains to be done in assessing the underlying mechanisms involved in water–solid interactions of pharmaceutical importance.

Auxiliary Information—
Staff Liaison : Gary E. Ritchie, M.Sc., Scientific Fellow
Expert Committee : (PW05) Pharmaceutical Waters 05
USP29–NF24 Page 3074
Phone Number : 1-301-816-8353