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[ Pharmaceutical Solids. John F. Bauer Wettability John F. Bauer “Pharmaceutical Solids” discusses scientific principles associated with pharmaceutical solids useful to practitioners in validation and compliance. We intend this column to be a useful resource for daily work applications. The key objective for this column: Usefulness. Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Case studies illustrating principles associated with pharmaceutical solids submitted by readers are most welcome. Please send your comments and suggestions to column coordinator John Bauer at [email protected] or to journal coordinating editor Susan Haigney at [email protected]. KEY POINTS The following key points are discussed in this article: •Wetting is an important phenomenon in the manufacture of pharmaceutical dosage forms •Wetting is also related to drug dissolution, drug bioavailability and in vivo performance—the efficacy of the drug product •Wettability of a solid is dependent on the nature of the functional groups on the solid surface and more polar surfaces increase wettability •Wettability is characterized by the contact angle of the liquid (usually water) with the solid surface. The smaller the contact angle—the greater the wettability of the solid. •The formation of a well wetted solid surface is a fundamental step in the formation of acceptable pharmaceutical granulations using a wet granulation process •The wettability of any particular drug substance can vary with crystal form, crystal habit, surface roughness surface area, porosity, and particle size For more Author information, go to gxpandjvt.com/bios 32 Journal [ of •The addition of surfactants as well as the formation of salts can increase the wettability of poorly wettable solids •Validation and compliance personnel should be knowledgeable of the problem tendencies of their products and be vigilant of changes in bulk drug manufacturing, particle size reduction processes, certain dosage form manufacturing processes, and certain major excipient changes. INTRODUCTION Solid pharmaceutical dosage forms are heterogeneous mixtures prepared from several individual solid powders (i.e., active drug and excipients) having varying physical properties. Granulation is one of the most important unit operations in drug product manufacturing. It is a size enhancing process by which small particles are formed into larger agglomerates. The smaller particles can still be individually identified and are chemically unchanged in the resulting granules. However, they exist in more uniformly sized and dispersed particles that can be further manipulated into dosage forms. There are both dry and wet granulation processes, but wet granulation is much more prevalent. The following are main objectives of the granulation process: •Improve the flow properties of the mixture •Prevent segregation of the components •Improve the compressibility of the mixture. Previous columns (1, 2) discuss specific individual physical properties of pharmaceutical solids such as crystal form, particle size, surface area, and morphology, and how these properties influence stability and manufacturing performance. This column addresses a property that is in effect the result of positive or ABOUT THE AUTHOR John F. Bauer, Ph.D., is president of Consult JB LLC Pharmaceutical Consultants. Dr. Bauer has more than 30 years of pharmaceutical industry experience, including work in solid-state chemistry, analytical chemistry, stability, pharmaceutics, regulatory CMC, patents, and litigation. He may be reached at [email protected]. Validation T echnology [Winter 2010] iv thome.com John F. Bauer. negative synergism among these individual properties. The phenomenon is wetting or the physical interaction of a solid with a liquid where there is no chemical reaction. This discussion focuses on the interaction of solids with water, although the concepts are applicable to other liquids, especially polar liquids. Wetting ability is critical in the granulation process as well as subsequent dosage form dissolution. DEFINITION OF WETTING AND WETTABILITY Compounds or drugs attract water to the solid surface to varying extents. Some moderately attract moisture while others seek water so extensively that they become excessively wet (hygroscopic compounds) and some even to the point of self dissolving (deliquescence). The large majority of pharmaceutical compounds will simply be wetted to some degree when brought into contact with water. Wetting can be defined in various ways but the following seems appropriate at this point. Wetting is the continued contact between a liquid and a solid surface resulting from physical interactions when the two are brought together. In other words, the liquid is in some way physically attached to the surface of the solid because of some bonding force. This phenomenon of wetting and the strength of the interaction are important in a wide range of practical applications from watering a garden to wet granulating a pharmaceutical preparation. The term used to describe the ease and extent of wetting for an individual solid is wettability. While watering a flower bed, one can observe how the water appears differently and spreads differently on the surface of different kinds of flowers. It also appears to stay longer and bead up more on the surface of some plants than on others. This is a reflection of the different wettabilities of the various plants and is a result of their physical surfaces. WATER AND WETTING In the oxygen-hydrogen bonds in water, the bonding electrons are not located equidistant from the two elements. This results in a partial negative charge on oxygen and partial positive charge on hydrogen. This uneven distribution of charge is known as a dipole. Because of these dipoles, the hydrogen atoms of one water molecule will be highly attracted to the oxygen atoms of neighboring molecules forming a weak “hydrogen bond.” This allows water to produce an extensive intramolecular network. This tendency of water molecules to attract each other is called cohegxpandjv t.com sion. The lowest energy or most stable state for such a system is when each water molecule is surrounded by the maximum number of other water molecules. This situation results in a drop shape with the minimum amount of surface area, i.e., a sphere. This can be seen as a droplet forms at the end of a faucet prior to gravity distorting the shape and making the drop fall (see Figure 1). Because of this high cohesion it often appears as if a membrane or thin skin has formed around the drop (see Figure 2). This skin is what allows insects to scurry across a pond without sinking. The cohesion is strong enough to support their weight as long as it is well distributed across the water surface (see Figure 3). This property that causes the surface of a liquid to behave as a skin or stretched membrane is referred to as surface tension. The relationship between surface tension and the pull of gravity is what determines if an object will float. Unfortunately, golf balls always sink. This same innate ability of water to hydrogen bond leads to a tendency for water to interact with solid surfaces through adhesion, a process where the surface molecules of water bond to the solid surface. At this point we can expand our definition of wetting to be the contact between a liquid and a solid surface resulting from the intermolecular interactions when the solid and liquid are brought together. The Figure 1: Spherical shape assumed by water drops. Figure 2: Representation of “skin” on water surface. “skin” due to surface tension reflecting water molecule cohesion Journal of Validation T echnology [Winter 2010] 33 Pharmaceutical Solids. extent of wetting is dependent on the energies or surface tensions of the interfaces involved. The degree of wetting of a solid surface, therefore, is a balance between the forces of cohesion and adhesion. This balance exists at the point of contact. Consequently the ideally spherical water drop on a surface becomes distorted and appears as a truncated sphere. The amount of wetting will result in greater or lesser truncation. Figure 4 depicts varying degrees of wetting and subsequent drop shape. This distortion is reflected by the contact angle (theta), which is the angle between the surface and a line drawn tangent to the curved surface of the drop. The larger the contact angle, the more spherical character is maintained and the less the surface is wetted. Table I presents the relationship between the contact angle, the wettability of the surface, and the relative cohesive and adhesive forces between the solid and the liquid. Although the contact angle is measured on the liquid drop, the wettability is a characteristic of the solid surface and can vary from solid to solid, from crystal form to crystal form, and even from batch to batch. Surfaces that have high contact angles and resist wetting with water are referred to as hydrophobic (water Figure 3: Insect supported by water surface tension. hating). Conversely, surfaces with low water contact angles are hydrophilic (water loving). Table II summarizes the properties of these two types of solids. IMPORTANCE OF WETTABILITY Non-wetting surfaces (i.e., materials with very low adhesion to water and consequently high contact angles) can be beneficial for products that are designed to repel water, such as foul weather clothing. However, high wettability is desired in many situations. Wetting is important in the bonding and adherence of two materials. For example the presence and quantity of water in mortar is critical to its bonding strength and spreadability. In pharmaceutical manufacturing, wetting plays a crucial part in granulation. Granulation Process The mechanism of granulation is directly related to the phenomena of cohesion and adhesion and, therefore, wettability. Reasonably strong physical bonds must be formed between the various powder particles in order to form granules. These bonds must be strong enough to assure that the granules will not break down during subsequent unit operations such as drying and compression. The strength of these bonds is related to Figure 4: Truncation of water drop as adhesion to surface increases (left to right). Amount of wetting is proportional to 1/θ. Table I: Relationship of contact angle to wettability, cohesion, and adhesion. Contact angle θ Wettability Adhesion strength Cohesion strength θ=0 Perfect wetting Strong Weak 0 < θ < 90 High wettability Strong/weak Strong/weak 90 • θ <180 Low wettability Weak Strong θ = 180 Completely non-wetting Weak Strong 34 Journal of Validation T echnology [Winter 2010] iv thome.com John F. Bauer. Table II: Summary of properties and terminologies related to wettability. Hydrophobic surface Solid property (with water as wetting liquid) Hydrophilic surface High Contact angle Low Low Adhesiveness High Poor Wettability Good Low Solid surface free energy High particle size, moisture content, and the surface tension of the granulation fluid. The wettability of the solids involved is critical in the mechanism. Ideally the first step will be the formation of a thin immobile layer of liquid (water) on the solids. The efficiency and effectiveness of this coating is very dependent on the wettabilities involved. Good wetting properties are required to get uniform liquid distribution and well controlled granule growth. If the solids have low wetting (i.e., high contact angles) the film will not be created and the necessary adhesion will not be obtained. If the solid wets too extensively or is highly soluble in the liquid, an excessive water layer may form restricting adhesion of the powders. Another concern may be the formation of hydrates on the surface of the solid that would have different adhesion properties than the original drug substance. The possible formation of hydrates is a property that should be thoroughly investigated earlier in development so that the risk of problems during granulation can be anticipated and avoided. Once the liquid layer is formed, there will be an increase in contact between particles, and bond strength will increase through Van der Waal forces. The contact area will depend on the wettability of all powders involved and not just the active drug. Therefore, it is important to be aware of the wetting characteristics of all ingredients in the formulation (i.e., active drug and excipients). There are three stages of moisture content during the granulation process. At first, when the moist content is low, the particles are held together by surface tension forces and hydrostatic pressure through liquid bridges between the solids. In other words the liquid will bind to the different solids involved and the surface tension of the water will be strong enough that the water will act as a bridge between the solids. This is called the pendular state. As the air on the surfaces is displaced from between the particles, the capillary state, where water spreads more evenly across the surfaces, is reached. Particles are held together by this capillary action. Throughout these stages the tensile strength increases significantly. These liquid bridges gxpandjv t.com are prerequisite to solid bridges that are formed as the liquid is dried away in the final stage. As the water evaporates the solid suspended in the liquid phase as well as the material dissolved will settle out and form solid bridges or a mortar-like binder between the solids. As can be understood from this mechanism, how well a solid wets is a critical element in its ability to be well formulated. Dosage Form Dissolution Additionally as one might expect, the first step in dissolving a solid is also wetting of the material’s surface. Consequently, the wettability will not only effect how a compound formulates but also the rate of dissolution of the drug from the dosage form. The wettability of the solid is dependent on the nature of both the solid and the wetting liquid. Consequently, the wetting step of the granulation can be enhanced by the use of surfactants. These are compounds that can be added to the liquid phase to lower the surface tension. They generally consist of molecules that have a hydrophobic end and a hydrophilic end. This dual nature helps create the effective liquid bridges necessary for granulation. NATURE OF THE SOLID Solids are traditionally divided into high energy and low energy solids. Materials such as metals, hard molecular crystals, and ceramics are held together by strong covalent and ionic bonds and have hard surfaces that require a high amount of energy to disrupt. The polar or semi-polar nature of these bonds generally make the surface completely wettable. Weak molecular crystals held together mostly by hydrogen bonds and Van der Waal forces are considered low energy and are often only partially wetted. In other words, the wettability of a solid surface can be influenced by the distribution and charge of the surface groups, number of hydrogen bonding sites, and configuration at the molecular level. An increase in the polarity of the solid surface will increase the wettability. Although the number of polar groups in the molecule is controlled by the drug structure, the exposure Journal of Validation T echnology [Winter 2010] 35 Pharmaceutical Solids. of these groups on the surface of the solid can be greatly influenced by crystal form. In any crystal form there will be a balance between internal association of polar groups usually through hydrogen bonding and the presence of polar groups on the crystal surface. For example, the protease inhibitor, ritonavir can exist in at least two crystal forms. Form I has polar groups exposed on the crystal surface. Form II has all the polar groups occupied in internal hydrogen bonding and they are not accessible from the crystal surface. As a result, Form II has very poor wettability compared to Form I. Because crystal form can have a significant effect on wettability, a less thermodynamically stable crystal form may be preferred as an active drug substance because of improved granulation properties. The primary impact on wettability comes from the outermost chemical groups and crystal packing. In some cases, the polarity of the outermost groups can be altered by the formation of a salt or complex as the active ingredient and consequently improve granulation reproducibility. As discussed in an earlier column (1), the same crystal form can be isolated in different crystal habits or external particle shapes (morphology). It is the surface of this crystal habit that is exposed to the liquid and consequently affects the wettability. A number of pharmaceutical companies are investing in the ability to manufacture drugs in specific crystal habits usually nearer spherical. This is called crystal engineering and their goal is to avoid problem habits such as needles that can cause flow and blending problems. Reliable control of the crystal habit can be of significant importance in effecting wettability as well. For example, while working with a fluoroquinone antibiotic that can exist in several polymorphic forms, our lab encountered an unusual wetting event. After several dozen successful granulation runs using multiple active ingredient lots, a single batch became dry and crispy during drying indicating that the granulation process had failed. The active drug particles had not wetted as expected. A thorough investigation into crystal form, particle size, surface area, purity, water content, etc., was conducted and revealed no difference between this lot and other well-behaved batches. The only testing that indicated a difference in this lot was dielectric analysis (DEA). This technique applies a current to the surface of a material and records the ability of the surface to accept and maintain a charge (capacitance). In this case the problem lot, although the same crystal form as previous successful lots, showed no ability to accept 36 Journal of Validation T echnology [Winter 2010] a charge (Figure 5). This indicated an absence of polarity on the surface and explained the very poor wettability. Because this was the same crystal form previously used, the explanation was the unexpected formation of a crystal habit that successfully masked the polar groups but was not significantly different when observed microscopically. Because crystal habit can be influenced by isolation techniques, it is important to control the entire synthetic process including the final isolation steps. Physical manipulation can also impact the wettability of solids. Surface roughness and porosity (Figure 6) can both lower the wettability of the solid as a result of water being drawn into the pores by capillary action and not remaining on the smoother surface areas. Drying techniques such as tray drying and tumble drying as well as size reduction by milling can impact the roughness and porosity of the solid surface. Size reduction by milling can be especially significant because the friction involved can create varying amounts of static charge on the particle surface. Since wettability is dramatically influenced by the polarity of the solid surface, the presence of non-reproducible charges can affect the dependability of granulation. These possible changes in wettability should be considered when evaluating possible manufacturing changes or process improvements. ANALYTICAL ASPECTS The standard measure of wettability is the contact angle. This is usually determined using a combination of microscopy and projection instruments. Table I shows how these contact angle measurements can be correlated to water wetting. In actuality, this is the only straightforward measurement of wettability. However, there are other less routine techniques that can be used to estimate how well a solid will wet. Surface tension is another important parameter when judging wettability. As a general rule, acceptable bonding adhesion is achieved when the surface energy of the solid is at least 10 dynes/cm greater than the surface tension of the liquid. Pure water has a surface tension of approximately 73 dynes/cm. Therefore, analytically the surface tension of the solid is important as well as the contact angle. The surface tension of a solid is estimated by interaction with a set of established test liquids that have known surface tension values. The force required to remove the liquid from the solid surface can be measured by a number of various ways and a practical surface tension estimated. iv thome.com John F. Bauer. Figure 5: Dielectric analysis curves for problem and typical drug lots. C a p a c i t a n c e Figure 6: Photomicrograph of solid surface showing roughness and porosity. 1.2 1 0.8 0.6 Typical lot Problem lot 0.4 0.2 0 20 40 60 80 100 120 Other techniques have some applicability in evaluating wettability but are more difficult to perform. Atomic force microscopy (AFM) is a microscopic technique that traces the surface of a solid using a probing tip. The adhesive force between the AFM tip and the solid surface can give an estimate of how strongly a liquid would adhere to the solid surface. Inverse gas chromatography in which a column is packed with the solid to be studied and the extent to which water vapor is retarded as it flows through the column gives insight into the adhesive force between the solid surface and water. Lastly, DEA can be used as a fingerprint for the type of polarity expected on the solid surface and can be used to identify nonconforming lots. IMPLICATIONS FOR VALIDATION AND COMPLIANCE This article has discussed the importance of solid molecule surface properties on wetting. Effects on wetting are important in both dosage form manufacturing and drug dissolution. Effects on drug manufacturing can cause failed batches with significant economic consequences. Drug dissolution is directly related to drug bioavailability and in vivo performance—the efficacy of the drug product. Solid molecular surface properties are thus directly related to the pharmacological performance of the drug product. Validation and compliance personnel with responsibility for solid products must be knowledgeable of the problem tendencies of their products. Development personnel will likely have addressed the surfaced properties of drug molecules during product and process development. Their findings and precautions should be communicated to validation and compliance personnel with product responsibilities. Thereafter, the validated processes that have been used to successfully manufacture bulk drugs and products must be maintained. gxpandjv t.com When a drug molecule with problematic tendencies has been identified, validation and compliance personnel should be watchful for process and material changes. The following general areas are especially prone to problem effects: •Bulk drug manufacturing. Changes in bulk drug manufacturing processes may affect the surface properties and wetting of pharmaceutical solids. These changes may in turn affect dosage form manufacturing when the bulk drug content is a quantitatively significant part of the formulation. Bulk drug changes affecting wetting may adversely affect drug dissolution. If drug dissolution is affected, there may be subsequent effects on in vivo bioavailability and pharmacologic response. •Particle size reduction processes. Bulk drugs particle size is typically reduced prior to subsequent granulation processes. These processes may occur as part of bulk drug manufacturing or as the first step in dosage form manufacturing. Particle size reduction is accomplished by use of specific equipment with specific process parameters. If different equipment is used or if different process parameters are needed, the effects of these changes on the solid surface properties should be evaluated. Any changes to the particle size reduction equipment or process parameters used for particle size reduction of susceptible molecules should be carefully evaluated prior to implementation and subsequently monitored. •Dosage form manufacturing granulation processes. Dosage form granulation processes, especially wet granulation processes, involve the interaction of multiple process parameters. Even relatively simple granulation processes with water require control of the amount of water added, the rate of addition, equipment operational paramJournal of Validation T echnology [Winter 2010] 37 Pharmaceutical Solids. eters such as mixer speed, massing time, end point judgment, and so on. Manual granulation processes in which manufacturing operators control these parameters are especially prone to variation in granule properties. Changes in granule properties are reflected in subsequent processes such as tablet compressing. Changes to granule properties may also affect drug dissolution and in vivo performance. Any changes to the granulation processes of susceptible molecules should be carefully evaluated prior to implementation and subsequently monitored. •Dosage form drying processes. Drying processes may have significant effect on the surface properties of pharmaceutical solids. For example, lyophilized solids, fluidized-bed dried solids, and oven-dried solids will be chemically identical, but will likely have markedly different surface properties. Any changes to the drying processes of susceptible molecules should be carefully evaluated prior to implementation and subsequently monitored. •Dosage form sizing processes. Dried granulation particle size is typically modified prior to subsequent mixing and blending processes. This process accomplishes particle size reduction of large granules and enables formation of the target granule size distribution for the formulation. Sizing is accomplished by use of specific equipment such as impact mills with specific process parameters. If different equipment is used or if different process parameters are needed, the effects of these changes on the solid surface properties should be evaluated. Any changes to the sizing equipment or process parameters used for particle size reduction of dried granulations should be carefully evaluated prior to implementation and subsequently monitored. •Excipient changes. Most of the above discussion addressed wettability of active drugs. How- 38 Journal of Validation T echnology [Winter 2010] ever, in formulations containing highly potent drugs (i.e., low dose drugs such as 1 mg per tablet) the inactive excipients are more critical to processing than the active drug. For example, for a tablet weighing 150 mg and containing 5 mg active drug, the formulation contains 145 mg inactive excipients or more than 95% inactive excipients. Validation and compliance personnel should be wary of changes to the major inactive excipients such as by sourcing from new vendors. These changes should be carefully evaluated prior to implementation and subsequently monitored. CONCLUSION The ability to form a uniform layer of water on the surface of a solid can be a critical step in some unit operations of the pharmaceutical manufacturing process, especially granulation. Poor wettability can require the use of special formulation techniques such as direct compression or the addition of excess surfactants. Therefore, wettability is a significant property of drug substances and should be evaluated during drug development. Wettability must also be considered whenever process changes are being introduced and considered as a possible cause if granulation problems are encountered. REFERENCES 1. Bauer, J.F., “Pharmaceutical Solids: Polymorphism—A Critical Consideration in Pharmaceutical Development, Manufacturing, and Stability,” Journal of Validation Technology, Vol. 14, #5, Autumn 2008. 2. Bauer, J.F., “Drying Pharmaceutical Solids—Hydrates and Enantiotropic Polymorphs,” Journal of Validation Technology, Vol. 15, #2, Spring 2009. JVT ARTICLE ACRONYM LISTING AFMAtomic Force Microscopy DEADielectric Analysis iv thome.com