Particle Engineering in Pharmaceutical Solids Processing: Surface Energy Considerations
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Send Orders for Reprints to [email protected] Current Pharmaceutical Design, 2015, 21, 2677-2694 2677 Particle Engineering in Pharmaceutical Solids Processing: Surface Energy Considerations Daryl R.Williams* Department of Chemical Engineering, Imperial College London, Prince Consort Road, Kensington London SW7 2AZ, United Kingdom Abstract: During the past 10 years particle engineering in the pharmaceutical industry has become a topic of in- creasing importance. Engineers and pharmacists need to understand and control a range of key unit manufacturing operations such as milling, granulation, crystallisation, powder mixing and dry powder inhaled drugs which can be very challenging. It has now become very clear that in many of these particle processing operations, the surface en- ergy of the starting, intermediate or final products is a key factor in understanding the processing operation and or the final product performance. This review will consider the surface energy and surface energy heterogeneity of crystalline solids, methods for the measurement of surface energy, effects of milling on powder surface energy, ad- hesion and cohesion on powder mixtures, crystal habits and surface energy, surface energy and powder granulation processes, performance of DPI systems and finally crystallisation conditions and surface energy. This review will conclude that the importance of surface energy as a significant factor in understanding the performance of many particulate pharmaceuti- cal products and processes has now been clearly established. It is still nevertheless, work in progress both in terms of development of methods and establishing the limits for when surface energy is the key variable of relevance. Keywords: Surface energy, contact angle, inverse gas chromatography, pharmaceutical powders, surface properties, powder processing. INTRODUCTION where U is the internal energy, S the entropy, p and T the conditions The formulation and manufacture of modern pharmaceutical of pressure and temperature, i the chemical potential of each com- particulate products is a complex and multi-faceted process. Indeed ponent, Ni the amount of component i, A the area of the interface our fundamental understanding of these processes does not meet the and ij the interfacial free energy. The interfacial free energy, ij is needs of industry, especially as more challenging types of powders defined as the increase in the internal energy of the entire system such as hydrophobic drugs and complex amorphous formulations per unit increase in interface area at constant volume and entropy of become more common place. The dominance of solid state dosage the system under closed conditions, as given in (2): forms which involve particulate materials necessitates that interfa- cial and surface phenomena have an important role to play in de- = G ij (2) A termining the quality and performance of both processes and final TPN,, i products. During the past 10 years particle engineering in the phar- maceutical industry has become a topic of increasing importance The interfacial free energy ij may be expressed in terms of the especially as engineers and pharmacists seek to understand and Gibbs free energy (3): control a range of key unit manufacturing operations such as mill- = U ing, granulation, crystallisation, powder mixing and dry powder ij A (3) inhaled drugs. It has now become clear that in many of these parti- SVN,, i cle processing operations, the surface energy of the starting, inter- mediate or final products can be a key factor in understanding the So for example, the spreading of a liquid i over a solid surface j processing operation and or the final product performance. This is determined by their interfacial free energies. At the interface, review will consider the role played by surface energy in pharma- with a new liquid surface area, Ai will result in the diminishing of ceutical particle processing operations, and will be preceded by a the solid surface area, Aj. This change will also cause the creation of discussion of the surface energy of pure pharmaceutical solids and the interface surface area, Aij. So for the spontaneous spreading of a experimental methods for its measurement. liquid i over a solid substrate j, Si/j is given by solving the exact differential shown in Eqn 4. Positive values of Si/j would indicate a SURFACE FREE ENERGY AND THERMODYNAMICS spontaneous spreading of liquid i over solid j. Si/j is also known as Our fundamental description of surface free energy follows the spreading coefficient. from the thermodynamic free energy per unit area, for two phas- ij es i and j in contact [1, 2]. From the first law of thermodynamics, G = = Si/ j j i ij A (4) the internal energy of a closed system is represented by: i TP, C = + + dU TdS pdV idN i ij dA However, commonly the liquid droplet does not fully spread i=1 (1) across the entire surface of a solid substrate to form a liquid film. Indeed for many systems such as organic solids, the liquid droplet *Address correspondence to this author at the Department of Chemical which exists in the presence of its own vapour, will eventually Engineering, Imperial College London, Prince Consort Road, Kensington achieve an equilibrium thermodynamic state whereby a contact London SW7 2AZ, United Kingdom; Tel: ++44 207 594 5611; angle can be defined between the liquid droplet and the solid sub- E-mail: [email protected] 1873-4286/15 $58.00+.00 © 2015 Bentham Science Publishers 2678 Current Pharmaceutical Design, 2015, Vol. 21, No. 19 Daryl R.Williams strate. LV, SV and SL represent respectively the liquid surface free angle of a series of liquids with different surface tensions, and thus energy (commonly called the surface tension for liquids), the solid- differing 's with the solid of interest, linked with a simple extrapo- vapor surface energy and the solid-liquid surface energy (Fig. 1). lation, typically graphically to =0. Fig. 2 below shows a Zisman The units for surface free energy are mJ m-2, though sometime an plot obtained for morphine sulfate powders by Prestidge and equivalent unit mN m-1 is used, especially in the case of surface Tsatouhas using a capillary wicking method [6]. The primary limi- tension measurements. The measurement of the solid surface free tation of the method is that the differing chemical nature of the energy SV for an unknown material is often determined by refer- interfacial interactions of the contact angle liquids (for example ence to the liquid wetting characteristics of known liquids as ob- hydrocarbons versus hydrogen bonding liquids like water) with the tained via contact angle measurements. solid being studied effected the estimates for c obtained. Further- more, the analysis provides no insight chemically to the interfacial LV phenomena associated with the wetting event. Adsorbed Vapour Liquid Droplet Molecules e SV SL Surface Fig. (1). Sessile drop contact angle schematic for a liquid droplet on a solid substrate with adsorbed vapor film. Young’s equation (5) describes the relationship between the interfacial tensions or free energies of the solid and liquid to the contact angle [3]: = SV SL LV cos( ) (5) The definition for work of adhesion, WG= , follows di- Fig. (2). Morphine sulfate wetting rates as a function of the surface tension AA of wetting liquids [6]. rectly from the interfacial free energy : W = + (6) A i i j The Zisman approach proved popular until the 1970's when a Similarly the work of cohesion, W , is defined: number of improved but related methods for surface energy analy- C sis were developed which could be broadly described as semi- = (7) WC2 i empirical in their nature. These developments were driven by the Equations (6) and (7) then lead to a key relationship between concept developed by Fowkes [7] who advanced the important the work of adhesion, the contact angle and the surface free energy assumption that the surface tension for many organic materials of the contact angle liquid- the Young-Dupre’ equation (8) [1]: could be considered to be composed of two independent compo- nents; one essentially relating to long range physical forces and = + (8) WA LV 1[ cos ] another term relating to shorter range chemical forces. Eqn (10) Sometimes a more detailed equation is provided (9) which takes below shows that simple equation where the surface energy or sur- into account the change in solid-vapour surface energy cause by the face tension for a liquid or solid respectively can be considered to be composed of a long range force component due to London van presence of adsorbed vapor which exerts a film pressure of e. The de Waals forces which is commonly referred to as d, as well as a significant experimental difficulty in measuring e means that Eqn (8) is the normally used form. second component which described shorter range forces, originally described as polar forces p. In his original paper, Fowkes consid- = + + (9) d WA LV 1[ cos ] e ered a wider range of sources for these interactions other than p The use of a contact angle liquid with known surface tension and including metallic bonding, induction forces etc for a general properties to determine the surface energetics of an unknown solid material system. state substrate seems a simple enough experimental concept. How- = d + p ever, the equations which link these concepts together have only (10) slowly evolved over the past 50 years. The reader is invited to read The development of Eqn (10) catalysed a number of semi- the excellent and comprehensive review on this topic by Eztler [4]. empirical models for predicting the work of adhesion between a In this review, we will summarise the major theoretical issues core pair of organic material phases. These approaches were based on (i) to this topic, in broadly a historical order. d and p being treated as independent quantities and (ii) geometric The determination of the surface energy of solids was pioneered mean approximations based on Berthelot’s principle being used to by Zisman who studied the surface energy of polymeric surfaces in estimate interfacial interactions.