Surface area - Analyses of powders

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Chapter: Pharmaceutical Drugs and Dosage: Powders and granules

Surface-dependent physicochemical phenomena are of pharmaceutical significance.

Surface area - Analyses of powders

Significance of surface area

Surface-dependent physicochemical phenomena are of pharmaceutical significance. For example,

·           Absorption of a drug from a dosage form involves dissolution of the drug substance into the absorption medium. The rate of dissolution is proportional to the surface area of the drug substance.

·           Lubricants, such as magnesium stearate, used during pharmaceutical processing are intended to cover the surface of the granules to provide adequate lubricity during unit operations such as tableting. Changes in the surface area of the granules or the lubricant can directly impact the surface coverage and effectiveness of the lubricant.

·           Wet granulation is a surface phenomenon, involving wetting and agglomeration of particles. Changes in the surface area of the raw materials can significantly influence the reproducibility of granulation.

Defining surface area

Total surface area available in a powder sample is a function of both its particle size and porosity. Particle size is relatively easier to measure and compare among different powders. Porosity of the particles refers to air-filled solvent accessible channels inside particles. Thus, porosity contributes to the surface area of the particles without impacting particle size or shape. A higher porosity particle of the same size and shape as a lower porosity particle will have greater surface area. The rate of disintegration and drug dissolution from granules depends on the penetration of the dissolution medium inside the granules, which is determined by the porosity of the granules.

In determination of total surface area of a powder sample, it is difficult to distinguish the area contributed by the surface of the granules from the area contribution attributable to the porosity. For all practical purposes, this distinction is ignored. It is assumed that the surface area accessible to the penetrating medium is representative of the surface area relevant to the pharmaceutical applications of the powder.

Quantitation of surface area by gas adsorption

Surface area is commonly measured by the adsorption of an inert gas on a solid surface. It is commonly expressed as specific surface area, which is the surface area per unit weight of the powder.

Adsorption of an inert gas (the adsorbate) on a solid surface (the adsor-bent) is driven by the weak van der Waals forces of attraction. The rate and extent of adsorption of the gas is primarily driven by the partial pressure of the gas (P). At isothermal (constant temperature) conditions, Freundlich proposed that the mass of gas adsorbed (x) per unit mass of adsorbent (m) is given by

x/m = k * P1/n

where k and n are constants.

Freundlich isotherm considers multiple layers of the adsorbate on the adsorbent. Langmuir proposed an alternative equation to describe gas adsorption on the solid surface that relies on the assumption of monolayer adsorption. The number of sites occupied on the surface of a solid (θ) is given by

Θ = k * P / (1 + k * P)

where, k = ka /kd, ka and kd representing the rate constants of adsorption and desorption processes, respectively.

Both Langmuir and Freundlich adsorption isotherms explain gas adsorp-tion at low pressures, but not at high pressures. Multilayer formation dur-ing gas adsorption was explained by the Brunauer–Emmett–Teller (BET) equation:


P and P0 are the equilibrium and saturated vapor pressure of the adsorbate

Wtotal is the total amount of gas adsorbed

Wm is the amount of gas adsorbed to form a monolayer

C is the BET constant that depends on the heat of adsorption for the first layer (E1), the heat of adsorption for the second and subsequent layers or the heat of liquefaction of the adsorbate (EL), gas constant (R), and absolute temperature (T) as

C = e E1EL/RT

BET adsorption isotherm adequately describes physical gas adsorption for θ = 0.8 to 2.0. This range covers the formation of the monolayer. The BET equation can also be expressed as a linear equation:

The determination of surface area of pharmaceutical powders is most frequently carried out using this equation. Assessment of binding interac-tions of a dissolved drug with solid particles in solution is carried out using Langmuir adsorption isotherm. Freundlich isotherm is used to characterize the types of adsorption profiles of different solids.

For the determination of powder surface area using BET method, adsorp-tion of an inert gas, such as nitrogen, is carried out at isothermal conditions. The number of moles of the gas adsorbed (Wtotal) as a function of the equilibrium pressure (P) is recorded. The use of BET equation allows the calculation of the amount of gas that would form a monolayer (Wm), which allows the calculation of total surface area using the molecular area of the gas (nitrogen, 15.8 Å2) and the Avogadro’s number of molecules per mole of substance.

Altering powder surface area

Specific surface area of excipients and drug substances is primarily deter-mined by their manufacturing process, which affects their PSD and poros-ity. Therefore, making changes to their manufacturing process can change surface area of raw materials. For example, the use of spray drying instead of slow solvent evaporation techniques, such as drum drying, results in the production of higher porosity particles. Changes in crystalline polymor-phic form produced as result of crystallization process, such as the solvent used for crystallization, can also result in changes to the specific surface area of the material.

High-specific surface area of APIs is often desired to increase their dis-solution rate from the dosage forms. This is commonly achieved by com-munition or particle size reduction. In addition, certain excipients, such as magnesium stearate, have a unique plate-type structural organization of the molecules, such that the application of shear and mixing results in the separation of plates leading to increase in surface area.

Reduction of particle surface area is desired for applications where, for example, reduction of undesired, surface-induced phenomena is needed. For example, sticking of the powder material to the stainless steel pro-cessing equipment during pharmaceutical manufacture is a function of the surface characteristics of the APIs. Therefore, reduction in the surface of the APIs per unit powder weight can minimize or mitigate this processing risk. This is commonly achieved by decreasing drug load in the formulation and granulation of the APIs with low proportion of fine particles.

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