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Ростовский Государственный Медицинский Университет

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particles that occurs as a result of particle collisions with molecules of the surrounding medium. The result of Brownian motion is that particles in the colloidal range remain suspended without sedimentation indenitely. As particle size increases, the tendency for particles to sediment increases.

Particles in a colloidal dispersion will diffuse from an area of high concentration to an area of lower concentration according to Fick’s law (shown below).



where

J=mass ux D=diffusion coefcient dC/dx=concentration gradient

The diffusion coefcient is described by the Stokes-Einstein equation:

where

D=diffusion coefcient k=Boltzmann constant T=absolute temperature

η = viscosity of the medium

R=hydrodynamic radius of the particle, droplet, or phase





7 Disperse Systems: Suspensions

As demonstrated by the two equations, the magnitude of the diffusion is inversely proportional to the size of the particle (dispersed phase) and the viscosity of the medium. Smaller particles (or droplets) will exhibit faster diffusion, while a more viscous medium will result in slower diffusion.

7.5.3 Nanoparticles inSuspensions

Delivery of particles within the nanometer range can increase the dissolution rate of a poorly water-soluble drug substance in the GI uids, thereby improving bioavailability in many cases. Reduction in particle size results in increases in particle surface areas and also decreases the diffusion layer thickness, resulting in a higher dissolution rate. However, this reduction in particle size also leads to a more unstable suspension as a result of the increased surface energy created through particle size reduction methods. Particles will thus have a tendency toward agglomeration in order to reduce the surface area and free energy. The inclusion of a physical stabilizing agent (e.g., a surfactant) is necessary to prevent the particles from

7.5 Colloidal Dispersions

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agglomerating. The amount of the stabilizer must be carefully balanced. While too little stabilizer will allow particle agglomeration, too much stabilizer can promote Ostwald ripening through solubility changes.

Stabilization of nanosuspensions may be achieved through:

(a) Thermodynamic stabilization, which utilizes a coating of surfactant or polymer

around the particles

(b) Kinetic stabilization, which utilizes additional energy input to compensate for

the increased free energy in the system.

Several technologies are used to manufacture drug nanoparticles for inclusion in suspensions. As examples, stable nanosuspension formulations have been achieved using wet ball milling and high-pressure homogenization in the presence of stabilizing excipients.

Wet ball milling is a process in which coarse drug particles are fed into a suitable container and lled with milling media (i.e., grinding media) and a stabilizing agent (e.g., surfactant) to reduce particle aggregation (Fig.7.6). High shear forces fracture the drug crystals into nanometer-size particles.

High-pressure homogenization uses jet-stream homogenization by pumping drug, dispersion medium, surfactants, and stabilizers under high pressure through a micro uidizing nozzle (Fig.7.7). Particle size reduction in this case is caused by cavitation forces, shear forces, and collision.

Fig. 7.6 Horizontal cross-section of a wet ball mill

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Fig. 7.7 Schematic of a high-pressure homogenizer

7 Disperse Systems: Suspensions

7.6 Excipients Used inSuspension Formulations

Excipient selection will depend on the route of administration, properties of the drug, and the target patient population. For example, in formulations intended for neonates, preservatives, colorings, avorings, or alcohol should be avoided as they may cause toxicity. Particularly for suspension formulations, the effect of excipients on vehicle viscosity, particle aggregation, and drug solubility must be considered, as this can affect the stability of the dosage form.

7.6.1 Suspending Agents

Suspending agents may be added to the suspension formulation to increase viscosity and reduce particle settling. Examples of suspending agents are provided in Table 7.1. Suspending agents that increase viscosity are also called viscosityenhancing agents.

7.6.2 Surfactants

A surfactant is an amphiphilic molecule (contains both hydrophilic and lipophilic components) that, due to its amphiphilic nature, preferentially adsorbs at the interface of two immiscible phases. Generally, the surfactant molecules can replace the molecules at the original (higher energy) interface and thus minimize the surface free energy.

7.6 Excipients Used inSuspension Formulations

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Table 7.1 Examples of suspending agents

Classication Examples

Cellulose derivatives Sodium carboxymethylcellulose

Microcrystalline cellulose Hydroxyethyl cellulose Hydroxypropyl methylcellulose (HPMC, also known as hypromellose) Hydroxypropyl cellulose Hydroxypropyl ethylcellulose Carboxymethylcellulose

Clays Bentonite

Magnesium aluminum silicate (Veegum) Silicon dioxides

Gums and derivatives Acacia

Gellan gum Pectin Tragacanth Xanthan gum Locust bean gum Guar gum

Natural polymers Agar

Alginate Carrageenan

Synthetic polymers Carbomer (Carbopol)

Polyvinyl alcohol (PVA) Povidone (also known as polyvinylpyrrolidone) Polyethylene oxide

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The surfactant molecule will orient itself according to the interface that is present (e.g., drug particle surface and liquid vehicle). At a solid-liquid interface, such as a hydrophobic particle in water, the hydrophobic end will be oriented toward the solid and the hydrophilic end toward the liquid which increases wettability (Fig.7.8). At a liquid-liquid interface, such as in the case of two immiscible liquids, the hydrophilic end of the surfactant will be oriented toward the more polar liquid while the hydrophobic end will point toward the less polar liquid.

Surfactants are included in suspension formulations to aid in the dispersion of the particles, especially if the powder is not wettable. They may also be incorporated in order to achieve a process of “controlled occulation” via their electrostatic attraction and bridging between particles.

7.6.2.1 Surfactants asWetting Agents

It can be difcult to disperse particles within a suspension due to the layer of adsorbed gas molecules upon the surface of the particle. This results in clumping of particles or oating of particles on the surface of the vehicle. A wetting agent is a surfactant that lowers the contact angle and aids in displacing the air phase at the surface, replacing it with a liquid phase.

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7 Disperse Systems: Suspensions

Fig. 7.8 Surfactant molecules surround a hydrophobic drug particle suspended in an aqueous vehicle. Surfactants enhance wettability and dispersion by reducing the interfacial tension and lowering the contact angle between the solid and liquid surfaces

Fig. 7.9 The contact angle is used to assess the wetting of a substance by a liquid

The term contact angle refers to the angle between the surface of a solid and a liquid (Fig.7.9). The size of the contact angle predicts the wetting of a substance by a liquid. If the contact angle is less than 90 degrees, wetting of the solvent by the liquid will take place. If the contact angle is greater than 90 degrees, wetting will not take place. Ideally the contact angle should be as close as possible to zero to ensure that wetting occurs.

7.6 Excipients Used inSuspension Formulations

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7.6.2.2 Surfactants asStabilizing Agents

Surfactants can increase the physical stability of suspensions through electrostatic or steric means. Electrostatic stabilization occurs through an increase in the electrostatic repulsion between particles as a result of adsorption of surface active ions. This results in a decreased tendency of the particles to coagulate. Steric stabilization is a process in which surfactants form a hydrophilic shell around a particle, preventing close contact between particles. Electrosteric stabilization is a combination of the two.

7.6.2.3 Micelles

As the surfactant concentration increases, all the interfacial surfaces become saturated with surfactant molecules. In order to shield the hydrophobic component of the surfactant molecules from the aqueous phase, an aggregation of surfactant molecules known as micelles are formed. The point at which increasing concentration of surfactant leads to micelle formation is called the critical micelle concentration (CMC) (Fig.7.9). The CMC is important to consider in a suspension formulation, as the tendency of a surfactant to adsorb onto the solid-liquid interface and act as a wetting agent is in competition with the surfactants tendency to form micelles (Fig.7.10).

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7.6.2.4 Categories ofSurfactants

Surfactants can be classied based upon the presence or lack of an ionic charge. Anionic surfactants possess a hydrophilic group that carries a negative charge, while cationic surfactants possess a hydrophilic group that carries a positive charge. Ampholytic surfactants, also known as zwitterionic surfactants, contain groups with both negative and positive charges. Nonionic surfactants have no charge and instead derive their water solubility from highly polar groups. Polymers can also function as stabilizers, as is the case for polymeric emulsiers (e.g., Pemulen), which contain both hydrophilic and hydrophobic components to their structure. Polymeric emulsiers can form stable O/W emulsions through generation of a gel network around the suspended oil droplets. They are used in topical, transdermal, and ophthalmic drug delivery. Examples of surfactants are listed in Table7.2.

7.6.3 Flocculating Agents

Flocculating agents are included in suspension formulations to induce weakly bonded conglomerates of particles (ocs). They include surfactants, hydrophilic polymers, and electrolytes such as potassium chloride, sodium chloride, citrates, or phosphates.

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Fig. 7.10 The point at which increasing concentration of surfactant leads to micelle formation is called the critical micelle concentration (CMC). For exemplary purposes, if drug solubility is increased by presence of micelles, then the gure represents graphically what happens to drug solubility as surfactant concentration is increased and more micelles are formed

7 Disperse Systems: Suspensions

Table 7.2 Examples of surfactants

Category Examples

Anionic Potassium laurate

Cationic Cetrimide

Nonionic Poloxamer 407

Polymeric emulsiers (high molecular weight copolymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol)

Sodium dodecyl sulfate (i.e., sodium lauryl sulfate)

Benzalkonium chloride Benzethonium chloride

Polysorbate (Tween®) 20, 40, 60, 80 Sorbitan esters (Span®) 40, 60, 80 Polyoxyethylene castor oil (Cremophor® RH) Polyoxyl 15 hydroxystearate (Solutol

HS 15)

Pemulen polymer TR-1 NF (USP/NF Carbomer copolymer Type B) Pemulen polymer TR-2 (USP/NF Carbomer copolymer Type A)

7.6 Excipients Used inSuspension Formulations

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Upon addition of electrolytes, the particles will adsorb the positively charged cations or negatively charged anions in a tight layer on their surface, and the particle zeta potential (see Sect. 7.2.4) will be reduced (see Sect. 7.2.4). In contrast, a large zeta potential (positive or negative) is indicative of particle repulsion and a deocculated system. Controlled occulation can thus be achieved through addition of electrolytes. The occulating power of electrolytes increases with increasing valency of the ions. However, if too much electrolyte is added to the system, the particle surfaces can be neutralized, and aggregation and caking may occur.

Both surfactants and hydrophilic polymers may act as occulating agents by adsorbing to suspended particles and creating a repulsive electric layer around the particles, preventing irreversible agglomeration. Just beyond this repulsive layer, however, a weak attraction layer exists that allows for occulation to occur between particles through weak interactions and crosslinking of surfactant or polymer molecules between particles. If too high a concentration of surfactant or polymer is added, deocculation will occur and particles will remain separated. Examples of occulating agents are listed in Table7.3.

7.6.4 Sweetening Agents andFlavors

Sweetening agents and avors are often added to suspensions to enhance palatability. Examples of sweetening agents are listed in Table7.4.

7.6.5 Other Excipients

Suspensions may additionally include excipients such as buffering agents, avors, colorants, and preservatives.

Table 7.3 Examples of occulating agents

Category Examples

Surfactant Docusate sodium

Hydrophilic polymer Carboxymethylcellulose sodium

Electrolyte Aluminum chloride

Polysorbate 80 Sodium lauryl sulfate Sorbitan monolaurate

Methylcellulose Polyethylene glycol Tragacanth Xanthan gum

Potassium dihydrogen phosphate Sodium chloride

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7 Disperse Systems: Suspensions

Table 7.4 Examples of sweetening agents

Aspartame Alitame Acesulfame potassium Dextrose Erythritol Fructose Glucose, liquid Glycerin Inulin Isomalt Lactitol Maltose Mannitol Saccharin sodium Sorbitol Trehalose Xylitol Sucrose

7.7 Sterility andSterilization ofDispersed Systems

Dispersed systems administered by injection (e.g., intravenous, intramuscular, subcutaneous, intravitreal) must be sterile. Sterilization is performed on the nal drug product (i.e., terminal sterilization) or while the product is being manufactured (i.e., aseptic sterilization). Several sterilization techniques are described and are as follows:

(1) Steam sterilization (autoclaving): This method uses high-pressure steam to heat

the injectable suspension to a specic temperature (e.g., 121°C) for a set period of time. The heat and moisture effectively kill the microorganisms present in the product.

(2) Radiation sterilization (gamma radiation or electron beam radiation): This

method uses high-energy rays that disrupt the DNA or RNA of the microorganisms, effectively rendering them nonviable.

(3) Gas sterilization (ethylene oxide): This method uses ethylene oxide gas, which

penetrates the packaging and inactivates the microorganisms by alkylation of their proteins and nucleic acids.

(4) Sterile ltration: This method is used to aseptically sterilize the product using a

sterile membrane with a dened pore size to remove the microorganisms from the suspension product. This method is a terminal sterilization, and must be carefully designed to ensure the suspended particles of drug can pass through the sterile membrane while the microorganisms cannot.