PHARMACEUTICAL SUSPENSIONS AND EMULSIONS

Coarse Dispersions (Lyophobic colloids) Oil-in-water emulsions (o/w) Suspension: Solid drug in liquid vehicle Emulsion: Liquid drug in liquid vehicle: Oil-in-water emulsions (o/w) Water-in-oil (w/o)

Reasons for Use Drug is insoluble Drug is more stable in suspension or emulsion There is a need to control the rate of release of the drug Drug has bad taste (oral)

Routes of Administration Oral Ocular Otic Rectal Parenteral Topical

I. Formulation of Suspensions

Wetting Wetting agent

Well Formulated Suspension Resuspend easily upon shaking Settle rapidly after shaking Homogeneous mix of drug Physically and chemically stable during its shelf life Sterile (parenteral, ocular) Gets into syringe (parenteral, ocular)

“External” Forces Acting on Particles Gravity Brownian Movement V(-o)g Sedimentation equilibrium: Gravity is neutralized by Brownian movement 2-5 m

Settling and Aggregation flock The suspension shall form loose networks of flocks that settle rapidly, do not form cakes and are easy to resuspend. Settling and aggregation may result in formation of cakes (suspension) that is difficult to resuspend or phase separation (emulsion) cake

Sediment Volume F={volume of sediment Vu}/{original volume Vo} Vu Vo

DLVO: Optimal Distance Energy No flocks can form Repulsion Attraction Attraction Distance

Controlled Flocculation Flocculating agent changes zeta-potential of the particles (it can be electrolyte, charged surfactant or charged polymer adsorbing on a surface). If the absolute value of the zeta-potential is too high the system deflocculates because of increased repulsion and the dispersion cakes. + - + Non-caking Caking Caking F=Vu/Vo Flocculating Agent - + + - Zeta-potential

II. Formulation of Emulsions

Emulsification Emulsifier

HLB and Use of Surfactants Amphiphilic surfactants are characterized by the hydrophilic-lipophilic balance (HLB): a relative ratio of polar and non-polar groups in the surfactant HLB ca. 1 to 3.5: Antifoams HLB ca. 3.5 to 8: Water-in-Oil Emulsifiers HLB ca. 7 to 9: Wetting and spreading agents HLB ca. 8 to 16: Oil-in-Water Emulsifiers HLB ca. 13 to 16: Detergents HLB ca. 15 to 40: Solubilizers HLB is an arbitrary parameter. Sometimes it is determined experimentally, for example, using reverse phase chromatography. There are numerous methods of computing of HLB. More information on computing of HLB (including blends of surfactants and requred HLB) can be found in: M. Stoklosa and H. Ansel, Pharmaceutical Calculations, Williams & Wilkins, Baltimore, 1996.

Required HLB HLB needed for emulsification of the oil phase. If there are several oil ingredients the required HLB is calculated as a sum of their respective required HLB multiplied by the fraction of each. Calculate the required HLB for the oil phase of the following o/w emulsion: cetyl alcohol 15 g., white wax 1g. Lanolin 2 g, emulsifier (q.s.), glycerin 5 g. water 100 g. Required HLB Fraction (from reference) Cetyl alcohol 15 x 15/18 12.5 White wax 12 x 1/18 0.7 Lanolin 10 x 2/18 1.1 Total required HLB 14.3 HLB is an arbitrary parameter. Sometimes it is determined experimentally, for example, using reverse phase chromatography. There are numerous methods of computing of HLB. More information on computing of HLB (including mixtures of surfactants) can be found in: M. Stoklosa and H. Ansel, Pharmaceutical Calculations, Williams & Wilkins, Baltimore, 1996.

HLB of Surfactant Blend Surfactant blends are commonly used to obtain desired emulsifying properties. What is the HLB of the mixture of 40 % Span 60 (HLB = 4.7) and 60 % Tween 60 (HLB = 14.9)? HLB of mixture: 4.7 x 0.4 + 14.9 x 0.6 = 10.8 In what proportion should Span 80 (HLB = 4.3) and Tween 80 (HLB = 15.0) be mixed to obtain “required” HLB of 12.0? 4.3.(1-x) + 15.x = 12 x = 0.72 72 % Tween 80 and 28 % Span 80 HLB is an arbitrary parameter. Sometimes it is determined experimentally, for example, using reverse phase chromatography. There are numerous methods of computing of HLB. More information on computing of HLB (including mixtures of surfactants) can be found in: M. Stoklosa and H. Ansel, Pharmaceutical Calculations, Williams & Wilkins, Baltimore, 1996.