DEPARTMENT OF PHARMACEUTICS

Introduction Disperse systems fall into two categories Emulsions Suspensions In addition, pharmaceutical products contain API, which may be solid or liquid, uniformly dispersed into the emulsion or dispersion base Hence, many types and variations of mixing, dispersion, emulsification and size reduction equipments can be used to prepare disperse systems

Factors influence selection process Suspension Viscosity Density Particle shape, size and size distribution Emulsion Surface tension Chemical activity of liquid phases Surfactants Stabilizers

Parameters Relationship of Mixing equipment to viscosity A large no. of dispersed products exhibit Plasticity Pseudo plasticity Thixotropy Macroscale versus Microscale mixing Macroscale mixing refers to adequate flow in all areas of mixing vessel (also called as blending) In microscale mixing individual components are mixed

Mixer power equation P = C.[ ρND 2 /ŋ] -a.[ N 2 D /g] -b ρN 3 D 5 Where P= power consumed D= impeller diameter N= speed of rotation g= acceleration due to gravity ρ= liquid density Ŋ= viscosity a & b = exponents determined experimentally C= proportionality constant [ ρND 2 /ŋ] = Reynolds number, [ N 2 D /g] = Frounde number When flow is laminar, a is close to 1 & b is close to zero When flow is turbulent both the exponents are close to zero

Methods Blending of miscible liquids Suspension of solids Dispersion of solids (size reduction)/ emulsification Emulsification of immiscible liquid systems Preparation of liposomes Scale up Vacuum processing

Scale up Scale up ratio = large scale production rate small scale production rate Scale up ratio 10 to 100 for laboratory to pilot and 10 to 200 for pilot plant to commercial production

Scale up parameters Power P P/V ratio= power consumed/ vol. of Vessel Tip speed of impeller = πDN Pumping rate per unit volume, Q/V Pumping rate Q α ND 3 Geometric, kinetic and dynamic similarity

Scale up For dispersions, the controlling factor is often tip speed, which determines the maximum shear rates. Never use laboratory scale or pilot scale equipment that can not be built or operated in larger sizes Optimization of scale up around only one parameter is not usually feasible. Some compromises are normally necessary

Vacuum processing Presence of dispersed air is almost a detrimental factor to emulsion stability All mixing steps should be conducted to incorporate least amount of air One way of combating the aeration problems is to perform the entire process in a vacuum Vacuum processing also allows the option of drawing powders into batch from the bottom outlet. This promotes immediate dispersion Foam may form even during processing under vacuum.

Steps to prevent foam formation Gentle mixing is best for initial deaeration step Increase the absolute pressure (decreasing the vacuum) outside of the foam bubble to crush bubble By increasing and then decrease in the vacuum, the batch can be deaerated Devices are available for deaeration on continuous basis.

Mixing equipment A. Mixers B. High speed dispersers C. Rotor stator mixers D. Combination mixers E. In- line mixers F. Non- mechanical disperse processing G. Fine suspension and size reduction equipment

Mixing equipment A. Mixers Propeller mixers Turbine mixers Anchor mixers Scraped surface agitators Counter rotation

B. High speed Dispersers Design: Also called as saw blade disperser This machine consists of a variable speed shaft connected to an impeller with a serrated edge The tip speed is set around 4000 ft/min The diameter of impeller should be 1/3 of diameter of vessel The impeller should be located one impeller diameter off the bottom of vessel Application: This is used to disperse pigments into liquids Limitation: The high speed disperse design is ineffective if the viscosity is low Suitable for suspensions not emulsions Air incorporation is another problem

C. Rotor/ stator mixer Radial flow with stator Rotating stator: In this both impeller and the stator both rotate on drive shaft and hence produce combined shear Hence no supporting rod necessary and no steady bearing is required Axial flow rotor/ stator mixer

D. Combination Mixers Anchor plus Rotor/ stator Anchor plus high speed disperser

In line Mixers Rotor/stator mixer disperser emulsifiers Colloid mills Piston homogenizers Ultrasonic vibrating homogenizer Micro fluidizer technology Low pressure cyclone emulsifiers Static mixers: pipe line mixers contain series of baffles in a cylindrical pipe

Microfluidizer Technologies This device uses a high pressure positive displacement pump operating at pressure psig through interaction chamber. The interaction chamber consists of microchannels as narrow as 50 microns and cause the flow of product to occur as very thin sheets Microchannels are Y- shaped divides flow into two micro streams At the impingement area the collision of two high speed flow streams in a very tight spot creates various droplet size reductions and mixing This technology is used to prepare unilamellar liposomes and micro emulsions

F. Non mechanical disperse processing Critical fluids liposome process Super critical or near critical fluids are gases CO2 and propane under ambient conditions When compressed at conditions above their critical temperature and pressure, these substances become fluids with liquid like density and gas like properties of low viscosity and high diffusivity. The gaseous characteristics increase mass transfer rate, thereby decrease processing time A circulating pump operating in a high pressure loop ensures good mixing between the supercritical fluids and the liposomal raw materials After specified residence time, the resulting mixture is trough the dip tube with its nozzle in a decompression chamber that contains aqueous solution or fine dispersion of drug for liposomal encapsulation.

Fine suspension and size reduction equipment Three – roll mills Ball mills or jar mills Continuous stirred media mills

Three roll mills Capable of dispersing small tightly bound agglomerates and hard discrete particles Premixed suspension allowed to travel between rotating rolls that are located about microns apart. The particles not only subject to very high shear mechanical crushing and smearing Three rolls are named as feed roll, center roll and apron roll

Three roll mills The shear rates in a three – roll mill are a function of The roll radius, R inches The difference in rpm of the rolls in contact, δ rpm Clearance between the rolls known as nip clearance, z (mils) Shear rate, = 105R δ /z

Ball mill For true size reduction of fine particles or for deagglomeration of very tightly bound agglomerates Small version of ball mill is known as jar mill Disadvantage is time consuming process For difficult to grind materials, ball mill is still the machine of choice

Agitated bead mills Just like ball mill,the bead mill uses a charge of inert small balls around 2-8mm in diameter If the beads are ceramic – media mill If the beads are steel balls- shot mill Large grains of sand(3mm)- sand mill The cylinder is either horizontal or vertical Not often used in ph. industry, except when particle size requirements fall below 10 microns

References Disperse systems,vol-1 to 3 Remington’s pharmaceutical sciences Ansel’s pharmaceutical dosage forms Dispencing pharmacy by cooper and gunn THAN-Q-U