**8. Cryogenic micronisation**

In the cryogenic micronisation process, lipid matrices are obtained either by melt dispersion (the drug is mixed in a molten lipid) or solvent stripping (the drug and lipid are co-dissolved into a solvent mixture under stirring, e.g. benzyl alcohol, ethanol). In the cryogenic microni‐ sation step, cooling is performed by insufflating liquid nitrogen nearly at-80 °C before the drug loaded lipid matrix being micronised by grinding.

Finally, the obtained powders are sieved in an automatic sieving apparatus. Regarding to the sieving step, this operation is depending on particle size requirements and on the type of mill used, the particle size of the product obtained by micronisation can already be suitable for some applications and therefore sieving is not necessary.

This technique can be used for the production of SLM of 1 to 500 μm in diameter according to the chosen sieves [48,49].

#### **9. Spray-drying**

Spray-drying is an one-step process which converts a liquid feed to a dried particulate form. The feed generally is a solution, but it can also be a coarse or fine suspension or a colloidal dispersion (e.g., emulsions, liposomes, etc.); this feed is first atomised through various techniques (centrifugal, pneumatic, ultrasonic and electrostatic atomisation) to a spray form, that is put immediately into thermal contact with a hot gas, resulting in the rapid evaporation of the solvent to form dried solid particles [50]. The dried particles are then separated from the gas by means of a cyclone, an electrostatic precipitator or a bag filter (Figure 6).

**Figure 6.** Spray-drying apparatus

**Figure 5.** Scheme of the apparatus for producing SLN with a membrane contactor. A (lipid phase), B (water phase), 1 (pressurised vessel containing the lipid phase), 11 (thermostated bath), 12 (thermostat), 2 (nitrogen bottle), 3 (manom‐ eter), 4 (vessel containing the water phase), 41 (thermostated bath), 42 (thermostat), 5 (stirrer), 6 (pump), 7 (tangential

In the cryogenic micronisation process, lipid matrices are obtained either by melt dispersion (the drug is mixed in a molten lipid) or solvent stripping (the drug and lipid are co-dissolved into a solvent mixture under stirring, e.g. benzyl alcohol, ethanol). In the cryogenic microni‐ sation step, cooling is performed by insufflating liquid nitrogen nearly at-80 °C before the drug

Finally, the obtained powders are sieved in an automatic sieving apparatus. Regarding to the sieving step, this operation is depending on particle size requirements and on the type of mill used, the particle size of the product obtained by micronisation can already be suitable for

This technique can be used for the production of SLM of 1 to 500 μm in diameter according to

Spray-drying is an one-step process which converts a liquid feed to a dried particulate form. The feed generally is a solution, but it can also be a coarse or fine suspension or a colloidal

flow filtration unit), 8-9 (manometer).

64 Application of Nanotechnology in Drug Delivery

the chosen sieves [48,49].

**9. Spray-drying**

**8. Cryogenic micronisation**

loaded lipid matrix being micronised by grinding.

some applications and therefore sieving is not necessary.

The design may be "open cycle", when the drying gas (usually air) is not recirculated and is vented into the atmosphere. If an organic solvent is employed, a "closed cycle" layout is more suitable than an open one, since the risk of inflammability and explosion is higher in the latter when organic feeds are heated in the presence of oxygen [51].

The main advantage of the spray-drying technique is the ability to manipulate and control a variety of parameters such as solvent composition, solute concentration, solution and gas flow rate, temperature and relative humidity, droplet size, etc. So the optimisation of particle characteristics can be performed in terms of size, size distribution, shape, morphology and density, in addition to macroscopic powder properties like bulk density, flowability and dispersibility [51].

However, the spray-drying process may induce degradation of some macromolecular drugs as a result of a number of factors such as thermal stress during droplet drying, high shear stress in the nozzle and peptide/protein adsorption at the greatly expanded liquid/air interface of the spray solution.

Sebti *et al.* have developed a spray-drying technique to produce SLM. These SLM are composed of biocompatible phospholipids and cholesterol, and can be used as a carrier or filler to deliver drugs directly to the lungs via a dry powder inhaler [52,53]. SLM are obtained by starting from an ethanolic solution of lipids and drug, which undergo to spray-drying process. Compared to other SLM production methods, spray-drying produces particles which are characterised by smaller and more homogeneous particle size distribution. However, the produced particles are not always spherical and may have convoluted surfaces, asperities and cavities. The shape is influenced by the drying rate, the surface tension and the viscosity of the liquid which constitutes the liquid feed.

**11. Spray congealing**

atomisation device.

the molten fluid [57].

as a finely atomised spray cone [57].

basically consists of three parts (Figure 9): **1.** the ultrasound piezoelectric generator;

sound wave;

In the spray congealing technique, lipids are heated to a temperature above their melting point and the drug is dissolved or suspended into the melted lipid. The hot mixture is then atomised through a pneumatic nozzle into a vessel, where the atomised droplets can solidify in the form of microparticles [56]. In this technique some variations can be performed, especially in the

Techniques for the Preparation of Solid Lipid Nano and Microparticles

http://dx.doi.org/10.5772/58405

67

The Wide Pneumatic Nozzle (WPN) (Figure 8A) is an innovative external mixing atomiser: the molten fluid and the atomisation air get in contact outside the nozzle; the former is delivered to the orifice by the Venturi effect, while the latter is delivered in radial direction with respect to the molten fluid. The atomisation occurs where the air input converges with

The Air Pressure Nozzle (APN) (Figure 8B) is an internal mixing device: the molten fluid and the atomisation air get in contact in the mixing chamber inside the nozzle. The swirling fluid impinges on the plate and the interaction between the fluid and the air creates extreme turbulence in the chamber, and then flows through an orifice, where the droplets are exposed to shear forces, before coming in contact with a circular deflector ring and leaving the nozzle

**Figure 8.** A) Diagram of the external-mixing WPN. B) Diagram of the internal mixing APN

Another particular type of atomiser is based on ultrasounds [58]. The ultrasound-atomiser

**2.** an interchangeable booster allowing for the modification of the amplitude of the ultra‐

**3.** a titanium vibrating surface (sonotrode) on which the atomisation of the liquid occurs. The atomiser is also provided of an inductive coil to keep the sonotrode at suitable temperature.
