High shear mixing: the pharmaceutical solution?

Agitators are usually the first thought when a mixer is being specified, but a high shear rotor/stator mixer may be a better option, particularly for pharmaceuticals and cosmetics. Chris Ryan of Silverson Machines* explainsFaced with the task of selecting a mixer for a new application, it would not be uncommon for an agitator to be considered first. The diversity of impeller designs suggests that there is an agitator to suit most mixing requirements. Agitators can handle a wide range of capacities and viscosities, from relatively low powered paddle or propeller types which can be used on low viscosity duties, to slow speed anchor or contra-rotating scrapers suitable for viscosities of up to 500,000cps.But whatever the type of agitator, their effectiveness is limited to relatively simple tasks such as generating flow, blending liquids of similar viscosity, promoting heat transfer, and maintaining uniformity in a vessel. In many cases, these functions are secondary to the actual mixing task. Blending liquids of widely different viscosity, disintegrating and solubilising of solids, creating fine emulsions or suspensions, and dispersion of active ingredients and rheology modifiers cannot normally be achieved efficiently by agitation alone, but these applications do not necessarily warrant the power and expense of equipment such as mills or high pressure homogenisers. The purpose of this article is to illustrate how rotor/stator type high shear mixers can provide an efficient and cost effective solution for these tasks.Powder/liquid mixing is one of the major challenges to the pharmaceutical, biotechnology and cosmetics industries, where low volume, high cost raw materials such as active ingredients and rheology modifiers must be dispersed in the most hygienic and safe manner available.Many active ingredients are hazardous and require special handling; some are reactive and must be properly dispersed into the base fluid as rapidly as possible to prevent degradation or inactivation. Heat sensitivity is also a factor to consider, requiring tight control of process temperature, and keeping mixing times to a minimum.Rheology modifiers, such as gums and thickening agents, and emulsifiers have a strong tendency to form agglomerates when added to the liquid in the vessel. This is often exacerbated by operator error, for example by adding the powder too quickly. Agitators do not produce sufficient shear to break down these agglomerates, relying on a simple washing action to slowly dissolve or hydrate the outer layer and expose the dry material on the inside to the surrounding liquid. This not only results in long mixing times, but a totally lump-free and homogeneous product cannot be guaranteed.Incomplete hydration can also lead to undesired changes in product viscosity during storage. Maximised functionality can only be achieved if the powder is correctly dispersed and fully hydrated. This may require a degree of mechanical energy that agitators simply cannot deliver.These problems can be overcome by using high shear rotor/stator mixers. The types of mixer available divide into either those which operate immersed in the vessel, and external or `in- line' mixers. The workhead assembly consists of a centrifugal type rotor which rotates at high speed within a fixed stator. The size and shape of the openings in the stator and the clearance between the tips of the rotor blades and the inner wall of the stator determine the flow pattern and shear rates of the machine.POWERFUL SUCTIONDuring operation, the high speed of the rotor creates a powerful suction that draws both liquid and solid materials upwards into the centre of the workhead assembly where they are rapidly mixed. Centrifugal force then drives the materials to the periphery of the workhead, where they are subjected to a milling action in the clearance between the tips of the rotor blades and the inner wall of the stator. Intense hydraulic shear follows as the materials are forced out through the openings in the stator and projected radially at great velocity back into the body of the mix.This positive mixing action results in dramatically reduced processing times - in some applications, a 90% reduction can be achieved. Other benefits include improved product quality and consistency, and more easily reproducible results. Many duties can also be carried out at ambient temperatures, eliminating the risk of damage through holding at raised temperatures for long periods.Rotor/stator mixers are normally supplied with a number of interchangeable workheads and screens which impart different mixing characteristics. For example, a workhead with round holes gives an exceptionally vigorous mixing action, ideal for general purpose use, and particularly suitable for the disintegration of solids and the preparation of gels, suspensions, and solutions.PARTICLE SIZE REDUCTIONSlotted holes produce a more scissor- like shearing action, suitable for disintegration of elastic or fibrous materials. Fine screens are used in applications where particle or globule size reduction is required, and for the preparation of emulsions and fine colloidal suspensions. A single machine can thus carry out duties which in the past may have required several different pieces of processing equipment.Batch rotor/stator mixers are suitable for volumes of up to 2000l, depending on viscosity, as the power requirement for a high speed unit capable of circulating larger batches can be uneconomical. For large batches, a more cost-effective approach is to use an in-line mixer that operates outside of the vessel in conjunction with a simple agitator capable of maintaining mass movement.Immersion or batch mixers are mounted either on the top of the vessel or on a mobile floor stand. In addition to the range of standard units available, numerous specialist units have been developed for specific applications. These include mixers with inverted workheads for incorporation of powders which tend to float or raft; and tubular units for operation in sealed vessels, suitable for dispersion of active ingredients into inhalants, injectibles, and manufacture of vaccines and so on.The in- line rotor/stator mixer is based on the same principle as immersion mixers. Materials are drawn through the inlet into the workhead, subjected to intense high shear, then self-pumped either back into the vessel or to further processes downstream. The advantage of this system is that the machine's effort is concentrated on the small volume of material inside the workhead at any given moment and power is not wasted moving large volumes of liquid. Consequently, a smaller unit can process volumes which would require a much larger immersion type mixer. Bypassing the workhead is impossible, and aeration is practically eliminated.Another major advantage of this type of mixer is that they are easily fitted to existing systems. Typical configurations for external or `in-line' mixers are recirculation around the vessel, work on a single pass (or continuous) basis, or passing the product backwards and forwards between two vessels. The latter gives greater control as the product can be processed by a defined amount.The latest developments in the design of in-line high shear mixers include units with two or more sets of concentric rotors and stators, which can quadruple the number of shearing actions per revolution of the rotor. This results in greater reductions in particle size and substantially faster mixing times. Fewer recirculation passes are required and more products can be produced in a single pass. The use of two separate stators also allows users to optimise mixer configurations to suit individual processes.POWDER DISPERSALAn effective method of hygienically dispersing powders into liquids is to add the powder to a stream of liquid, which avoids the problems associated with adding the powder directly to the liquid in the vessel. The venturi principle is a well established system for achieving this. A basic venturi consists of a short cylinder, with a funnel at the top, an inlet for the liquid, and an outlet at the bottom. A smaller cylinder is located inside, forming two chambers connected by a tapering slot. The high speed flow of liquid through the slot from the outer chamber creates a vacuum in the inner section, which pulls the powder from the funnel into the fluid stream and simultaneously wets and disperses it. This can greatly reduce the formation of agglomerates, but cannot produce a completely lump-free dispersion.Silverson Machines combined the venturi principle with high shear rotor/stator mixing technology to produce the Flashblend powder/liquid mixing system. Powder is fed into a specially designed hopper which is separated from the venturi assembly by a valve. The base fluid is forced through the venturi at great velocity by a centrifugal pump.Once the valve is opened the powder is drawn by vacuum into the high speed fluid stream and both liquid and powder pass immediately into a modified high shear in-line mixer. This subjects the mixture to intense high shear before pumping the product into the process vessel or subsequent manufacturing stages. The result is that the powder is completely wetted before agglomeration can occur, and low density powders are easily incorporated. Powder handling is reduced to a minimum, and operator error is virtually eliminated. Flashblend units are designed for clean-in-place (CIP) and sterilise-in-place (SIP) operation and facilities to link the electrical control panel to process computers can be offered. Customisation to accommodate conveyors, bulk powder dispensing systems, dust extraction systems and flow aids for cohesive powders can be offered.Typical applications include manufacture of tablet coatings, pharmaceutical syrups, and dispersion of active ingredients and excipients for injectibles and inhalants. More demanding applications such as the production of sterile suspensions and dispersion of sterile powders into sterile liquids are also carried out using specially modified units.Manufacturers of process equipment are having to develop new products to keep in step with increasing demands for lower particle sizes, finer emulsions, single pass processing and faster processing times. Increasingly, pressure is being placed on equipment suppliers to conform to and even exceed standards such as cGMP and EHEDG, and also to provide levels of traceability and documentation, for example packages to comply with FDA regulations - which a few years ago would not have been deemed necessary.ULTRA-HYGIENIC MIXERSSeveral advances have recently been made in the design of `ultra-hygienic' rotor/stator mixers for the pharmaceutical, biochemistry and cosmetics industry. Silverson has launched a range of UHLS ultra-hygienic in-line mixers, to satisfy both current and future demands for the hygienic construction of process equipment. They are designed to comply with FDA, 3A, cGMP and EHEDG standards. The units offer all the qualities and flexibility of standard multi-purpose in-line mixers but include many additional features. These include self-draining bottom outlets, single piece inlet plate and stators, and hygienic metal bellows mechanical shaft seal.All wetted parts are in 316L stainless steel with crevice-free construction, electropolished to 0.5Ra. Stainless steel motors are available as an optional extra. The hygienic construction shortens the required CIP/SIP cycle time and minimises the use of cleaning chemicals. Manual cleaning and dismantling is not required, significantly reducing downtime and operating costs.This combination of proven techniques with new technology is one of the ways in which rotor/stator mixing equipment provides the solution to today's mixing problems. Joint research and development projects between manufacturers and mixing equipment suppliers are ensuring that they will also be capable of meeting the requirements of the future.* Chris Ryan, Silverson Machines, Waterside, Chesham, Bucks, HP5 1PQ, UK; tel [phone]; fax [phone]