Sunday, June 14, 2009


At first glance, some manufacturing processes seem to be a lot more complicated than they need to be. After all, why can’t we just place everything into a blender at one time and mix until homogenous? What’s the reason for all of these additional side blends like:
An active pre-blend?
A pre-granulation pre-blend?
A flavour pre-blend?
A colour pre-blend?
A glidant pre-blend?
A lubricant pre-blend?
In the “old days”, many pre-blends were simply performed by bag mixing and because of the relative ease and lack of additional equipment to prepare these blends, there wasn’t much resistance to performing these additional processing steps. However, “bag mixing” has NOT been an acceptable practice in the North American Pharmaceutical Industry for quite some time now. Validation requirements mandate that processing steps must be performed by mechanical means whenever possible to ensure consistency and reproducibility. As a result, in place of the trusty “plastic bag” and some shaking, pre-blending must now involve the use of appropriate equipment and properly documented procedures. Along with this has come the perception that the preparation of pre-blends may be un-necessarily adding time and cost to a process.
As a formulator and a consultant to the pharmaceutical industry, I also like formulations and processes to be as simple as possible. I don’t like to complicate a process anymore than is necessary. After all, “time is money” so saving time is important. However any time or money saved in the short term can quickly be erased with product and/or process failures. In some cases, it may very well be possible to forgo the use of pre-blends and not have an issue for a number of batches until suddenly, a problem arises that would never have happened if a pre-blend had been used. The use of the “pre-blend” is a valuable technique for making a robust process that will perform consistently batch after batch. Furthermore, the use of these “extra steps” does not necessarily always add “time” to a process; in some instances to be discussed later, a pre-blend may actually serve to speed up the overall manufacturing process.
The Active Pre-Blend:
The active pre-blend (also know as an “ordered mixture”) is one of the most useful tools in a formulator’s “bag of tricks”. It is primarily used for direct blending applications where the active ingredient constitutes a small portion of the overall formulation and has a particle size that is significantly smaller than that of the other components in the blend. By first blending the active with a portion of a suitable “carrier” excipient, it is possible to have the active “stick” to the carrier quite intimately. The forces holding the drug to the “carrier” may be electrostatic, van der Waals, gravitational, or a combination of these forces. The more substantial “carrier” excipient is then used to facilitate the distribution of the active ingredient during blending. For very small concentrations of active ingredient in a formulation (less than 10%), it is always advisable to build-up or “triturate” the active mixture progressively by blending it with increasing amounts of the remaining components to further enhance its ultimate homogeneity within the final blend.
Pre-Granulation Pre-Blend:
Most granulations involve an active ingredient that is initially dry blended with some other components prior to the application of the granulating solvent. This pre-blend is important to ensure that the granules to be formed have a reasonably consistent concentration of the active ingredient and other components prior to wetting. It is also important to assess the blend and determine whether a screening step should be inserted to remove any soft agglomerates that may have formed. If there are very fine and cohesive components in the pre-blend, they may agglomerate upon initial blending. If the agglomerate strength is weak, further blending will often cause them to break apart and become diluted with the remaining components of the pre-blend. However, if the agglomerate strength is strong enough, the agglomerates may survive blending. In this case, the pre-blend should be screened to remove the agglomerates and further blended for several minutes.
Without this blending/screening step, it may be possible to have granules containing widely variable concentrations of active or functional excipients that could ultimately affect the blend homogeneity and/or performance of the final blend and/or dosage form.
Flavour Pre-Blend:
Flavours or sweetening agents used in dry suspensions for reconstitution or chewable tablets often, depending on the type of flavour or sweetener used, comprise only a small percentage of the overall formulation. Obviously, a flavouring component must be considered a “functional” excipient so it’s important to ensure that it is distributed as evenly as possible in the final blend to yield a product with uniform organoleptic attributes. Additionally some flavouring components can be very fine, cohesive, and of a low bulk density with a tendency to agglomerate. Therefore, to ensure their incorporation and uniform distribution into a final blend, pre-blending and screening of these components with other excipients is essential.
Colour Pre-Blend:
The colorants in tablet blends are used in extremely small quantities. Additionally, they need to be very finely dispersed in order to achieve uniform coloration of the tablets while avoiding or minimizing any mottling effects. A good way to achieve this is through the preparation of a “colour pre-blend” in which the colorants are first blended with some other components of the formulation and subsequently milled or screened to produce the final uniformly dispersed colour pre-blend. This pre-blend is then subsequently added to the main mixture for final blending with the remaining components of the formulation.
Glidant Pre-Blend:
The most commonly used “glidant” in solid oral dosage form formulations is colloidal silicon dioxide; also know by the trade names of Cab-o-Sil or Aerosil. This material is extremely effective in improving the overall flow characteristics of a blend by coating the surfaces of its components thereby reducing their inter-particulate friction. The effective concentration required to perform this function is usually below 0.5% (w/w). Colloidal silicon dioxide is an extremely fine material with a bulk density of well under 0.1 g/cc. It also has a tendency to form soft agglomerates and must be screened prior to its incorporation into a blend. Without pre-blending this material with some other, denser components, screening of colloidal silicon dioxide alone is virtually impossible, or if not impossible, it is extremely time consuming and inefficient. A lot of the material becomes airborne and is lost. Furthermore, material passed through the screen promptly re-agglomerates on the other side of the screen, negating the whole purpose of screening in the first place. This is a case where a pre-blend of cab-o-sil with another component of the formulation in a ratio sufficient to densify the glidant will dramatically improve its passage through a screen and dilute the material sufficiently to prevent its re-agglomeration after screening.
Lubricant Pre-Blend:
Magnesium stearate is still one of the most widely used lubricants in the pharmaceutical industry because of its effectiveness. It is usually used at levels of less than 1% (w/w) and like colloidal silicon dioxide, it needs to be screened prior to its addition to the batch. Although a minor component in terms of concentration, magnesium stearate can cause many problems if not incorporated into a blend properly. Over blending with this lubricant can dramatically and adversely affect the compressibility and dissolution characteristics of some formulations.
Therefore, blending times with magnesium stearate are always kept to a minimum. But for the lubricant to be effective, it still needs to be distributed throughout a blend. One way to achieve this is through the use of a lubricant pre-blend in which magnesium stearate is first blended with a small portion of another component in the formulation for a brief period of time, and then screened prior to its addition to the main mixture for final lubrication. The pre-blend here serves two major purposes in that it improves passage of magnesium stearate through a screen (compared to screening magnesium stearate on its own), and it facilitates the distribution of magnesium stearate throughout the final blend while keeping the lubrication blending time to a minimum.
A specific case that shows the value of a lubricant pre-blend is the addition of magnesium stearate into a high shear mixer for lubrication (Although high shear mixers are better known for granulating than blending, there are some cases where they are used for this). If the material is added on its own to the surface of the material in the high shear mixer, a good portion of the material will stay on the surface during mixing and form soft agglomerates or balls that can be seen when the mixer is opened up. This is due to:
the material’s low density relative to the other components.
a lack of enough vertical mixing action to pull the magnesium stearate into the blend.
the very short mixing time required, especially in a high shear mixer.
A pre-blend of the lubricant with other components prior to screening and addition to the mixer would certainly address this problem by densifying the magnesium stearate sufficiently to be drawn into the mix in spite of the limited vertical mixing with the high shear mixer.
Other pre-blends:
Whenever a small concentration of a component is to be added to a formulation, first preparing a pre-blend or incorporating this component into another appropriate pre-blend will facilitate its distribution. Failing to do this may result in this component being poorly distributed. Unlike an active ingredient, the lack of homogeneity of a functional excipient is not as easily determined by routine analytical testing and may only be found when strange and inconsistent problems arise in the final product, the ones that are very difficult to understand, investigate, recognize, and resolve.
To summarize, the use of a pre-blend really does serve a valuable purpose in modern pharmaceutical processes. The specific need or lack of need for a pre-blend needs to be evaluated on a “case by case” basis. There actually are some products where you can virtually throw everything into a blender and blend to completion without any problems, but these are rare. Although they may take a little more time and effort, the investment of an appropriate pre-blend step may ultimately save you from a lot of problems you could otherwise experience.

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