Optimizing the Precision Blending of Pharmaceutical Tablets
Tumble blender technology enhances the speed and homogeneous blending of tablets and capsules with trace levels of additives
To meet stringent regulatory requirements, such as the United States Pharmacopeia (USP), National Formulary (NF) or FDA, as well as production and budgetary demands, pharmaceutical manufacturers require high-volume precision blending of formulations on equipment that provides exceptional batch-to-batch consistency and repeatable results.
When manufacturing compressed tablets or capsules, however, the blending of several solid ingredients is easier and more uniform if the ingredients are approximately the same size. It is more difficult to create precise blends with trace ingredients (<1%) that are vastly dissimilar in size and density. In some cases, this might require doing multiple key blends in a time-consuming and costly process.
“We have to essentially achieve results within our blend uniformity requirements for every batch, whether the formula is predominantly active ingredients and several excipient ingredients, or predominantly excipient ingredients with very small amounts of active ingredient,” says Douglas Van Pelt, Senior Director of Operations at Sigmapharm Laboratories LLC, a privately held specialty pharmaceutical company based in Bensalem, PA that develops, manufactures and markets generic and branded products in tablet and capsule form. “Homogeneity is very important because our finished products are only as good as how well we blend them.”
Van Pelt adds, “A typical blend uniformity specification of 90.0% to 110.0% with a standard deviation of not more than 5.0% can be a challenge, but when you produce tablets with dosing as low as 5 micrograms like we do, that is a much more difficult endeavor. We are consistently and successfully doing that here.”
Fortunately, with tumble blending equipment that is engineered to meet the requirements of the application, the process can be simplified to rapidly produce a more precise, homogenous blend containing necessary trace elements. Such blending can not only eliminate the need for key blends, but also produce a better distribution of active ingredients.
Advancements in dryer technology can further improve quality and speed production, giving pharmaceutical manufacturers even greater control over the process along with additional savings.
The Limitations of Traditional Mixing Equipment
Traditional equipment such as plow, ribbon, and paddle mixers, which use blades or paddles to push material, face a number of challenges.
First, these mixers are limited to moving the material within the confines of their active area. The mechanics force the material bed outward, leaving dead spots inside the vessel where material moves more slowly or remains stationary.
Also, because these units are stationary, they have one stationary port at the bottom of the machine. This port has a long neck, which isolates the material from any processing force during mixing. Operators often need to empty the discharge area and manually reintroduce it back into the top of the mixer. This means some portions of the mix will receive more additive than others. In fact, such mixers cannot accommodate blends with 7% or less of any one ingredient.
Another issue lies in the positioning of the intensifier bars or fluidization zones. These intensifier bars should ideally be located in the mixing zone, where every particle passes through. Many times, however, traditional mixers have their intensifier bars in dead zones. When this happens, the material will not be fluidized properly, and active ingredients will not be incorporated throughout the batch.
Traditional mixers also tend to waste expensive additives. Because additives being
added to the vessel initially contact only a very small portion of the material, they get quickly absorbed into the material bed. The typical response is to add more additives to achieve the desired mix concentration, which drives up the cost.
Finally, because the pharmaceutical manufacturer is now wetting the material with higher quantities of the additives, a longer drying stage is required to achieve the targeted results.
The Benefits of Tumble Blending and Vacuum Tumble Drying
To address the deficiencies of traditional mixers, a growing number of pharmaceutical manufacturers utilize tumble blending. As a low-impact processing technique for handling sensitive or abrasive solids, tumble blending is commonly used to create precise pharmaceutical blends that contain trace ingredients (<1%) that are vastly dissimilar in size and density.
In contrast to traditional mixing, to eliminate dead spots, tumble blenders apply even turbulence in all corners of the mix through a combination of macro and micro blending. This can eliminate the need for key blends and produce a better distribution of active ingredients.
Macro blending is achieved by rotating the shaped vessel, allowing the material bed to fall away from the vessel’s walls. Tumble blender vessel shapes are engineered to create a repeatable pattern in which the entire bulk material moves to form a homogenous mixture. The blender moves at a precise speed, with the vessel wall at a precise angle, so that the material cascades over itself. There is no additional force from paddles, plows, or spiral ribbons – just gravity.
While this occurs, micro mixing (if needed) simultaneously proceeds via agitator blades located in the mixing zone center of the vessel, where fine processing in the material transpires. This allows for a gentle repeatable pattern that maintains a superior blending design while preserving the product’s physical characteristics. Together, the macro and micro mixing evenly expose each particle to six times more active blending per revolution than traditional mixers.
Because Sigmapharm’s Van Pelt had successfully used tumble blenders at a previous company, he trusted their capabilities.
“At my previous employer, I made a product that had a narrow therapeutic range using a 30 cubic foot tumble blender by GEMCO,” says Van Pelt, who notes that blend uniformity specification was a very stringent 95.0% to 105.0%, not a typical 90.0% to 110.0%. “The potency was 0.125 milligrams inside a 125-milligram tablet, and we were able to achieve blend uniformity in 15 minutes, with good repeatable results every time.”
GEMCO, a Middlesex, NJ-based manufacturer of tumble blending and vacuum tumble drying equipment, founded in 1916, is a technical expert in the pharmaceutical field. This includes understanding powder chemistry, physical attributes, and how powders will interact when blended. The company also has expertise in material handling and equipment integration into larger processing system as well.
“Over decades, GEMCO has essentially perfected tumble blending,” says Van Pelt. “They engineered the precise angles and speed of revolution needed to achieve proper blending inside the vessel and can adapt this based on product requirements.”
According to Van Pelt, Sigmapharm has effectively implemented a 30 cubic foot V blender and a one cubic foot slant cone blender from the tumble blender manufacturer.
With the preciseness of the technology, a V-shape tumble blender is capable of achieving a standard deviation of less than 2%, and a slant cone configuration can achieve a standard deviation as low as 0.33%.
Van Pelt also appreciates the unique Gemcomatic loading option that provides an operational advantage, compared to time consuming manual loading methods.
“The Gemcomatic lifts the drum containing the material to be blended against a gasket forming a dust-tight seal,” he says.
According to Van Pelt, the tumble blender then rotates until the drum is inverted while opening the discharge valve allows the contents to flow into the blender. The valve then shuts automatically and the emptied drum returns to the loading position. The latest version allows for a pre-programmed discharge sequence where the blender rotates back and forth several times in the discharge mode to further ensure that the drum empties completely. “The entire operation is essentially dust free,” he says.
With Sigmapharm’s success with tumble blenders, the company is now looking into purchasing more slant cone blenders as well.
“The slant cone blenders are more versatile when it comes to loading capacities and offer increased mixing efficiency when compared to other tumble blender configurations,” says Van Pelt.
In addition to tumble blending, a growing number of pharmaceutical manufacturers are finding that vacuum tumble drying equipment offers significant advantages as well.
Most pharmaceutical powders for processing contain solvents or free radicals that need to be removed to dry them effectively. Traditionally, to dry such powdered product, manufacturers use tray dryers, where wet material is laid in thin layers on multiple racks of heated trays.
However, this can lead to uneven drying as heat is applied. Also, volatile material may be trapped on bottom layer particles as a crust forms on the top layer of material. As the inner materials are insulated from the inert atmospheric drying process, they remain unstable.
As a solution, advanced vacuum tumble drying equipment can resolve such issues and speed drying while reducing cost. While typical tray drying relies solely on heat, vacuum tumble drying equipment like GEMCO’s utilize gas purging in addition to heat application.
In contrast to tray drying that essentially dries statically from the surface first and takes a long time to affect the entire mass, dynamic vacuum tumble drying dries pharmaceutical powder energetically as it rotates inside the vessel. This dries the powder faster, more evenly, with less labor, and is particularly helpful in reducing residual organic solvents.
Protecting Pharmaceutical Quality and the Bottom Line
Some pharmaceutical manufacturers may be inclined to use traditional blending and drying methods because of their familiarity with such systems.
However, those who take advantage of the superior capabilities of tumble blending and vacuum tumble drying systems will protect product quality, process control, and the bottom line to a degree not possible with traditional systems.
For more info, call 800-654-3626 in the U.S.; Fax 732-733-1175; email [email protected]; visit okgemco.com; or write to GEMCO at 301 Smalley Ave, Middlesex, NJ 08846 USA.