Scanning electron microscopy (SEM) provides a qualitative assessment of size, shape, morphology, porosity, size distribution, crystal form, and consistency of powders or compressed dosage forms (see Figure 1). This information can be correlated to assess dissolution behavior, bioavailability, and crystalline structure. SEM images also help analysts determine whether particles are maintaining desired physical characteristics during processing, including after compaction or direct compression (see Figures 2, 3).  

As an analytical tool, electron microscopy in general has changed extensively, especially with the incorporation of automation and software. An SEM instrument in the 1940s, for example, had a resolving power of about 50 nm and a magnification of 8000×. Today, SEM devices have resolving power of 1 nm and a magnification as high as 400,000× (1). Simple, low-end SEM instruments now have touchscreen user interfaces and provide a fast visual inspection of samples. On the  very high end, transmission electron microscopes have recently demonstrated the capability to identify individual atoms (2).  

Figure 1: (FIGURE COURTESY OF FEI COMPANY) 

"Commonly called the laboratory 'workhorse,' microscopes have come a long way to the present day in terms of advancements in automation, higher precision, and better resolution," says Sharon Mathews, a research associate for Technical Insights at 

. "With digital imaging gaining momentum in the recent years, microscope manufactures are now designing microscopes with image analysis at the forefront" (see sidebar, "Microscopy advances").  

Mathews attributes the following factors as primary drivers to increasing use of microscopy:   

Innovations in digital imaging: "Digital imaging offers numerous capabilities to the microscopy market opportunities in terms of enhanced features to extract information or modify the images captured. The convergence of digital imaging and information technology is enabling microscope manufacturers in tailoring their product offerings to suit the specific requirements."

Cost effectiveness and ease of operation: "With the diversity of the end-user and lower cost, the microscopy market is steadily growing. Simple automated systems are now increasing the usage of microscopes." 

Novel applications: "The clinical market, namely, pathology, cytology, and hematology have greatly relied on microscopy over the years. Owing to new imaging applications and research funding, the pharmaceutical, academic, and government laboratories are now propelling the microscopy market. Live cell imaging, molecular imaging enabling identification of events at molecular level and specific applications such as dynamic behavior of cells ... has been responsible for the rapid progress of the microscopy market" (3).  

Figure 2: (FIGURE COURTESY OF FEI COMPANY)    

 Traditional SEM analysis required trained operators who knew how to find and sharpen images using various controls on the instrument. "A lot of these labs are spending thousands of dollars looking at samples; and the lead time and preparation time needed to take these samples to contract labs is likely quite time consuming," says Joe Fillion, 

 (Hillsboro, OR). In 2007, FEI launched "Phenom," a tabletop point-and-shoot version of a traditional SEM. "We redesigned the entire user interface to be very intuitive. Operators simply touch the area you want to look at and you click a picture. Whereas a traditional method you may be turning dials for many minutes or hours in some cases. We're finding that pharmaceutical companies are using this in place of outsourcing their SEM work to analytical laboratories," says Fillion.  

Figure 3: (FIGURE COURTESY OF FEI COMPANY) 

Traditional optical microscopes are incapable of capturing an image of the ever-smaller particles the industry is currently producing. "You can go to about 1000×, but it's very featureless and very flat," says Fillion. "Most of our customers want to see particles in the 3000–8000× range, where most of our customers use it. As these grain sizes get smaller, we're seeing a lot more interest in SEM. I've been told on a number of occasions that, as these particles get smaller and smaller, scientists want to be able to see the samples they are evaluating. They can do laser scattering to determine the distribution, but a picture is a powerful thing to see." 

 Sophisticated SEM instruments generate images uses low-energy secondary electrons "pulled" from the sample surface after impact with the electron as well as electron back scattering (elastic scattering from the high-energy electron beam) to generate an image. Trained operators use this combination to obtain detailed images and elemental information (see Figures 4, 5). Gaining clear definition of particle edges allows measurement of various parameters characterizing particle size, including the diameter and particle shape measurements encouraged in 

Figure 4: (FIGURE COURTESY OF FEI COMPANY) 

Resent advances in high-end SEM instruments include the coupling of SEM visualization with statistical software. The software automatically provides direct measurements for several characterization parameters ("Quanta Morphologi," FEI Company and Malvern Instruments). The data for each particle can be stored with the image in a database and viewed at a later time.  

Figure 5: (FIGURE COURTESY OF FEI COMPANY) 

To provide the resolution necessary to generate images that can be statistically analyzed, FEI had to modify its detectors. "The high energy primary electron beam causes low energy (secondary) electrons to emerge from the specimen and are then accelerate (pulled) toward the detector," says Ben Lich, strategic marketing manager of SEM and DualBeam at FEI. Using a standard secondary electron detector  the particles in the image appear to be illuminated from one side only, resulting in a dark and a bright side. The company engineers created a special symmetrical secondary electron detector that eliminates this effect. "But when you do that, normally you will get a dark side of the object and a bright side of the object, with the bright side being the side facing," says Lich. "For particle detection this is not desired because you want a good impression of the outer area of the particle so you can do a precise measurement." Engineers then made a special detector that collects a secondary electron symmetrically around the column and around the primary beam, thereby providing uniform illumination of the entire specimen surface and a good definition of the edge around the entire particle. 

The advances in SEM instrumentation are making it easier for tablet manufacturers looking into adding SEM instrumentation to their quality laboratories. "With a low-entry type of tool, people get exposed to electron microscopy and may then follow with a higher-end instrument," says Lich.  "They find that it is not as hard as some people think it is." 

All You Wanted to Know about Electron Microscopy

 2.  D.A. Muller et al., "Atomic-Scale Chemical Imaging of Composition and Bonding by Aberration-Corrected Microscopy," 

Articles

Recent advances in SEM, particularly the incorporation of automation and software, have made simpler, lower-end SEM instruments easy to operate and have improved the capabilities of larger, sophisticated instruments.

Developments in Scanning Electron Microscopy for Tablet and Granule Characterization

Despite advances in alternative methods, tablets remain the most widely used method of drug delivery. Well-manufactured tablets are extremely stable, provide excellent dose uniformity, and are well accepted by users. Formulation development is, however, challenging, with the apparent simplicity of a tablet belying the challenges of its manufacture.  

Tablet production demands the transformation of a relatively free-flowing powder into a compressed solid form. Stability is a defining performance characteristic, but rapid dissolution is also essential for efficient 

 delivery. Other properties such as taste, smoothness, and shape must also be taken into account. As a result, tablets are complex multicomponent blends of binders, glidants, lubricants, disintegrants, sweeteners, flavors, pigments and, of course, active pharmaceutical ingredients (APIs).  

Tableting has a long history, and substantial experience has been gained over many decades. Processors and formulators have traditionally relied heavily on this experience, taking an empirical, as opposed to knowledge-based, approach. Now, with the introduction of quality by design, the situation is changing. There is recognition of the importance of more fundamental knowledge and of investing heavily in its development. 

Taking tableting as an example unit operation, this article explores how modern powder characterization techniques can provide valuable information that enhances understanding. Measuring dynamic, bulk, and shear properties of powders allows identification of the parameters that best define product performance, both during processing and in final application. This knowledge underpins fast, successful formulation development and effective process control.

Direct-compression tableting is a common method of solid dosage form manufacture. With this approach, the constituents of the tablet are blended and are then fed directly to the press. In most cases, however, the formulation cannot be used without first completing several preprocessing steps such as a wet or dry granulation. Granulating the blend reduces problems such as segregation and improves flow behavior by densifying and increasing the size of "particles." 

Figure 1 shows a schematic of a single-sided rotary tablet press. Powder flows from the hopper or intermediate bulk container, down the transfer chute, and onto the table. The blend is distributed through the feeder and flows gravimetrically into the die. As the table rotates, excess powder is scraped away from the top of the die before the punches apply compression to create the tablet. The tablets are ejected before the dies reach the filling point again. 

Because the aim is to produce tablets of defined weight, geometry, hardness, and composition, consistent flow from the hopper onto the table and through the feeder into the die is necessary. A free-flowing powder may avoid blockages and intermittent flow, but it also may be more prone to flooding or segregation (the separation of dissimilar-sized particles). 

During the compression stage, the goal is to produce a stable form that can be cleanly ejected from the press with minimal force. Achieving this objective makes other aspects of powder behavior important. For example, if excess air is retained in the die and compressed along with the powder, then it may expand once the compression force is removed, causing the tablet to burst or cap. Blends that release air relatively easily are therefore preferred. Tablet strength also is directly affected by cohesivity—compressive strength. A blend with low cohesivity may form a weak, unstable tablet, while highly cohesive materials may adhere to the tablet press and cause variability in fill weight. 

This brief analysis highlights some of the compromises involved in addressing just a few of the issues connected with processing and final product quality. Other performance criteria overlay additional and often conflicting priorities. For example, fines may be attractive to a formulator because they help achieve rapid dissolution and increase tablet-compression strength but are problematic during processing because  they increase the risk of cohesive behavior and affect productivity. Balancing these variables is the formulator's art. 

Experience-based formulation is possible, and indeed still common, but greater emphasis on effective processing and early definition of the design space is reducing the scope for error. Formulators need tools that provide relevant data at an early stage, thereby allowing rationalization of experience in terms of quantifiable parameters. This result gives insight and understanding, promoting a knowledge-based approach. Processors too require data to understand the reasons for both good and poor performance at the press. Such knowledge feeds back into formulation development and facilitates the successful processing of challenging blends.

It is no coincidence that the majority of powder processors share with tablet producers a heavy reliance on experience-based manufacture. Powders are challenging materials to characterize because their behavior depends on so many variables, including the properties of the particles themselves (e.g., hardness, porosity, size, shape, surface texture) and system variables such as air content and humidity, for example. 

The complexity of powders makes a first-principles analysis of behavior beyond our current capabilities and severely challenges the relevance of single-number characterization. A more robust approach is to measure powders using reproducible methodologies that quantify certain aspects of behavior in process-relevant ways. Relating the resulting data to product performance allows the specification of powders that will perform in the required way in a given process environment. 

A visual comparison of two different types of lactose—one spray dried, the other finely milled—provides a qualitative evaluation of flow behavior. Spray-dried lactose, with relatively large spherical particles, moves easily around a jar. The finely milled sample, with smaller angular particles, forms agglomerates, and its flow is more erratic. The finely milled sample is highly cohesive, but the spray-dried sample is not. 

Simply pouring these samples into a vessel or funnel confirms these observations. Nonetheless, if attempts are made to force the powders through an orifice (with a diameter significantly larger than the particle size of the materials), then behavior is markedly different. Under these conditions, the finely milled lactose will extrude through the orifice like a paste, and the spray-dried lactose will tend to resist this forced flow. Selecting a lactose with good flow properties may not be the straightforward task it initially appears. 

Table I shows a selection of shear and dynamic parameters for both samples. Shear properties are determined by measuring the stresses required to rotate one plane of a (usually) consolidated sample against another. Dynamic characterization, on the other hand, involves measurement of the forces and torques required to maintain a specified flow pattern under various test conditions. With dynamic instruments (e.g., powder rheometers), samples can be measured in an aerated state, giving information for a broad range of applications. Comprehensive details of testing methodologies are provided in Reference 1. 

Finely milled lactose is usually cohesive; that is, the particles stick to one another and to other surfaces such as container walls, thus inhibiting consistent flow. Shear testing measures parameters such as cohesion and unconfined yield strength, thereby quantifying the higher cohesive strength of the finely milled lactose. Here, though, the focus is flow, so which parameters define flow behavior rather than the more general parameter of cohesivity? 

Specific energy (SE) is a flow parameter measured under noncompacting conditions by rotating a rheometer blade upward through an unconfined sample. Like most dynamic properties, it is measured using a conditioned sample—one that has been prepared by being made to flow in a low-stress manner to establish a homogenized, slightly aerated, bed of powder. Conditioning before the measurement ensures a consistent baseline state, essentially eliminating any effects associated with sample loading or processing history such as previous levels of consolidation. The conditioning step is essential to ensure the best possible reproducibility. The SE for the spray-dried lactose is much lower than that for the finely milled sample, which indicates that it will flow more readily when unconfined and when the flow is initiated by gravity, such as when tumbling in a jar or flowing into a die during tablet manufacture. 

By contrast, basic flow energy (BFE) is measured by pushing a rheometer blade down through a sample, thereby inducing compaction against the base of the vessel (confined flow). BFE values are highly differentiating and in this case clearly demonstrate that finely milled lactose will be superior in a confined forced flow processing (see Table I). Other measurements clarify the reasons for this apparent reversal in relative flow behavior. 

Table I: Bulk, shear, and dynamic parameters for a spray-dried lactose and finely milled lactose. 

The compressibility of the finely milled lactose is much higher than that of the spray-dried sample. In this case, compressibility was defined as the change in bulk density induced through the application of a normal stress (<20 kPa). In general, finer cohesive materials tend to have a higher porosity or air content, so compression has a marked effect, forcing out air and increasing bulk density. Conversely, the spray-dried lactose has minimal cohesion and in its conditioned low-stress state, packs efficiently. The gravitational forces acting on each particle exceed the cohesive forces between them and thus minimizes the number of void spaces in the powder. The result is a stiff powder bed for which density changes little as a result of compression. 

These differences in compressibility provide a rationalization of the measured BFE values. With the finely milled lactose, the compacting motion of the blade generates only localized compression and the flow zone is relatively small. The spray-dried sample, on the other hand, does not easily compress, so the compacting force is transmitted through the sample. A large flow zone is created with many particles in motion simultaneously, thereby resulting in a high BFE. 

It is clear that flow behavior can vary and can be characterized in different ways, even when complicating factors such as aeration, consolidation, and humidity are not considered in any detail. Powders are not intrinsically good or bad, but it is the match between material and process that is crucial. The key to successful formulation and processing is identifying and controlling the parameters that define performance for any given application. This information is uncovered by correlating various powder properties with experience  from the existing skill base or experimental work. The following examples highlight correlations between measurable parameters and aspects of tableting.

Flow additives such as colloidal fumed silica and magnesium stearate are widely used to improve the flow properties of a blend. An incorrect level of flow additive can be detrimental, with too little producing suboptimal flow and too much promoting lamination of the final tablet. It is understood that lamination, breakage along a plane, occurs when flow additive separates into a layer within the tablet, a process accentuated by high additive levels. Optimizing additive concentration is therefore important.

Figure 2 shows how BFE varies with flow-additive concentration for two different blends that exhibit markedly different behavior. BFE is an extremely sensitive detector of differences in flow behavior and therefore ideal for this type of study. With sample 1, BFE passes through a minimum where there is clearly an optimum concentration. With the second sample, the optimal level may be similar, but it is clear that low additive concentrations have little effect. 

Particle morphology can be a dominating factor in terms of how a material responds to a flow additive (see Figure 3). The relatively smooth particles (A to D) will exhibit the behavior shown by sample 1. As flow-additive levels increase, the large particles become more uniformly coated with the smaller lubricating particles, and flow energy decreases steadily. Once all surfaces are coated, excess additive builds in the void spaces, resulting in mechanical interlocking and increased cohesion, hence flow energy begins to increase again. 

The irregularly shaped particles (E to G) are initially unaffected by the inclusion of additive because the small particles are unable to provide an effective lubricating effect. Only when sufficient additive has been added to lubricate the contact points between the larger particles is a rapid reduction in flow energy observed (sample 2).

Flooding describes the uncontrolled flow of aerated powder, which can be hazardous and is mostly undesirable. Aeration plays an instrumental role in flooding because the air between the particles acts as a lubricant and inhibits the mechanical interlocking that would normally result in a stable bed. Flooding is common with fine but noncohesive materials that easily pick up and retain air.

It is clear that when flooding occurs, little energy is required to make the powder flow. Consequently, measuring flow energy under aerated conditions is effective in highlighting possible problems. Figure 4 shows flow energy as a function of air velocity for two different materials. Measuring the affect of aeration is simple with a powder rheometer because air can be fed at a controlled velocity through the sintered base, up into the powder sample, during testing.

The flow energy of sample A falls markedly with aeration, and that of sample B remains relatively unchanged (see Figure 4). This decrease in flow energy with increasing aeration is symptomatic of noncohesive powders that are prone to flooding and is particularly problematic when combined with a low BFE. Generally speaking, powders with an aerated flow energy ,10 mJ are more likely to fluidize and flood. 

Although it is tempting to suggest that flooding is avoided by preventing aeration, this is not a practical proposition because air content cannot be precisely controlled during processing. Powders can easily pick up air, for example during blending or emptying from a keg.

Although a degree of aeration is beneficial because it encourages continuous flow through the press, it is desirable that any entrained air is released easily as the powder settles in the die and is compressed. This release of air enhances dose-weight consistency and prevents tablet breakage that may occur when compressed air is released upon ejection of the tablet from the press.

Figure 5 shows the deaeration characteristics of three different lactose samples. Once the air supply has been removed, it is clear that both the spray-dried and coarsely milled lactose rapidly release air, and flow energy returns to stable, conditioned values quickly. The finely milled lactose, on the other hand, deaerates much more slowly because the air takes longer to permeate out from the powder bulk. These data correlate directly with the likelihood of tablet capping as a result of air release postcompression.

A process closely related to direct-compression tableting is the production of compacts for blister filling. Like tableting, this process involves die-filling and subsequent compression of a dose. The compressing force, however, is much less: around 10 kPa rather than the MPa stresses used for tableting.

For this process, an optimum level of cohesion and other mechanical properties are required to form stable compacts or plugs under the application of moderate compressive force. Excessively cohesive materials adhere to the punches, thus compromising dose uniformity and production rates. Figure 6 shows measurements made during an experimental investigation of the effect of flow additive on the properties of a pharmaceutical blend.

As the concentration of flow additive rises, compressive strength (as measured by shear stress) falls. Initially the material is so cohesive that it adheres to the punches during compression. As compressive strength falls, there is a range over which good-quality compacts are produced, but then, below a certain compressive strength, the compacts fall apart upon ejection. The optimal compressive-strength range is clear.

The pressures on the pharmaceutical industry are catalyzing change. Designing quality into the product and manufacturing process (quality by design), monitoring and controlling processes to consistently produce the correct material (process analytical technology), and the long-term trend toward continuous processing are all evidence that the sector recognizes the need to work more efficiently. The success of such approaches ultimately rests on the development of better understanding.

The current trend within the pharmaceutical industry toward more efficient development, manufacturing, and specification is fueling demand for analytical tools that provide highly relevant information. Effective powder characterization has a valuable role to play.

Powder Characterization for Formulation and Processing

Granulation is one of most important unit operations involved in solid dosage form manufacturing and several granulation technologies have been developed. Traditionally, an aqueous solution of a binder is sprayed on the powder during mixing in a granulator. In 2003, The Dow Chemical Company (Midland, MI) introduced foam technology for delivering aqueous binder systems in high-shear and fluid-bed wet granulation applications (1) (see Figure 1). A foam generator can be set up with a binder solution tank and high-sheer granulator to introduce the binder as a foam rather than spraying or pouring in binder onto a moving powder bed. Last year, 

 published an article discussing the scale-up of foam granulation technology in a high-shear process (2) (see Figures 2, 3). As a follow-up to that discussion, Paul Sheskey, research and development leader at Dow, provides an update on foam granulation, including process challenges the company has encountered from industry and future applications of the technology. 

Q. What was the motivation to develop a new granulation technology versus conventional granulation techniques?

 We became aware of the granulation needs of the industry through the sale of our functional polymers, whether it was for granulating a matrix controlled-release system using METHOCEL cellulose ethers polymers or immediate-release granulation using our low molecular-weight polymer family. A significant issue experienced throughout the industry, as represented by a large number of research papers published throughout the years, is the uniform distribution of the liquid/binder combination evenly throughout a moving powder bed. It may appear to be uniform when spraying, but it doesn't always happen. We've referenced papers by Litster and Hapgood that showed this is not a very easy thing to accomplish. In their studies they proved it at the very basic level. 

Manufacturers of pharmaceutical granulations would call us saying that they were having trouble either during their formulation development work or in a production setting.  We determined that a significant proportion of their issues directly related to the even distribution of the granulating liquid. They have hydrophilic polymers in their formulations that tend to preferentially grab the water in the granulating liquid and sometimes this would interfere with its uniform distribution. So we investigated various atomizing techniques when spraying the binder solutions. We did a lot of work to better understand the issues so that we could provide the pharmaceutical formulators specific, hands-on type of advice. However, even that was not doing as good a job as was needed for the pharmaceutical industry. Then we discovered foam technology for granulation applications in our laboratory. My colleague and co-inventor, Colin Keary has a lot of expertise in the area of foams when he was a scientist in the oil well industry. Working in combination, we serendipitously came up with this for pharmaceutical granulating. That satisfied the need of evenly distributing the liquid binder phase much better than a spray could do. That is a recognized need of the industry and that is what foam helps with tremendously. 

Q. What are some of the unique  challenges and applications of using foam granulation?

The pharmaceutical industry is very conservative when it comes to new applications and new technologies. Our job has been to educate people on the use of this technology globally. This has become better, but it always takes time. We've seen that once it gets into a company, they'll also use it for the everyday-type granulations.

We have found that most people are using it for new applications and some are looking at it as replacement for current methods, especially because of potential cost savings. For example, the technology does not use nozzle systems. The technology also has been helpful in some cases where there may be difficulty in scaling up a process because of over-wetting and the number of nozzle systems that may need to be used. Foam technology has been proven to scale very easily for both immediate release and matrix controlled-release products.  The technology also uses less water per granulation, which means less drying time and less impact on the environment.

This technology appears to help solve the issues that people have been having with wet granulation of highly water-soluble and even very poorly water soluble drugs. These issues include areas of concentrated over wetting and over granulated products. The technology seems to provide a better and a wider endpoint in which to granulate to even with some very difficult actives that we work with, including natural ingredients in the nutritional supplement industry.

People have approached us who may initially have had an issue with a particular active ingredient that is water sensitive but they still want to go with an aqueous system because of EPA (Environmental Protection Agency) concerns. Or they have issues with distributing a very low concentration drug level—milligram or microgram per tablet—in a powder bed, which has been an issue for years in the industry. People have used many techniques to solve the low-dose distribution issue. Foam does a good job of solving this problem because it is a good carrier of components, not just the liquid itself and the polymer, but it also can carry active ingredients at very low concentrations.

Q. There is interest in converting some unit operations from batch processing to continuous processing. Has continuous application of foam granulation been explored?

One of the application areas we are looking into is continuous granulation using foam. Some manufacturers of continuous granulation equipment have approached us regarding possibly working with them to use foam to deliver the liquid binder system to a continuous manufacturing system. If you have a continuous granulation, definitely one of your key questions is whether you are getting uniform distribution of a binder under short residence times during the process. This is one area where foam technology might be able to provide some advantage. 

Q. Are there any remaining regulatory issues or concerns with foam granulation technology?

We have met with and have presented this technology to the US Food and Drug Administration's Center for Drug Evaluation and Research. They were very excited and approved the concept because they could see how this technology could resolve issues in getting better reproducibility of granulations. They are very supportive of the technology, and they have told us that if people come in using this technology, it would not slow down any approvals.

Q. What are the future plans for this technology? Will its applications be extended?

One of the things that we are continuing to develop and that we have patents for is to fine-tune the technology for coating of tablets using foam rather than conventional spraying. We are working with equipment vendors on that. On the granulation side, we are continuing work on using foam to distribute low-dose drugs uniformly within a powder bed or to improve content uniformity of low-dose active pharmaceutical ingredients. We are also working with fluid-bed applications.

1.  P. Sheskey et al., "Foam Technology: The Development of a Novel Technique for the Delivery of Aqueous Binder Systems in High-Shear and Fluid-Bed Wet-Granulation Applications," poster presented at AAPS Annual Meeting and Exposition, Salt Lake City, UT, Oct. 26-30, 2003. 

2.  P. Sheskey et al., "Scale-Up Trials of Foam Granulation Technology—High Shear," 

Paul Sheskey of Dow Chemical provides an update on foam granulation technology.

Foam Granulation Technology Update and Future Applications

Tablet-tooling inspections present many challenges. Inspecting punches and dies can be time-consuming and costly for tablet manufacturers. Sometimes the cost is prohibitive and leads to cutbacks in the frequency of inspections or even eliminates them entirely. This situation is unfortunate because the quality of the tablet is determined in large part by the quality of the tooling. Every aspect of tablet production may be set up and run perfectly, yet if the tooling is of poor quality, the tablet quality will suffer. The only way to truly determine that tooling conforms to allowable specifications is to inspect the tooling for defects and excessive wear. Inspection data represent an additional challenge of the tool-inspection process. Often, inspection results are recorded on paper stored in a file and never seen again. Improvements in equipment  and computer-software technology, however, have helped to make in-process tooling inspections more efficient and productive for tablet manufacturers (1, 2). 

Tooling inspections by tablet manufacturers

A misconception is that the tablet manufacturer needs to conduct in-process tooling inspections in the same manner that a tool manufacturer conducts them. The tooling manufacturer must inspect all dimensions to ensure that the tools were manufactured to industry standards. The tablet manufacturer, however, does not need to inspect all punch dimensions and can concentrate on a few critical dimensions. Once dimensions  have been confirmed during the tool-manufacturing process, only a few key wear points are of concern. For the most part, in-process inspections performed by the tablet manufacturer should be limited to the working length of the punch and cup depth as these two dimensions have the greatest impact on tablet quality (see Figures 1–3). The remaining dimensions, such as barrel diameter, tip dimensions, and overall length, are not critical because they do not change often or are difficult, if not impossible, to inspect accurately and consistently.  

Figure 1: (FIGURE COURTESY OF THE AUTHOR) 

 Measuring the working-length of a new punch is different than measuring the same dimension of a worn punch during an in-process inspection. Unlike other dimensions, the working-length tolerance applies to each punch only in relation to the other tools within the set. Working length is graded on a curve. For example, if new tools are designed to have a working length of 5.230 in. with a tolerance range of 0.002 in. (i.e. ± 0.001 in.), the analysis of new tools simply requires that each punch have a working length of at least 5.229 in. but not greater than 5.231 in. Worn tools, however, can wear to a length that is less than 5.229 in. as long as they all are within the 0.002 in. range. The key point to consider is the total range of 0.002 in. provided by a working-length tolerance of ± 0.001 in.  

Figure 2: (FIGURE COURTESY OF THE AUTHOR) 

Continuing the example, although working lengths of 5.228, 5.227, and 5.226 in. are below the lower limit of 5.229 in. for a new tool, these dimensions are still within the 0.002 in. range of each other. Manually calculating which tools are within each other's specific tolerance range and at what working length can be difficult and time-consuming. Using a computer with the proper software, however, can make the process much easier. Moreover, using the first punch as the basis for comparison and simply comparing the measurements of the remaining punches with the first is not recommended as the condition of the first punch is not always certain. After completing an entire inspection, it would be unfortunate for the tablet manufacturer to discover that the first punch was the most severely worn, but was used as the comparative basis for the entire tool set.  

Figure 3: (FIGURE COURTESY OF THE AUTHOR) 

 Data entry presents various obstacles during the inspection process. Overcoming these obstacles requires that the process be as efficient as possible. Several methods for capturing inspection data directly into a personal computer's database or spreadsheet may be used rather than typing or writing the measurements by hand. The most basic approach is to connect the measuring gauge to a USB-connection tool activated by a button or foot pedal. With this approach, the inspector transfers the value (i.e., the reading) on the gauge directly to the computer database or spreadsheet whenever he or she pushes the button or steps on the foot pedal. The inspector no longer needs to take the time to write or type the inspection measurements. This approach eliminates the potential for typographical errors, which are common when dealing with measurements that have three- or four-place decimal-point accuracy. Some inspection systems provide greater convenience and efficiency by enabling communication between the measuring devices and the software through a serial cable or USB connection. Usually, systems with sophisticated communication can eliminate the need for the technician to step on a foot pedal or press a button to capture data. 

Storing inspection data electronically facilitates easy data retrieval for review or analysis. Inspection results with allowable tolerances can be readily compared by clicking a  mouse to produce a report that lists each tool and identifies  any measurements that exceed allowable tolerances. This automated approach is much better than visually reviewing a printed document for such occurrences. Summary information such as average, minimum, and maximum dimensions and range can be included in the automated report. An automated system can easily issue a report that compares each dimension and calculates the difference between two inspections.  

 Tool matching is an excellent example of how an automated system can utilize inspection data that have already been collected to generate reports which are difficult to produce in a manual system. The purpose of matching the longest upper punch with the shortest lower punch based on their working lengths is to allow the tablet manufacturer to minimize deviations in tablet thickness and hardness (see Figure 3). The process consists of sorting the upper punches in sequence from longest to shortest and sorting the lower punches in opposite order (i.e., from shortest to longest). If the working-length measurements collected during the last inspection are stored electronically, producing this report takes only a matter of seconds (see Figure 4). Completing the process manually would take much longer and possibly prevent a tablet manufacturer from improving consistency in tablet thickness and hardness.  

Figure 4: (FIGURE COURTESY OF THE AUTHOR) 

 Establishing a comprehensive database of a tablet manufacturer's entire tooling inventory creates a great source of information. By transferring electronic files between computer systems, data can be passed from the tool manufacturer to the tablet manufacturer, downloaded, and integrated directly into a tooling database. No manual data entry is required. An electronic tooling database can include information such as size, shape, steel type, purchase order number, tolerances, cup configuration, embossing, and inspection data. An additional benefit of using a database to store tooling information is that it eliminates the need to retype the same information every time that it is needed for a report or an inspection. 

Laser technology allows tooling to be inspected without the inspector touching the tip of the punch. Relatively low-cost laser measurement devices may be incorporated for a noncontact inspection. In a noncontact inspection, various tool dimensions are measured without a gauge probe ever physically touching the surface of the punch tip. This technique  eliminates the potential for scratching the sensitive tip face of the punch. Typically, a punch tip with a deep cup, bisect, or embossing requires a relatively sharp gauge tip to access the deepest point of the cup. Measuring the deepest point of the cup is necessary to obtain the working length of the punch accurately (see Figure 5). Unfortunately, the sharper gauge tip has a greater risk of scratching the face of the punch tip.  Noncontact laser measurements eliminate the risk of tip-face damage and will speed up the process because this method typically requires few moving parts. A button is pressed to activate the laser for a measurement, and the value is collected and recorded instantly. Electrically powered laser measuring devices further reduce overall maintenance costs and the requirement for supporting systems such as compressed air.  

Figure 5: (FIGURE COURTESY OF THE AUTHOR) 

Alternative methods for monitoring tool wear

There are other ways to monitor tool wear besides tool inspections. One method is to track the number of tablets produced with a set of tools and to use the historical data for forecasting. For example, if history indicates that a set of tools has typically produced 1 million tablets on average per tool and 800,000 tablets were produced, the tool wear is 80%. A database designed to record tool use and compare it with an estimated total yield makes monitoring tool wear relatively easy. This information can also  provide a notice to prepare a backup set of tooling or signal a warning that the tooling should be monitored more closely. Properly forecasting tool-replacement needs allows tablet manufacturers to contact tool suppliers in a timely manner to improve lead times for  procuring needed equipment.   

Other tool control-related information is useful to maintain in a tooling database. For example, storing drawing files electronically is much more efficient than keeping track of hardcopy drawings. Using a database to track tool-related activities such as maintenance or issues found during visual inspection provides many opportunities for trend analysis to justify changes in approach to tool-care procedures.  

Multi-tip tooling is a relatively new phenomenon in the tablet industry and presents its own set of challenges to the inspection process. With multi-tip punches, a tool has a separate cup, working length, and overall length for each tip on a single punch. The software that tracks this information must differentiate between each tip on a punch. For example, a punch with three tips will typically be numbered as Tool Number 1 with Tips A, B, and C, then Tool Number 2 with Tips A, B, and C, and so forth. The preferred method for tool-matching  with multi-tip punches is to measure the working length of each tip, then average the values for the combined working length for the punch assembly. The average working length of each upper punch then is matched with the corresponding average working length of the lower punches during the tool-matching process. Although it is still possible to match each tip of an upper punch with each tip of a lower punch according to individual working lengths, this approach would be very time-consuming.  

Vision-system technology and digital photography make the practice of taking pictures of punches during inspection more common. A digital photo of a suspected issue with a particular punch can be saved as an electronic file. The electronic file can be linked to inspection records, attached to an email, or forwarded to the tablet manufacturer's management team or to the tool supplier for analysis. This process allows other interested parties access to the same view of the punch as the tooling technician has.   

Technology has yet to provide a cost-effective solution for die inspections. As with punches, the tablet manufacturer does not need to focus on every dimension of a die in the same manner as the tool manufacturer. The crucial wear points on a die are the inner diameter (I.D.) and the inner surface area of the die wall (known as the die bore). Measuring the I.D. of a round die is relatively easy; it is the nonround or oblong-shaped die bore that presents a problem. Measuring an oblong die bore requires the measurement of both the minor and major axis. Determining the center line of each of the minor and major axis is difficult to do accurately and consistently. Failure to correctly measure each axis could result in an incorrect measurement. 

Another key wear point of a die is the location inside the die bore where tablet compression takes place. This location is often referred to as the wear ring. Any occurrence of a wear ring may indicate that the die is unacceptable for continued use. The most common inspection method is to "bore sight" through the die bore with a bright light on the far side. Any visual ring indicates dimensional wear. Further inspection of a wear ring using a sensitive deviation indicator may help determine the functionality of the die. Although inspecting a wear ring can require a certain amount of equipment setup, depending on the extent of variation of each die bore, the depth within the wear ring can be measured with a bore gauge. The primary method for inspecting dies, however, is to conduct a visual inspection that diligently looks for damage in the form of nicks, cracks, and abrasions on the outer walls and wear rings within the die bore.       

Because measuring the tip diameter of a worn punch can be  difficult, this dimension is not recommended for in-process inspections. Measuring the tip diameter of new punches is relatively easy, but the tip diameter of a worn punch is difficult to measure accurately and consistently. Typical punch tip wear occurs only at the leading edge of the tip (see Figure 6), so conventional contact-measuring devices are ineffective. Using a micrometer on the tip straight will often fail to capture the diameter of the outermost edge of the tip (see Figure 7). Because the amount of wear can be difficult to see with the naked eye, an inspector may be left with a false sense of accuracy. This situation is typically not a problem for new tools because they are not worn. The tip-diameter dimension is another example of a measurement that is included in the inspection by a tool manufacturer but excluded from the in-process inspection by a tablet manufacturer. Various imaging equipment such as optical comparators and digital-measuring systems are available to assist with viewing and measuring this dimension.  

Figure 6: (FIGURE COURTESY OF THE AUTHOR) 

Electronic-audit and security features should be built into any tool-management database to prevent the loss or corruption of data. An electronic audit is the function of recording data as they existed prior to any modification or deletion. Referring to previous audit data records can be helpful if any data are modified inadvertently or otherwise altered.  

Figure 7: (FIGURE COURTESY OF THE AUTHOR) 

Improvements in tooling management and inspection have  been long overdue, and advances in technology bring the tool room into the 21st century. What was once a costly and time-consuming process that often involved storing paper in a file has become an efficient procedure for capturing valuable tooling data that can be used to improve tablet quality. The once-difficult task of analyzing working lengths, the most critical punch dimension, is now incorporated into the inspection process. An entire database of tooling data can be created and maintained with little effort and used to provide information, tool forecasting, and historical analysis. Automated and noncontact inspection systems reduce the risk of punch-tip damage from handling or scratches during the inspection process. Magnified images that highlight tool conditions can be circulated for improved troubleshooting. At last, tool-control functions are using technology to help the tablet manufacturer produce better quality tablets more efficiently. 

is the software support manager at Natoli Engineering, 28 Research Park Circle, St. Charles, MO 63304, tel. 636.926.8900, fax 636.926.8910, 

L. Young Ed. (American Pharmacists Association, Washington, DC, 7th edition, 2006).  

Encyclopedia of Pharmaceutical Technology, Thermal Analysis of Drugs and Drug Products to Unit Processes in Pharmacy: Fundamentals (Vol. 15), 

J. Swarbrick and J. Boylan, Eds. (Marcel Dekker, New York, 1997). 

Inspecting punches and dies can be time-consuming and costly for tablet manufacturers. Advances in technology, however, have greatly improved in-process inspections. The author examines improvements in equipment and computer software for in-process tool inspections.

Developments in Tooling Inspections and Technology

Taking a risk-based approach to product quality is an excellent way to uncover potential weaknesses in process designs or control strategies. A risk assessment is different from an impact assessment because the former considers the severity and the likelihood of the impact. A properly performed risk assessment is a valuable tool in designing experiments, defining design space, and planning design-of-control strategy. The ultimate goal of risk assessment is not only to achieve the desired quality, but also to produce predictable and consistent quality. 

Target product quality and product-quality consistency

The target product quality in this instance may be the desired product quality for full-scale production or a quality that is sufficient for the current scale and stage of development. Product-quality variability is a common problem that can be difficult to solve. Product-quality risk assessment is an effective tool to reduce product-quality variability.

The first stage of performing a risk assessment is identifying potential hazards. A hazard is something that influences the process directly or indirectly (e.g., materials of construction or instrumentation). A typical impact assessment will identify hazards, the type of hazards, and the documentation required such as material or calibration certificates.

Impact assessments are typically designed to identify potential hazards, but not the severity or frequency of exposure to the identified hazards. Since neither the severity nor the frequency of the hazards is identified, an impact assessment is inadequate for designing future experiments or control strategies.

Risk is a combination of the severity of exposure to a hazard and the frequency of being exposed. Being struck by lighting is a good example of a low-risk hazard. Despite the severity of the hazard, the likelihood of it happening is small. 

A product-quality risk assessment requires both product and process understanding to be performed effectively. Consequently, it is best performed after process development has been completed. Ideally, the target product quality is known at that point, including the extent to which the different product-quality attributes can vary without unacceptable quality loss. The limits of acceptable variability are rarely known for all product attributes, however. A quality risk assessment can often identify the aspects of the process that require further investigation. Quality risk assessment must be included in the experimental design or receive special attention in the control strategy. 

It is important that personnel have adequate general understanding of the process type (in this case, spray drying), especially if the process will be scaled up at a later stage. 

An ideal control strategy would allow large input variation but maintain low output variability. Unfortunately, these criteria are rarely met in the real world. A good control strategy would allow some input variation, maintain low output variability, and provide early warning of deviations. The success of such a control strategy is ultimately limited to known input variation. Process analytical technology (PAT) is a valuable tool in identifying input variation that previously was overlooked or deemed insignificant (because of multivariate effects, for example). 

The control strategy can be simplified if the product-feed variations are small, as they frequently are. In this case, a good control strategy is to fix the process parameters that have the greatest product-quality impact by controlled variations in the process parameters with the least product-quality impact.

In a spray dryer, a liquid feed (e.g., solution, suspension, or emulsion) is atomized into a spray of fine droplets and suspended in gas while drying. Spray drying is a fast method of drying because of the product's large surface area and high heat-transfer coefficients. The product's large surface area also enables drying at low to moderate temperatures. The rapid drying and consequent fast stabilization at moderate temperatures make spray drying feasible for heat-sensitive materials.

Spray dryers must always be cleaned and sometimes sterilized. These and other subprocesses are often as critical as the main drying process, but are not part of the assessment as described below.

Identifying the important process parameters

In a spray dryer, droplets or particles are dried while they are suspended in the drying gas. During the drying process, heat is transferred from the drying gas surrounding the droplets or particles, and solvent evaporates from the droplet or particle surface into the surrounding drying gas (see Figure 1). The process also involves various complex diffusion processes, most of which are specific to the product–solvent combination used. This complexity makes liquid-feed composition an important part of early process development. Because the liquid-feed composition rarely can be used for process-control purposes, however, the parameters available for process control are drying temperature, drying-gas humidity, and droplet size.

The conditions under which the droplets are transformed into particles influence the final solvent content and the particle morphology.

In a spray dryer, it is important to distinguish between dryer-inlet temperature, product temperature, drying temperature, and dryer-outlet temperature. In a well-designed cocurrent spray dryer, the intense mixing of spray and drying gas results in fast cooling of the drying gas by the evaporation of solvent. The end result is that the temperature in the drying chamber is practically equal to the spray-dryer outlet temperature. This parity can be measured and calculated with computational fluid-dynamic models (see Figure 2). 

Because of the evaporation of solvent from the product, the droplet or product temperature remains lower than the spray-dryer outlet temperature during the entire drying process. The droplet or product temperature also remains lower than the spray-dryer outlet temperature in the high-temperature region at the drying-gas inlet, where the rate of evaporation is at its highest and the droplet temperature is at its lowest (i.e., approaching the wet-bulb temperature). The product temperature at the discharge is typically between 5 and 20 °C colder than the drying-gas temperature at the outlet.

The importance of the drying-gas temperature at the spray-dryer outlet is clearly seen in experiments where the correlation between product characteristics and outlet temperature is stronger than most other process variables. The outlet's drying-gas temperature is usually fixed at a product-specific set point by a feedback control loop. The feedback loop normally adjusts the inlet's drying-gas temperature or the liquid-feed rate to maintain the outlet's drying-gas temperature at the set point (see Figure 3).

The solvent-vapor content in the drying gas is the sum of the solvent-vapor content in the inlet drying gas and the evaporated solvent. In most applications, the evaporated solvent is the major contributor. Because the evaporation rate is proportional to the difference between the inlet and outlet drying-gas temperature, an increase in the inlet drying-gas temperature (at constant outlet drying-gas temperature) results in an increase in drying-gas solvent-vapor content.

The control of the inlet's drying-gas temperature depends on the control strategy applied for the outlet's drying-gas temperature. When the outlet drying-gas feedback loop adjusts the inlet's drying-gas temperature, the fixed set point for the liquid-feed rate indirectly sets the inlet's drying-gas temperature level (see figure 3). Alternatively, a feedback loop maintains the inlet's drying-gas temperature at the set point by adjusting the main process gas heater. 

The solvent-vapor content in the inlet drying gas is controlled effectively and accurately by adjusting the condenser's outlet gas temperature (i.e., the dew point of the gas). In applications that use ambient air as the drying gas, the condenser is replaced by a dehumidifier or sometimes completely omitted. 

Droplet size is controlled through the atomization process as long as suspended particles in the liquid feed are small compared with the droplets created. Atomization is a complex but reproducible process in which droplet size and droplet-size distribution depend mainly on the rheology of the liquid feed, the energy applied, and the liquid-feed rate. The atomization energy can be applied and controlled in various ways such as adjusting the speed of a spinning wheel in a rotary atomizer, the flow of a gas in a two-fluid nozzle, and the liquid-feed pressure in a pressure nozzle (see Figure 3). For a given pressure nozzle and liquid feed, the liquid-feed rate and the liquid-feed pressure are mutually dependent. Either of them can be used in a feedback loop to the feed pump to maintain constant atomization conditions and thereby constant droplet size and droplet-size distribution—as long as the liquid-feed rheology remains constant. 

Spray dryers are generally designed to work correctly within a limited range of drying-gas flow rates: typically ± 10–20%.  The process parameters that have been selected as critical above, however (i.e., inlet's drying-gas temperature, outlet's drying-gas temperature, and feed rate), are sufficient to calculate the heat and balance across the system. The drying-gas flow rate is thus a dependent process parameter, not a variable process parameter.

Though the drying-gas flow rate is a dependent process parameter, it is impractical to control it according to real-time mass-balance and heat calculations. A simple feedback loop between a gas-flow measurement and the main process gas fan works just as effectively. Gas-flow measurement in this case does not require an accurate absolute measurement: a reproducible relative measurement also suffices. 

Assessments of risk are relative. A risk's magnitude is gauged in comparison with other risks, and "high risk" is relative. 

 In most spray-drying applications, a strong, reproducible correlation exists between product quality attributes that are influenced by the process parameters and the basic process measurements (e.g., temperature, pressure, and flow). Basic process measurements are reliable. Regular calibration and preventive maintenance reduce the risk of deviations even further. The undetected failure of a process measurement or control loop is not likely. Because the process parameters must satisfy the heat and mass balance, an undetected error in one instrument would cause other process measurements to deviate from the normal values.

Process measurements and control loops are effective and reliable process controls and constitute a low risk. 

A few spray-drying applications do not exhibit an adequately reproducible correlation between the product-quality attributes that are influenced by process parameters and the basic process measurements. In those cases, the process measurements and control loops are not effective for controlling the process and constitute a high risk.

 Dried products' characteristics change with liquid-feed variations. The process impact of long-term variations in feed characteristics can be difficult to evaluate because the varations are complex and frequently multivariate. One problem is that a limited number of raw-material batches are used in product development, and some sources of variability are easily missed or deemed insignificant. 

The combination of control loops that rely on constant response to constant conditions and the difficulty in detecting and analyzing variations in the liquid feed make liquid-feed variations a moderate risk. 

In cases with simple liquid feeds (e.g., a solution of one simple chemical compound), the liquid-feed variations become a low risk. 

 Mechanical failures and assembly errors (e.g., missing or damaged gaskets) may cause contamination, deposits, or malfunctions that are not readily detectable. Operator training, standard operating procedures, and preventive maintenance reduce the risk of error, but a high risk of mechanical errors remains. 

 The process measurements and control loops are effective and reliable. A real-time heat and mass-balance calculation based on the process measurements is used to detect instruments that need calibration or certain liquid-feed abnormalities.

Spray-drying applications with an inadequate correlation between product-quality attributes and the basic process measurements require careful reevaluation of the process design space. The lack of correlation is frequently explained by the choice of a marginal or unsustainable operating point.

For example, an operation close to the limits for drying often results in particle agglomeration in the drying chamber and a high risk of deposits or irregular powder discharge (see Figure 4). Furthermore, single particles rarely have the same performance as agglomerates of the same size. The result is a poor correlation between atomization conditions and particle size because the drying conditions are marginalized typically by lowering the outlet drying-gas temperature. 

Process designs and control strategies can be improved by adopting a risk-based approach to product quality. The author describes how this approach can be applied to spray-drying operations.

A Risk-Based Approach to Product and Process Quality in Spray Drying

Controlling tablets' individual weight is critical to tablet pressing. Two factors that are difficult to control, yet are fundamental to a tablet's bioavailability and clinical effect, are tensile strength and disintegration rate. This article will examine a recent development in tablet compression that enables consistent tablet production. The article will explain how the development's flexibility can take into account the critical factors in tablet production and improve tablet quality.

Traditional tablet presses measure a tablet's weight either by measuring its variation in tablet height at precompression or the force at main compression. These techniques, however, overlook one fundamental characteristic: tensile strength. A tablet's tensile strength influences its bioavailability and clinical effect, which are crucial characteristics for any dosage form. 

All rotary tablet presses on the market use the same compression principle. They compress a volume of powder, captured in a die, between two rollers using an upper and lower punch.

By changing the distance between the rollers, one adjusts the force used to compress tablets. Once the distance between the rollers is set, the compression force will stay the same, thus ensuring that tablets are compressed to an equal thickness (ET). 

Several factors affect the precise amount of powder that is captured within each die. For example, granule size, size distribution, and variation in punch length can have an effect. In addition, an excessively high rotational speed allows the powder insufficient time to fall into the die. Variations in the amount of powder in each die result in tablets of different weights and densities, and these tablets require different forces for compression to ET. 

Figure 1 shows a simple force graph for different tablet weights. Tablet weight variations cause different forces to be applied to the tablet because of the fixed distance between the rollers. Note that although the weight tolerance is symmetrical, the forces are not. The force limits are clearly visible in the figure. 

Khan and Rhodes showed that the magnitude of the compression force affects tablet hardness and disintegration time (1). An increase in compression force produces an increase or decrease in disintegration time, depending on the formulation. These results show that an inconsistency in the maximum compression force can result in inconsistent tablet properties, thus affecting the efficacy of the dosage form.

Compression to equal force (EF) is a new concept that allows tablets to be compressed at the same peak compression force, independent of tablet weight. This method relies on an air compensator. (see Figures 2 and 3). 

The air compensator is installed at the precompression and main compression stations. The assembly is attached to a compression roller mounted on a piston. The piston moves vertically in a cylinder filled with compressed air. The air pressure in the cylinder is preset and kept constant by a pressure-regulating valve and an expansion chamber. Because the surface of the cylinder and the air pressure are constant, the force is also constant. 

If the air pressure in the cylinder is such that this maximum compression force is higher than the actual compression force, the system compresses tablets to ET. On the other hand, the press can be set up so that the distance between the two rollers and the air pressure in the air compensator make the compression roller move up at each compression. 

In this arrangement, all tablets are compressed at the same peak force, which is determined by air pressure and the distance between the two rollers (see Figure 4). The thickness of individual tablets might vary as their weight varies. Variance is measured and kept within limits, however, to ensure that no problems arise during packaging. The tablet press is equipped with a linear variable displacement transducer sensor that measures compression-roller movement accurately. 

A heavy tablet causes the compression roller to move more, a light tablet causes less movement. When compressed to EF, variations in tablet weight do not affect tensile strength. Therefore, tablets maintain a consistent clinical efficacy. 

The compression roller's upward movement also has another important advantage: it increases the total compression time (i.e., the dwell time). The more the compression roller moves, the longer the dwell time.

The effect of equal porosity on tablet properties

The author performed an experiment using an ibuprofen 85 DC formulation with 0.5% magnesium stearate. The tabletting was done on the "MODUL P" tablet press (GEA Courtoy, Halle, Belgium). This press is equipped with the air compensator at precompression and main compression.

The advantage of equal porosity tableting is the reduction of variability in density, tensile strength, and disintegration. 

 For the above formulation, a series of tablets was compressed at a constant force of 650 daN with a nominal tablet weight of 233 mg. 

Tablets were compressed within ± 4% of their nominal weight. All tablets were compressed to the same peak compression force. 

 The same series of tablets was compressed to ET. The distance between the two rollers remained constant throughout compression. 

Figures 5–8 show the analysis. The weight variation demonstrates an increase of force when the machine uses the ET mode and tablet weights increase. 

The influence of tablet weight on density for ET and EF.

 Density increases as tablet weight increases. Density decreases when tablet weight decreases. The variability of the density during compression to EF is 1.1%. The variability of the density during compression to ET is 8%. Both tests used the same series of tablets within the same weight range. 

Testing the tablets for tensile strength.

 The variability in tensile strength was more significant than that of density. Tablets compressed to EF showed as little as 1.2% variation. Tablets compressed to ET showed as much as 29.6% variation. 

Testing the tablets for disintegration time.

 Disintegration time varied widely according to the compression technique. Tablets compressed to EF showed only 14.5% variability in disintegration time. Tablets compressed to ET, however, showed more than 105% variability in disintegration time. 

The data were gathered under controlled conditions for ibuprofen 85 DC, and tablets were compressed within the US Pharmacopoeia's weight-variation limits.

Tablets compressed under equal force (EF) showed a much more consistent density, tensile strength, and disintegration rate than tablets compressed to equal thickness.

Different results might be expected from other drug formulations, but these data clearly indicate the advantage of a rotary press with EF capability.

Machines with both capabilities, therefore, give formulation and production departments great scope for improving tablet quality.

 is a product and compression-technology manager at Courtoy, 9165 Rumsey Rd., Columbia, MD 21045, tel., 410.997.6692, 

1. K.A. Khan and C.T. Rhodes, "Effect of Variation in Compaction Force on Properties of Six Direct Compression Tablet Formulations," 

Traditional tablet presses do not measure tablets' tensile strength, yet this characteristic strongly influences tablet quality. The author describes a compression technique that accounts for tensile strength and produces tablets with consistent weight and disintegration time.

Pharmaceutical Technology-05-01-2008

Developments in Scanning Electron Microscopy for Tablet and Granule Characterization

Powder Characterization for Formulation and Processing

Foam Granulation Technology Update and Future Applications

Developments in Tooling Inspections and Technology

A Risk-Based Approach to Product and Process Quality in Spray Drying

Improving Tablet Quality with Compression to Equal Force Technology