Robert Caruso

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

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.