Maribel Rios

In 1985, when Hubertus Folttmann, now head of global marketing excipients at BASF (Limbergerhof, Germany) started his career in the pharmaceutical industry, his company manufactured a drug product in three strengths, including an 80-mg tablet and a 120-mg tablet. To manufacture the 80-mg tablet, formulators simply replaced 40 mg of active ingredient in the 120 mg tablet with filler. "At that time, the world of pharma was okay," he says, "Health costs were not a topic, and manufacturing costs in the pharmaceutical industry were of minor importance."  

(ALEX CAO, RAY MASSEY/GETTY IMAGES. ILLUSTRATION: M.MCEVOY) 

Today, concerns about manufacturing costs and process times are at the forefront of fiscal budgets, and improving formulations is on every company's agenda. "Nowadays, smaller tablets are the advantage, and if you need less active ingredient, you are happy because then you need less excipients to formulate it." Not only do patients want to swallow smaller tablets, but if the capacity of process equipment determines the batch size, then there are more smaller tablets in a batch, which means less batch documentation, smaller packaging, less volume for transportation, and so forth. "Nowadays, these issues count," says Folttmann. "Excipients that perform their functions at lower concentration so that less material needs to be handled have a good chance of success in the marketplace." 

The US Food and Drug Administration's quality-by-design (QbD) initiative has changed the way excipient suppliers develop, characterize, and manufacture their materials. "We have seen some benefits of implementing QbD into the pharmaceutical manufacturing process, including a reduction in approval delays, a more streamlined approval process and an easier course for implementing postapproval changes," says Nandu Deorkar, director of research and development, laboratory and pharmaceutical products at Mallinckrodt Baker (Phillipsburg, NJ). "However, the concept of QbD can present implementation opportunities and challenges to both raw-material (excipient) suppliers and pharmaceutical manufacturers. As a part of the QbD system, raw-material characteristics and their variability on the process and product quality or performance should be studied and documented. As such, raw materials must be well-characterized and developed using QbD principles to reduce variability" 

QbD principles also can facilitate the evaluation of excipient functionality performance and its correlation with physical and chemical properties. Better understanding of excipient properties related to intended uses can help design better dosage forms. "That is where we are getting involved now," says Dave Schoneker, director of global regulatory affairs at Colorcon (West Point, PA), "to build quality into the design from the beginning in terms of what customers want to achieve to make it a better product in the marketplace. In the past there has been a limited number of people within some pharmaceutical companies who could to do that." The company has built a computer-aided design program to help pharmaceutical clients virtually design their dosage forms, including size, shape, and color and produce physical models before producing placebo-type coated tablets. The modeling tool allows manufacturers to get a firm grasp of the tablet designs they want to take forward in development. 

Engineering and coprocessing are additional sophisticated tools that can help excipient suppliers enhance their materials to the high-quality level demanded by drug makers. "QbD initiatives require well-characterized and highly functional excipients to enable their implementation by drug formulators," says Deorkar. "Excipient technology development is centered on particle engineering and new chemical entities." For example, Mallinckrodt Baker recently developed "PanExcea" performance excipients, spherical homogeneous particles for immediate-release oral dosage forms and orally disintegrating tablet forms, using a proprietary particle engineering technology. This technology enables the precise tailoring of physical attributes such as particle size, distribution, porosity, and density in homogeneous particles containing multiple components, without changing the chemistry. "This reduces unfavorable attributes, while enhancing the functional characteristics of individual components through synergistic effects," says Deorkar.  

Optimum functionality is a primary goal for many types of excipients. Take into account, for example, materials used in coating systems. The industry's basic needs in terms of functional coating are generally the same as they have always been. There is still demand for coating systems to aid in achieving various drug-release profiles while providing good flexibility, taste masking, adhesion, mechanical strength, and ability to withstand small variations in processing. Industry does not always agree, however, that these needs are actually being met. "Although the fundamental needs have not changed, needs are not currently being met satisfactory to the industry overall," says John Brown, marketing director at International Specialty Products (Wayne, NJ). "Those manufacturers have been able to work with what is available, but if you ask them they would tell you that it is not delivering 100% of what they are looking for. In some cases, it has been a product-driven market, so there is still a void. As the industry comes under a considerable amount of pressure because of cost savings, brand extension, and patent expiration, companies are looking to gain functionality." 

There are several ways to increase the functionality of coating systems and other excipients, both for immediate-release and for modified-release purposes. The following describes a chemical and a statistical technique. 

Coatings are continuously improving in terms of the types of polymer systems, and excipient users and makers seek materials that will provide better performance at faster coating times. Hydroxypropyl methylcellulose (HPMC), for example, is one of the most commonly used polymers for tablet coating because of it forms films easily. However, the disadvantage with HPMC is that it has low flexibility, and brittle tablets with HPMC coatings may swell under the high humidity storage conditions present in some areas of the world. Swollen tablets then crack the coating. To avoid the effects of humidity, tablets must either be packaged in 100% sealed blisters, which require an expensive polymer or plastic foil as opposed to the typical PVC blisters that don't protect against humidity, or plasticizers must be added to the coating formula. However, as Folttmann observes, the disadvantage of plasticizers is that they may either migrate into the tablet core and interact with the active ingredient or they may migrate out of the film, outside of the tablet, making the coating  brittle again. 

In addition, aqueous coating polymers are spray dried, and the process time, energy, and amount of material required varies greatly, depending on the particular polymer used. For example, HPMC is diluted in water and then a plasticizer, color, and other materials are added before being sprayed onto tablets. However, only very low concentrations (~12%) of HPMC solution can be made, because when diluted in water, HPMC greatly increases the viscosity of the solution. Moreover, in a spray-drying coating process there is a lot of heat involved with the warm inlet air and the colder exhaust air and the energy that is used to remove the water. "When you work with a low concentration of a polymer such as HPMC, the spray process is rather long to get enough polymer onto the tablets, and you have to remove quite a lot of water to end up with a solid coating," explains Folttmann. 

Improving polymers to reduce time, energy, and material is thus an important research area for coating formulators. BASF's instant-release coating material is a chemically new polymer (as opposed to a new mixture or a new coprocessed polymer) made of well-known polyethylene glycol (PEG) and polyvinyl alcohol (PVA) covalently bonded as a graft polymer, in which the sidechains of PVA are chemically bonded to a PEG backbone ("Kollicoat IR," see Figure 1). "Because PEG is part of the polymer and because it is chemically bound to PVA, it cannot migrate to the core nor escape the surface, and remains an extremely flexible film for all types of tablets," says Folttmann. Kollicoat IR can be diluted to concentration of up to 30%, so the spray process requires less water and a shorter period of time. As Folttmann observes, the challenge, as with many new excipients, is that companies are reluctant to try a formulation that has not been reviewed by regulators or monographed in a pharmacopeia. This year, Kollicoat IR received a draft monograph in 

 which is expected to become final in the next year. (Visit the 

  regarding the International Pharmaceutical Excipients Council's new efforts to reduce regulation hurdles for new excipients). 

Figure 1: Grafted polymers, such as polyethylene glycol with polyvinyl alcohol, provide flexibility and reduce spray-coat time. (IMAGES ARE COURTESY OF BASF.) 

 When ISP entered the pharmaceutical coating segment of the industry in 2005, it set out to apply a statistical design of experiment (DOE) to create databases that would facilitate the design of coating formulations and to ascertain the ideal processing conditions for a given platform. "This approach has not been exploited to a high degree," says Stuart Porter, senior science fellow of film coating technology at ISP. "When you look at FDA's quality-by-design inititiatives, clearly using a statisitical DOE is one of the preferred approaches to creating the knowledge about the product. We have taken that same approach and created knowledge about our component of that product, which is the coating system." 

The key variables of the database are the various properties of the coating systems, including mechanical strength, flexibility, adhesion, disintegration, dissolution, film roughness or smoothness, gloss, and cost. All responses are measured for each formulation in the DOE and the database is created as the ratio of ingredients and the types of ingredients in the formulation are manipulated. The database allows minimum values to be set in one area that needs to be achieved and how much the formulation can change to maintain those minimum values while improving the value in a different characteristic that is also important.  

For example, consider the three important physical properties of coatings: strength, flexibility, and adhesion. "Making a coating with high film strength and high adhesion can be challenging because when you improve film strength, you have a negative effect on film adhesion and 

 So the challenge is to come up with a coating system that is a compromise between good enough film strength and good film adhesion characteristics that are required for that given application. Because typically when you manipulate the formulation, you gain something in one area and you lose something in another. There is a fine line between how much can you afford to give up in one area to gain something in another area," says Porter. "You can never say with a high degree of certainty that the formulation that seemed to have ideal properties for an application last week is going to be ideal for another similar application. There are so many variables. You might pick out a formulation today that meets 60% of the market needs and tomorrow it might be 20% and you have to come up with a variant of that formulation to meet those other 80%. The needs keep on changing. That's why having the database and the capability of manipulating it to meet these changing needs is so important." 

The DOE database also factors in various process environments and the types of equipment. "The database gives us flexibility to make micro adjustments as necessary as we gain feedback information from customers. Having this information has allowed our regional labs to access this database and work at that customer interface level wherever they are. Anyone can access the database, the expertise is not centered within one or two individuals for ongoing business," says Brown. "Our interest educates our customers about what film coatings are and how they are tested, what they look like, and demystifying what these systems are really about, how they work, and why they work the way they do." 

The technical knowledge gained from particle engineering, polymer science, and statistical design is of critical importance as companies strive to establish brand recognition, combat counterfeiting,  and prevent medication errors. There are easily visible distinguishing markers such as edible ink branding and two-dimensional barcodes that can be placed on individual tablets. Other technologies include coatings of unique color. Colorcon's aqueous film coating "Opadry fx," for example, is a pearlescent pigmentation that applies light-reflection principles with both dark and light tablet cores (see Figure 2).   

Figure 2: Using the basic principles of reflected light (top), Colorcon has developed pearlescent pigments (left). The effect of a subcoat color (e.g., light or dark tablet surface) influences the degree of pearlescence. (IMAGES ARE COURTESY OF COLORCON.)

Most anticounterfeiting efforts have focused on packaging, including radio frequency identification (RFID), holograms, and specialty labels. It is now equally, if not more, important to have on-dosage chemical and physical solutions built into the product. Chemical and physical taggants are covert technologies that can be added into a coating. "A chemical taggant may be an excipient that is not typically part of the coating formulation that acts as a marker within the coating at the parts per million or even parts per billion levels. "You can't detect that it's there through standard analytical technology unless you know it's there in the first place and you have specific systems that allow you to read it," says Schoneker. Physical taggants or microtaggants are particles that contain unique features or images. These microtaggants may be present at very low levels and can be easily assessed to determine authentic product versus a counterfeit. "In many cases, a counterfeiter wouldn't know these taggants are there. Or even if they knew they were there, they would have no ability to be able to make or get these unique microtaggants to try to counterfeit it," adds Schoneker. "It allows you to authenticate the products throughout the supply chain even if they have been repackaged or diverted." 

 In 2000, the company NanoInk (Chicago, IL) was founded by licensing technology from the Northwestern School of Nanotechnology to place nanoscale features on certain substrates in a patterned manner.  NanoGuardian, the brand protection division of NanoInk, used many of the aspects of that initial technology to develop pharmaceutical NanoEncryption, a state-of-the-art technology that places micron-scale and nano-scale security features on-dosage 

 manipulation of a finished product's coating. A proprietary "NanoEncrypter" typically located at the manufacturer's site, works to manipulate the coating of tablets (as well as capsules and vial caps) to place multitiered security features on each dose without affecting bioavailability, dissolution, and other performance characteristics. The technology has also been proven with uncoated tablets. 

As Dean Hart, executive vice-president at NanoGuardian explains, the technology places three levels of security within the coating. The first is an overt feature, meaning it can be seen with the naked eye by authorities, pharmacies, investigators, and others just by knowing what to look for. The second level is a covert feature, which is a security mark placed within the easily visible overt mark. Detection of the covert mark requires the use of a handheld tool such as a microscope or jeweler's loupe.  

The final security feature is at the forensic level and consists of specific "NanoCodes" placed within the coating. According to Hart, approximately 350 NanoCodes can fit in the width of a human hair, and NanoCodes can be associated with an unlimited amount of information. "A NanoCode can be associated with, for example, 30 different data points, and those data points can be manufacturing oriented such as batch number, lot number, production location and production date; product oriented such as strength and expiration date; or distribution oriented such as the state or country of distribution, and even the specific wholesaler or distributor to whom the product was sent. And once e-pedigree gets its legs, the NanoCode can be associated with the on-package RFID code, or two-dimensional barcode," says Hart. 

"There are two things that pharmaceutical manufacturers need to accomplish to ensure protection of their products," says Hart. "The first is authenticity, which is easily done by NanoGuardian's overt and covert security features. The second is the ability to track and trace each product along the supply chain." NanoGuardian's forensic NanoCodes help manufacturers achieve that second 'need' by capturing an unlimited amount of distribution data on each dosage, thereby giving manufacturers the ability to trace each tablet, capsule, or vial back to its original packaging.  

"When you look at the value of coatings, and the benefits of on-dosage security, that is where the real value of this technology comes into play," says Hart. "ePedigree will only tell you that this is the same piece of cardboard and piece of plastic that came from the plant all the way down the supply chain to the pharmacist. It doesn't really tell you that this is the same pill that was in that bottle to begin with. That is a risky assumption at the heart of ePedigree. But if you can take each dose and connect it to the on-package ePedigree technology that was used to track it through the supply chain, you remove that assumption and you have a closed loop of security that protects the medication from plant to patient."  

Articles

Sophisticated excipient development, especially for coatings, is staying on top of new challenges and meeting expanding industry needs.

A Fresh Coat: Innovation in Excipients

-The US Food and Drug Administration has awarded the National Institute for Pharmaceutical Technology and Education (NIPTE), a not-for-profit organization comprising 11 universities, a $1.19 million contract to develop quality by design (QbD) guidance elements for design space and scale-up of unit operations. 

The two-year project will provide background information for a future guidance document. "We see this as a beginning," says Prabir K. Basu, NIPTE executive director. "At the end of the two-year project, we hope to hold an open workshop with industry and academia. One of the conditions of the funding is that the research knowledge gained from the project will be available to the public." 

The project will involve taking gabapentin (marketed as “Neurontin” by Pfizer) as the prototype compound active pharmaceutical ingredient through blending, granulation, and drying operations. According to Basu, the project will aim to answer two fundamentally important manufacturing questions: "How do these unit operations scaleup (i.e., How can one develop a design space from one scale to the other)?" And, "How does scale-up influence stability?"

The project will begin at the laboratory scale (5 k) and be scaled up to the 30-60 k size, with stability being monitored at each unit operation. 

The focus of stability is a major part of the project, mainly as a result of the industry concerns about safety. “Manufacturing is not always a major focus when healthcare issues come up,” says Basu. "We believe manufacturing is probably the hidden crisis in healthcare. Some of the stability issues that we are seeing today are a result of manufacturing. For example, the recent heparin contamination issue was essentially a manufacturing issue. We believe that by improving manufacturing, making it more reliable by using quality by design, we can ensure drug safety. By actually doing the design space and QbD, we can have a better understanding of stability.”

Of the 11 member universities that comprise NIPTE, the major institutions that will be involved in this project are Purdue, Duquesne University, Rutgers, Illinois Institute of Technology, University of Iowa, University of Kansas, and the University of Minnesota. 

“We have put groups together consisting of well-known engineers and scientists,” says Basu. For example, the design-space portion of the project will be led by James Drennan (Duquesne Univ.), Fernando Muzzio (Rutgers), Hamid Arastoopour (IIT), and James Litster (Purdue). The stability testing portion of the project will be led by Lee Kirsch (Iowa), Eric Munson (Kansas), and Raj Suryanarayanan (Minnesota). Overall API development will be directed Robin Bogner (Connecticut) and Rex Reklaitis (Purdue).

The award follows a separate $94,500 FDA seed grant for developing a QbD framework for parenteral products. NIPTE aims to expand this project in 2009 to develop guidance elements for parenterals. Basu also says NIPTE plans to apply for future grants to expand this project, possibly including the tableting step, or to start similar projects.

This is a corrected version of the original story, which clarifies a quote by Prabir K. Basu

The US Food and Drug Administration has awarded the National Institute for Pharmaceutical Technology and Education (NIPTE), a not-for-profit organization comprising 11 universities, a $1.19 million contract to develop quality by design (QbD) guidance elements for design space and scale-up of unit operations.

FDA Awards NIPTE $1.19 M for QbD Guidance Project

 has been the authoritative source of the industry for more than 30 years. One of our unique resources is the annual employment survey, which has been part of this publication for the past 20 years. The article, appearing in the December issue, is more than a salary update; it provides a look into the industry workplace from the perspective of those who know it best. Readers have let us know that they turn to the survey as one of their resources when making hiring decisions or future career plans.  

Globalization is leading to big changes in the industry, but one of the most universal topics of interest to professionals worldwide is the current work environment. About 10 years ago, to make the results of the employment survey more comprehensive, we gave the survey an international perspective. This year, we would like to expand on this goal and encourage even greater participation from our readers outside the United States.  

We've also added a new segment to this year's survey. Recognizing that high levels of job satisfaction come from good employers, the questionnaire invites participants to nominate their company as one of the "Best Companies to Work for" in the industry. Past survey participants have voiced their opinions about what they enjoy the best about their jobs, and many of these opinions have centered around the job environment at their particular company. This year, we hope to recognize these companies and perhaps inspire new and future employers. 

 anytime until Sept. 30 to make yourself count and participate in this important survey. And perhaps you may want to nominate your company as one of the "Best Companies to Work for" in the pharmaceutical industry. 

This year, the employment survey will acknowledge the industry's best employers.

Make Yourself Count

HANDS: MIKE KEMP/GETTYIMAGES; 
CABLE: IMAGE SOURCE/GETTYIMAG

The great disadvantages of new technology are that its commercialization involves a high degree of risk and its future holds an even higher level of unpredictability. Wireless industrial automation has been slowly embraced by some petrochemical and chemical processing companies. Meanwhile, the highly conservative pharmaceutical industry has so far, and not surprisingly, taken a wait-and-see position—and for good reason.  

To build the most robust and secure wireless devices, suppliers build according to an approved standard. Wireless Internet communications, for example, all comply to the familiar IEEE 802.11 (b, g, and n) standards. Currently, both the 

 (Research Triangle Park, NC) are involved in putting forth an industrial wireless standard at the basic "bits and bytes" level (i.e., sensors) (see sidebar, "Which wireless?"). HCF released its standard, WirelessHART (HART generation 7), in September 2007. To date, ISA is continuing to develop a draft of its standard, officially noted as ISA 100.11a (often referred to as SP 100).  

Both organizations aim for global acceptance, including by the pharmaceutical industry, which thanks to the move toward quality by design, is preparing for increased in-process monitoring. Both HCF and ISA agree that a wireless standard is the right step to advance process automation and communication. Both are aware they are competing to achieve the same objective. And of course both would argue that their standard is the most beneficial, robust, and secure.  

Dual standards are not new to process automation. For example, the original wired HART digital standard was developed more than 15 years ago to be carried on top of the existing 4-20 mA analog signal. At that time, HART was an emerging communications protocol. "If you look back 10 years, HART wasn't supposed to be where it is now. I recently looked at the articles that were written and they said HART was an interim technology and by 2005 it was supposed to be dead or dying from a technology standpoint," says Ed T. Ladd, Jr., director of technology programs at HCF. HART is now worldwide and is the most used protocol for field devices in the process industries. HCF built upon that technology when developing its WirelessHART standard, which was reviewed and approved by its membership and ratified by its board for release on Sept. 7, 2007.   

Figure 1: 
Prestandard wireless transmitters are now in use, 
and Emerson Process Management 
has announced the availability of 
SmartWirelessHART transmitters. 
(PHOTO COURTESY OF EMERSON 
PROCESS MANAGEMENT) 

 is currently the only company that has announced the availability of WirelessHART devices (see Figure 1). Although none have been installed at this time, prestandard wireless devices continue to be in use. "To date, we know that member companies are actively developing WirelessHART products to be offered for sale by the end of the calendar year," says Ladd. "Major vendors, including ABB, Emerson, Endress +Hauser, and Siemens, have all committed to support the technology."  

At the time WirelessHART was released, ISA had been working on ISA 100.11a. "ISA began to work on a wireless standard in 2004. I'm not sure what the motivation was on the part of the people who decided they would not wait for ISA 100 but would build on available technology and develop WirelessHART," says Richard Caro, certified automation professional, CEO of 

, and chair of a user-working group for ISA. "ISA 100.11a is beginning to develop rather quickly and at this point is almost complete. The standard is scheduled for voting and approval by the end of 2008." 

As a member company of HCF, Emerson attributes the speedy approval of WirelessHART to the organization's size and approval process. HCF is a small organization comprising the major vendors and users of wireless devices. "It's consortium of companies and customers that have a vested interest in making something happen, so they tend to be more efficient at making things, and it shows up in a standard that goes to market much quicker," says Bob Karschnia, vice-president of Wireless, Emerson Process Management. 

ISA is a worldwide standards-making body that operates under 

 (ANSI) rules. Following ANSI rules means that the document must undergo several rounds of comments, resolution, and voting to become a US national standard and a cycle for becoming an international standard and approval through IEC. So far, the 100.11a prestandards document has undergone a round of comments and resolution, and, according to Caro, the final standards document is being drafted. "Right now, we are on schedule and the next seven months or so will be devoted to voting and comment resolution."  

Designing a standard starts with conducting a number of "use cases." Use cases help determine whether prototypes can solve specific real-world industrial applications such as monitoring temperature in a tank or controlling the flow of steam into heating and cooling jackets. Both ISA and HCF have conducted use cases. According to Karschnia, HCF went through all of the use cases that had been developed for 100.11a. "We found that every one of them is met by WirelessHART." 

Use cases differ from validated confirmation tests, which prove that an application meets an accepted standard. This is one difference between WirelessHART and ISA 100.11a. "As a matter of fact, WirelessHART is still preparing its confirmation test sweep," says Caro. "With ISA 100, the production of a validation sweep is going along in parallel with the standard. When the standard is issued, it will be just a few weeks afterward that the validation sweep is complete."   

Ladd questions this approach. "You have to write the standard, then build to the standard, then test to the standard. How do you build a device to a standard that doesn't exist? To me, that doesn't make sense. Once the standard is complete, then you can begin to develop your product to validate the standard, you make modifications to the standard if you find discrepancies, that is part of continuous process improvement." 

According to Caro, the intent for ISA 100 is that before the standard is published, a number of companies will have already used the draft standards document to build product, and therefore they will get the actual use of the standards document and will have a chance to make corrections to it during the comment period. "The HART organization has the freedom of being independent to choose to issue their standard without that kind of comment-resolution period, which they have done. That shortcuts the timing requirement, but it doesn't necessarily make the standard available for production devices any sooner because they will have to go through the next revision of their document. It is now HART 7.0. Before that standard is completed it will certainly be at the 7.1 phase, reflecting the comments of the companies who have tried to build products to that standard." 

Ladd explains that HCF provides 60 days for review and comment and a 30–60 day resolution period before the board of directors vote on ratification of any member-approved changes. 

The most important question is whether there are any differences between ISA 100.11a and WirelessHART. The answer depends on who is asked.  

According to Caro, "The main differences are very technical and not easy for users to identify. Some users have an immediate need for wireless protocol, so that is one benefit for devices conforming to WirelessHART, which will be on the market some number of months in advance of products that conform to ISA 100.11a. Users needing to augment safety systems, for example, are installing whatever wireless they can put their hands on for many of these applications simply because they want the functionality and they are not willing to wait for the standard with the idea that perhaps someday they may go back through those installations and replace them with something that conforms to their plant standard. Many users, particularly those on the ISA committee, say that to them the early availability of wireless devices is not an advantage. Being first to market doesn't necessarily mean that it's the one that is going to prevail." In addition, says Caro, "the time and effort being devoted to ISA 100 has benefits in the information-security area that exceed the requirements for WirelessHART."  

Karschnia disagrees. "There are no differences that are important to solving the customers problems, and this is key. It is like one person saying something in English and another  saying it in French. They use the same underlying basics, except that SP100 has deviated from an IEEE standard [802.5.14], and WirelessHART used the IEEE standard as is." 

Ladd says the radios are the same and the frequencies are the same, but there is a difference in how they communicate and how passwords are established. "WirelessHART only allows join keys or passwords to be keyed in via hard wire, whereas [ISA] intends to transmit them via wireless. From our standpoint, this could be a security risk. Our standard requires a maintenance port that is secure and backward compatible to all handheld communicators and PC-based applications that are in the field today." 

Emerson donated a lot of intellectual property to HCF and ISA. "It's the same intellectual property for security, time-synchronized mesh protocols, and 802.15.4 radios. Both of those standards have adopted those pieces. If you peel back all the noise in the system, you'll find that they look exactly the same," says Karschnia. 

ISA 100.11a and WirelessHART are built using the same chip (i.e., the physical layer of the two standards is identical). They operate at the same frequencies and use the frequencies in approximately the same way. However because of differences in the upper-layer protocols, they are not compatible. But compatibility is not the same as the ability to coexist. "The biggest questions that users ask are, 'We know they are not compatible, but can they coexist? Can I have a network of WirelessHART instruments that I've installed this year and then I go back later on in the same area of the plant and install another network of ISA 100.11a instruments?" says Caro. 

Because the two standards use the same frequency, Caro says they have the potential to interfere with each other. "However, because we have recognized that the 2.4-GHz spectrum is busy, we have to provide ways for devices to share that spectrum and to recover from any collisions that may occur. And we have built in the recover mechanisms so that the user generally will not be required to intervene at all; that is, they will self recover, and the two networks will coexist peacefully within that same domain. We believe that to be true and we have additional adjustments that can be made to ISA 100, although it is not clear that any of those things can be done to WirelessHART." 

Caro explains that technically, both protocols use a pattern of frequency hopping, and the patterns of frequency hopping are different. But occasionally they will hop to the same frequency at the same time. The result of that will be collision, an error message, and then a retry. The retry will occur at a different frequency and because the hopping patterns are different, then the retry in both cases will be at different frequencies. So there is an automatic recovery mechanism that will enable the two systems to coexist without the need for elegant software tools to adjust the networks. 

"There is just a difference in philosophy of how the systems work," says Ladd. "We're using mesh networking, where all of the devices are routers. We're using 802.15.4 radios, and that is the same radios ZigBee [ZigBee Alliance, San Ramon, CA] uses. We added the frequency-hopping technology, additional security measures, and a number of things that will make the WirelessHART network much more robust and backward compatible to 26 million devices already installed." 

 are two organizations that build their communications protocols on top of either ISA 100.11a or WirelessHART. "To the extent they have simple networks, then WirelessHART could serve as a base for Foundation Fieldbus. But to the extent that their customers want to do more like control any of the field devices, then they will find that the additional flexibility of ISA 100.11a will allow their networks to work better for control reasons," predicts Caro. "Profibus appears to be less interested in the additional security and the other requirements that are given by ISA100 and appears to be leaning toward founding the wireless version of Profibus on top of the WirelessHART protocol. That of course could change as the users of Profibus change. For example, Profibus is largely influenced by the German chemical industry, which is the largest industrial category in Germany and includes companies such as Bayer. To the extent that Bayer recognizes the additional reliability and security added by ISA, it could change the product specifications that are currently occurring within the Profibus organization. But since our standard is not yet complete, there is no basis for them to do that at this point." 

On Sept. 27, 2007, HCF announced a collaboration with Foundation Fieldbus and Profibus to work on wireless technologies for process industries. The release mentions that "the organizations have agreed to base their work on WirelessHART technology ... and the emerging ISA SP 100.11a standard."  

On the same day, ISA announced that HCF and ISA had collaborated to "develop a single wireless standard for process measurement and control applications." According to this statement, each organization had granted copyright license to the other such that HCF would have access to ISA100 documents at all stages of development and ISA would have access to HART protocol specification, including WirelessHART. ISA announced the formation of a joint technical committee "to assess WirelessHART technology for meeting ISA objectives and recommend possibilities for incorporation into the ISA100 family of standards." Whether the incorporation of WirelessHART into ISA standards will or can actually take place remains to be seen.  

Says Caro, "For a long time, I have been a very strong advocate of trying to get the WirelessHART group to abandon what they have done and simply use those parts of ISA 100 that appear most like WirelessHART. That could be done without real technical compromise, but they seem to be unwilling to do that. We have an investigation to look at WirelessHART and make it a proper subset of ISA100, but that doesn't seem to be happening."  

According to Ladd, "WirelessHART is not going away. WirelessHART incorporation into ISA 100 is up to ISA at this point. We have talked about it. There was a ballot posted on the SP 100 website to begin a WirelessHART subcommittee, so there are things definitely moving forward to incorporate WirelessHART into SP100." 

"[In April], there was a motion raised within SP 100 to make WirelessHART as it exists, with no changes, an SP 100 standard, and I think that will be approved," says Karschnia. "If it doesn't, you end up having competing standards that are in the industry and that will be an issue because it will just confuse customers and less people will buy in general." 

So is it political? "I don't know," says Caro, "It's more economic. And it's not economic in serving the end user, it is economic in serving the customers of the HART Communications Foundation who are the vendors." 

Profibus, Profibus International, Foundation Fieldbus, and HART have formed a working group to develop a specification that will give common interface using a wireless gateway. "We want to give users some assurance that whatever they chose [Foundation Fieldbus, Profibus, or Profinet], they are going to be able to use it going forward," says Carl Henning, deputy director at PTO, Profibus, and Profinet North America. According to Henning, the group will look at both WirelessHART and the ISA standard, although because WirelessHART is complete, Profibus has been working mainly with that standard. "I've been told that we will probably see the Profibus gateway by the end of the year. This should help users because it will result in a common interface so they won't be stuck deciding which wireless sensor network to choose." 

Says Karschnia, "It seems it would be worthwhile for SP 100 to change its focus from the bit-and-byte communication sensors to bigger problem of gateways." (In a network, a sensor transmits data, the data hops through a time-synchronized mesh protocol network, and arrives at a gateway.) "ISA should focus on how does that gateway will interface to the rest of the process control systems that exists—to the DCS, to the historians, to the business systems, and to the diagnostics systems. Once someone defines that, then the industry will adopt wireless more readily. To date, Emerson has its solution, Honeywell have its solution, and everyone will have a different solution. That is where ISA can add value."  

Henning offers this perspective: "The thing to remember is that it doesn't matter who puts out the standard, it's what the users adopt that is going to be important. From that standpoint, I like the idea of having competing standards. The users are winners by having competitions because the standards organizations are spurred on to do better by that competition. There is a limit, but I think with two or three competing technologies, it's a positive." 

ISA 100.11a and WirelessHART both seek to become the global standard for industrial wireless automation.

Unplugged: Developing Standards for Wireless Automation

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

Like most of the world, the scientific community is now more than ever reliant on images to gain valuable information. When pixels replace pens, and the image of a new drug candidate can make or break a project, it becomes clear that a picture can be worth much more than 1000 words.  

(BACKGROUND: PHOTOS.COM, IMAGING PHOTOS: CHEMIMAGE) 

Uniting single-point spectroscopy and digital imaging, chemical imaging is slowly being adapted for the analysis of tablets and capsules. Advanced from traditional optical microscopy, which uses a material's refractive index among other material properties as the basis for generating image contrast, chemical imaging instead uses the underlying spectroscopy associated with the materials being analyzed at each spatial location as a means to produce image contrast. Multivariate analysis and chemometric software then translate this chemical image information into useful quantitative data.  

The motivation for adapting chemical imaging lies primarily in the changing nature of today's dosage forms. "Definitely the business is moving in the direction of more complicated formulations, and the standard tools don't provide the information needed to characterize these products," says Linda Kidder, product manager, Chemical Imaging Systems, at 

 Instruments, Inc. (Columbia, MD). "The single-point spectroscopies just can't do it, and HPLC [high-performance liquid chromatography] just can't do it. This is where the need is growing, and most of the companies working on advanced formulation, really understand this need."  

The advantage of chemical imaging in solid-dosage form analysis is the ability determine the distribution and size of the active pharmaceutical ingredients (APIs) and excipients. The information is then correlated to optimize process operations and understand how ingredients interact within the tablet. "This information aids in quality control, trying to help understand how things dissolve, and their lifetimes with respect to shelf lives," says Richard Bormett, PhD, business manager at 

 (Hoffman Estates, IL). "Tableting processing can change the crystal form of the API, and being able to map where the API is and discriminate between its polymorphic forms is an important tool."  

Previous methods of viewing the distribution didn't offer the quality that analysts needed. The time required to collect the data was long, making it not feasible, and high spatial-resolution mapping could take days. As Bormett observes, "If you looked at a whole tablet at a time, the spatial resolution of the probe became poorer and poorer so you had to look at larger and larger sections. If an API reached 5 to 1 microns, it wasn't always easy to see or determine its distribution." 

 The primary distinction between chemical imaging systems is the type of spectroscopic technique. Within the pharmaceutical industry, numerous spectroscopies have advanced, including Raman, mid-infrared (mid-IR), near-infrared (NIR) absorption–reflectance, UV–vis absorption–reflectance and luminescence. Each have been demonstrated useful for many applications.   

Vibrational techniques such as Raman spectroscopy can pick up the unique chemical signatures for polymorphs of an API, which help analysts determine the cause of poor efficacy. Imaging with Raman spectroscopy is also useful in contamination identification. "In the world of tablet or capsule analysis, we often have the luxury of knowing what is present in the tablet based on a list of ingredients," says Matthew Nelson, PhD, director of application science at 

 (Pittsburgh, PA). "Often, this information allows us to develop a spectral library of the compounds that are present and to understand the chemical signatures for those components. We can collect data on small parts of a tablet, the whole tablet, or multiple tablets using chemical imaging. With data processing software, we can provide qualitative and quantitative information" (see Figure 1). 

Figure 1: Data processing software allows analysts to obtain quantitative information about a whole tablet or portions of a tablet. 

Chemical imaging using NIR spectroscopy can obtain data from rounded surfaces, powders, granules, beads, and intact capsules. "With NIR spectroscopy, we can look at beads in a capsule without having to take a capsule apart, it would be very difficult to do that with the mid-IR or Raman," explains Linda Kidder.  

"NIR, mid-IR, and Raman can tell formulators whether an API is co-localizing with a particular excipient," adds Kidder. "[Formulators can determine] whether the API has a tendency to associate or aggregate with a particular excipient, which may be affecting the tablet's dissolution properties. You can't get that [information] with HPLC and you can't get it with single-point spectroscopy. That is absolutely unique to imaging."  

Another common application of NIR, mid-IR, and Raman imaging is mapping thicknesses of coatings and (for Raman) of pigments (see Figure 2). This analysis can be performed two ways. First, imaging can be a primary technique; that is, no correlation with other data is necessary. The tablet is cut in half and the cross section is imaged. The coating is seen as a series of pixels and pixel size variation relates to coating thickness. "We can generate an image through the use of color and show where the thin spots on the tablet are. Because it's imaging, you can actually tell that the coating is 100 μm. And by looking at hundreds of locations, you can obtain a statistical representation of the coating distribution—the mean value—and a standard deviation in that value," explains Kidder.  

Figure 2: An RGB (red/green/blue) composite generated from a Raman Chemical Image of a controlled release system. The image was taken on a "Falcon II Raman chemical imaging system (ChemImage). The green and red areas of the image indicate chemically different layers (or coatings) on a bead (indicated by in blue). The goal of the project was to study the uniformity of thickness of multiple controlled-release coatings. This image clearly indicates that the coatings are not uniform in thickness across the bead's surface. 

It is also possible to collect data from the surface of a tablet without first taking a cross section. A tablet is placed on its bottom or its top, and the analyst looks down on the surface. The variation in intensity of the vibrational band associated with the coating across the surface of the tablet provides a statistical variation of the coating thickness. This is a secondary analytical technique, and therefore obtaining absolute (rather than relative) values of the coating thickness requires a correlation with real distance measurements. 

For NIR techniques, there has been some confusion between the terms "chemical imaging" and "mapping" because both provide an image and generate the same data. The difference is in how an image  is produced and data are collected. "Chemical imaging uses a two-dimensional detector, so you are taking pictures, whereas mapping or 'fast mapping' uses either linear arrays or collects a line of spectra at one time to build up an image while the sample is moving on a stage," explains Kidder. In chemical imaging, the sample does not move—a picture is taken over a series of wavelengths—whereas mapping uses an interferometer, which is based on a moving mirror. This differentiation is also found in both Raman and mid-IR, where both mapping and imaging are used.  

Because NIR mapping is based on an interferometer, sample surfaces must be very flat to collect good data. In contrast, "the depth of focus for NIR chemical imaging is very forgiving," says Kidder. "We can look at rounded sample and get reasonably good data from the whole sample" (see Figure 3). In addition, Malvern has developed an NIR-based imaging system that has no moving parts. As a stable system, it can move from an R&D setting into QA/QC setting or manufacturing setting and collect data. Mapping systems based on an interferometer have moving sample stages and the instrument stability and therefore spectral quality may be compromised by the vibrations found in a manufacturing or QA/QC environment. 

Figure 3: NIR chemical image reveals granule distribution in tablet (wavelength = 2060 nm) IMAGE COURTESY OF MALVERN INSTRUMENTS INC. 

Tablet manufacturers seeking vibrational spectroscopy-based chemical imaging use three factor when choosing between Raman, mid-IR, NIR—and in some cases fluorescence—methods: specificity, sensitivity, and spatial resolution.  

Patrick Treado, PhD, chief technology officer at ChemImage explains that in general, fluorescence is the most sensitive approach but the least specific, and spatial resolving power can be on the order of a couple hundred nanometers. NIR is reasonably sensitive but also relatively nonspecific, and resolution is on the order of tens of microns. NIR is the most inexpensive, however, and provides fast data collection. Raman is not as inexpensive, though cost effective, but it's very specific although a little less sensitive. Moreover, explains Bormett,"IR is limited in its lateral spatial resolution. It's hard to perform IR imaging with lateral spatial resolutions better than about 30 microns." 

 "NIR spectroscopy has been seen to be a workhorse in industrial technology, whereas the Raman and the mid IR are seen more as specialist techniques," says Kidder. In some ways this parallels on the imaging side as well. "NIR can probably solve 85% of the problems we see for the pharmaceutical industry. Some of our customers who have multiple technologies tend to go to NIR first and determine whether they can solve it with NIR because of its fast data collection time time (just over a minute for a standard tablet), no sample preparation required, and ability to accommodate different types of samples. For samples that require higher spatial resolution or higher spectral selectivity though, other techniques may be needed." As with the single-point technique, chemical imaging with NIR and mid-IR spectroscopies do not work well with inorganic compounds. 

 Raman spectroscopy, however, can accommodate inorganic compounds and recent advances are extending its application. ChemImage, for example, has innovated a dynamic chemical imaging capability. "Historically if you are going to use Raman to evaluate an entire tablet or a process that is occurring in real time, it took a long time to gather the information," says Treado. "Our approach has been to capture images dynamically in real time or near real time, in the time scale it is relevant to the process you are trying to monitor. Another way of thinking of this is Raman imaging 'movies' —it is drilling down and extracting information content from the monitoring of these dynamic processes." Capabilities include monitoring processes that can't be slowed down (through temperature control for example) and the kinetics of the process is not on the time scale of seconds or a few minutes. "Crystallization, dissolution, and recrystallization are specific application where dynamic chemical imaging is proving itself," says Treado. 

Dynamic chemical imaging with Raman spectroscopy uses wide-field imaging. "Typically this means the use of wide-field illumination in combination with liquid crystal imaging spectrometers, electron multiplying CCD detectors, and a high degree of automation in the software to allow the instrument to monitor a process in real time or near real time in an unbiased fashion," says Treado.  

Raman mapping techniques also have advanced. Renishaw, for example, has developed a Raman spectrometer that is designed for high-speed imaging of small parts or a whole tablet. For Raman-based instruments measure individual spectra in a "raster mode" on the tablet. Rows of data are collected to create a two-dimensional map. "Ten to 15 years ago when the pharmaceutical industry started doing this kind of mapping on a tablet, it might take from 8 to 12 hours to obtain," says Bormett. "Providing a tool that can create images for these same tablets in tens of minutes, at an hour at the longest, is a phenomenal tool for the  industry." 

Helping to push the industry into adopting chemical imaging into its analytical labs are developments in both hardware and software.  

 New types of electronic packages have been developed for spectrometers' data acquisition software. "Historically Raman spectrometers were put together with piece components that were just bought off the shelf," explain Bormett. "You would buy a spectrometer, gratings, and a detector. Once you decided exactly how these pieces fit and function together, you could customize the electronic packages in each of these components to allow high-speed data acquisition." Renishaw customized its electronic packages that go into the CCD to control stage and sample movement, then synchronized it with spectrometer data acquisition. "The individual pieces have been always there, but they have never been able to be packaged together until the last couple of years," says Bormett. 

Data transfer also has evolved. "In our initial products, the camera spoke to a frame grabber which then dumped the data," says Kidder. "Now our cameras connect through gigabyte Ethernet cables, enabling data to transfer more quickly." Kidder also explains that the speed and duty cycle of the cameras have increased. Whereas earlier systems would collect 80,000 spectra in 4 minutes, for example, data can now be collected in about a minute with the same signal-to-noise properties. "You may wonder if [data collection speed] matters," says Kidder. "One of the interesting cases is when you are doing QbD [quality by design] and your DOE [design of experiments] includes 100 different tablets, for example. If it takes you 40 minutes to collect the data, you have to multiply that by100, compared with 10 minutes or even 1 minute for data collection. It really starts to make a difference if the technique is used as a routine tool."  

Treado attributes the innovations in spectrometers, specifically the liquid crystal imaging spectrometer. He also credits the use of imaging cameras or focal-point arrays. In IR, it's typically indium gallium arsenide, indium antimonide, or mercury cadmium telluride cameras. For Raman- and fluorescent-based systems, it's CCD or CMOS detectors. "If you couple those with multivariate software, you have powerful combination," he says. 

As the tools to analyze data advance, so too should the tools to increase the understanding of the information that is generated. "Early on, people would pull out a single wavelength image without having properly preprocessed their data with a baseline correction or normalization, for example," says Kidder. "These steps were standard for single-point spectroscopy, but somehow analysts lost track of the fact that imaging was really just parallel spectroscopy, and the basics still had to be applied. There have also been strides in the quantitative , versus qualitative, assessments that can be made. People used to look at a picture and compare it with another picture and say 'this looks more homogeneous.' Obviously that doesn't work, and it doesn't help you." 

Data analysis tools are now much more sophisticated, and researchers are developing metrics to see an image from a statistical point of view. "The 'standard deviation' of a image can actually give you a quantitative measure of the heterogeneity of a tablet, and you can then start putting the image to good quantitative use," says Kidder. "In our early days, most of our reports were filled with pictures. Now, they're mostly filled with tables of numbers comparing the statistics of our results.The ability to generate quantitative, objective, and reproducible results allows imaging to become an analytical workhorse, rather than just a fun tool." 

Chemical imaging companies see real promise in applying their technologies to the tableting market and are eyeing validation. "The industry is struggling with the best way to validate these techniques, but we have started working with customers in QA/QC departments to get them accepted," says Kidder. "Large pharmaceutical companies want to roll chemical imaging out to replace or complement wet chemistry techniques." Although single-point spectroscopies methods have been validated for some time, the respective imaging technique will still take considerable revalidation work. 

But the promises that imaging may bring can make that the revalidation work worthwhile. One future application, for example, includes correlating an image with a dissolution curve. "If they can prove this correlation—which has been done for a variety of products already—and because it is a fast technique, we could look at a lot of tablets in a batch to make sure they have the correct 'image parameter,'" says Kidder. The parameter could indicate whether the tablets were good dissolution candidates and wet chemistry would only be used to sample a small subsection of that. Regular dissolution testing would still be done on a subset of samples, but more if not all samples could be tested using vibrational imaging. "It's definitely cutting edge ... that is the big picture people are looking at." 

Chemical imaging of solid dosage forms has become a powerful analytical tool for the development of solid dosage forms.