This article is part of a special issue on API Development, Formulation, Synthesis and Manufacturing.

Pharmaceutical companies face the ongoing challenge of how to best allocate research and development (R&D) resources to make the drug-development process work in the most time efficient and cost-effective way. Industry estimates put the average time to develop a drug at 10–15 years at an average cost of $1.2–1.3 billion (1). As a result, pharmaceutical companies have to consider new ways to make the process work better in an overall economic environment of declining budgets and tighter resource allocation. Such is the case for Bristol-Myers Squibb (New York), which implemented a "fit-for-purpose" model for how the company develops and produces clinical- trial materials for early-stage drug development. 

The crux of the fit-for-purpose model comes out of a concept of "cost-disciplined science," says Mark Powell, senior vice-president of pharmaceutical development at Bristol-Myers Squibb. "Cost-disciplined science is a development strategy that we are applying throughout R&D," he says. "But in the specific context of drug development, this concept is based on maximizing overall productivity by selectively allocating resources to compounds based on where they are in the drug-development continuum. Among pharmaceutical companies as a whole, we know that there is a high level of attrition of drug candidates as they proceed through the drug-development process. So how do we allocate our resources in the best way to focus on the right drug candidates, and what is the best way to apply our resources so that the most promising candidates have the best chance to succeed?" 

To address that issue, Bristol-Myers Squibb implemented a fit-for-purpose model for early-stage compounds. Under this approach, the company reduces the level of process optimization early in development for both the drug substance and drug product (i.e., formulation). Historically, the company's chemical development department invested significant resources in synthetic process optimization prior to producing early active pharmaceutical ingredients (APIs) batched for clinical studies. In the new fit-for-purpose model, process optimization is generally delayed until a compound proceeds beyond Phase I and approaches or achieves proof of concept. Using this approach, the company liberates resources that can be applied to additional early-stage compounds or can be applied later in development after a compound has been shown to be a viable drug candidate from a clinical perspective. Often the company will elect to outsource the manufacturing of the smaller quantities of the API needed at this early stage (i.e., Phase I) using the discovery-chemistry route that was developed internally. If a molecular target is of particular interest or priority to the company, process optimization can begin internally in parallel to the outsourced early API manufacturing work, but that is reserved for only the highest priority programs, Powell says. 

Bristol-Myers Squibb applies a similar philosophy in formulation development by using a 

 approach to the development of dosage forms that will be used in early clinical testing. Historically, tablet or capsule formulations were developed prior to the start of Phase I clinical trials. Given the wide dosing ranges employed in these early clinical studies, the formulation development work was significant and time-consuming as well as API-consuming. Approximately 70% of all the early API manufactured was used for this formulation-development work. The new fit-for-purpose formulation approach has significantly changed that.   

The company predominantly uses a "powder-in-a-bottle" formulation approach in which it puts the API directly in a bottle and makes a simple solution or suspension for drug administration in Phase I clinical studies. Applying this approach requires several additional factors to be taken into consideration for a Phase I clinical trial, says Powell. For example, a pharmacist has to be physically present at the clinical-trial site to make up the final dosing solution. The on-site pharmacist requirement can be an additional cost and also may limit clinical-site locations for a given trial.  

By minimizing formulation development, vital resources are freed to support additional early-stage projects, and/or focus on the highest priority projects. Additionally, early clinical projects proceed at a much faster rate, thereby reaching critical decision points earlier. Bristol-Myers Squibb may elect to do more advanced formulation development for a given early-stage compound if it feels that it is necessary, but that decision is made on a case-by-case basis and is reserved for the highest priority programs or compounds.   

Powell explains that the fit-for-purpose approach involves purposeful trade-offs in resourcing support levels for early- development stage compounds. "The advantage is that by limiting our upfront investment, we are now effectively supporting an early clinical pipeline which has increased more than 50% in the last three years with the same headcount and budget as before," he says. "Additionally, early compounds are proceeding to critical decision points faster then they ever have before. The trade-off is that for those selected compounds that make it successfully past proof of concept, there could be a significant amount of concentrated API and formulation work necessary to progress the programs and support timely progress in late-stage clinical development. But we are looking at our resource allocation across the entire product portfolio and feel these trade-offs are worth it." 

Bristol-Myers Squibb has developed specific metrics to quantify the cost and time benefits in this fit-for-purpose model. The company has reduced the amount of API that it produces for early-stage clinical-trial materials by approximately 50%. The company also uses a metric to assess the time it takes between declaration of an exploratory candidate nomination (ECN), the term the company uses to identify an early-stage drug candidate that has moved from the discovery phase to early development, and the start of the first good laboratory practice (GLP) toxicology studies. The rate-limiting aspects of this metric are normally the availability of GLP API. Using that metric of time from ECN to first GLP toxicology studies, Bristol-Myers Squibb has been able to reduce this average time from a historical base of approximately six months to essentially zero time, meaning that GLP toxicology studies can start immediately upon ECN declaration. That is a time savings that directly allows projects to reach critical decision points sooner than ever before and faster than industry benchmarks. A direct result of working more efficiently is that the Pharmaceutical Development group can now support a clinical development pipeline with 64 active compounds with the same number of people that previously supported 40 compounds.     

Powell explains that the fit-for-purpose model was adapted by Bristol-Myers Squibb three years ago and was born out of the need facing many companies of how to do more with less. "In evaluating our strategy in drug development, I assumed that our resource allocation for early drug development would be tied into the company's overall R&D organic growth projections, and we needed to adopt a model that would fit into those constraints," says Powell. "We needed to accept some trade-offs in implementing the model and get comfortable with the idea that not every compound would be supported at the same level early in development."   

Although delaying formulation optimization is part of the fit-for-purpose model, the company still deploys new formulation technologies for specific compounds where necessary in early development, notes Powell. Examples are technologies that enhance the bioavailability of poorly water-soluble molecules. As a consequence of the increased number and diversity of new molecules coming from combinatorial chemistry and high-throughput screening in drug discovery, solubility has emerged as an important problem that often has to be solved before dose selection in clinical studies. Solid-based systems, such as coprocessed solid dispersions and liquid-based systems, are both amenable to the model. Coprocessed solid dispersions can be manufactured using spray drying at small scales without extensive optimization and be delivered in either simple powder-in-a-bottle or powder-in-capsule formulations. Lipid/surfactant solutions are amenable to the bottle-based approach as well as hard-gelatin capsule formulations. If the drug candidate proceeds to commercialization, both approaches can be readily extended to larger-scale manufacturing—spray drying or hot-melt extrusion for the solid-based approach, or soft-gelatin capsules for the liquid-based approach. Powell concludes that the selection of the solubilization approach mirrors the fit-for-purpose model for poorly soluble compounds: the choice is based on a balance of cost versus technical considerations that are appropriate to the candidate in early development.     

Powell sums up the fit-for-purpose model: "It is all about how to best apply money, people, and technology to reach the key development decision points for every compound as fast and as efficiently as possible. We think this is an overall model that best addresses those issues."  

 (Pharmaceutical Research and Manufacturers of America, Washington, DC, 2010).  

Articles

Bristol-Myers Squibb's fit-for-purpose mode for clinical-trial materials for early-stage development seeks to achieve a better way in resource allocation. This article is part of a special issue on API Development, Formulation, Synthesis and Manufacturing.

Strategies for Early-Stage Drug Development

The current trend in the pharmaceutical industry for the manufacture of small-molecule therapeutic agents is moving toward continuous flow processes. In 2007, the Novartis–MIT Center for Continuous Manufacturing was established with $65 million in funding from the drug company. The center is proposing a "Blue Sky" concept where there is a continuous process from the start of a chemical synthesis through final pharmaceutical dosage form (1, 2). The Blue Sky program is an ambitious goal but is gaining ground rapidly among thought leaders in the pharmaceutical industry and US Food and Drug Administration. Consequently, the momentum for this concept is likely to have a trickle-down effect for contract manufacturers (CMOs) that design and develop early-stage manufacturing processes for clients developing innovator small-molecule drugs.  

Continuous-flow technology involves the continuous introduction of a stream of chemical reactants into a flow or microreactor to yield a desired reaction product on a continuous basis. The versatility and usefulness of continuous-flow reactor (CFR) technology is expanding rapidly with an ever broadening scope of applicable chemistries and the development of new flow technologies (3). Champions of continuous-flow technology cite a wide range of potential advantages compared with traditional batch manufacturing of pharmaceuticals.  In general, the greater optimization and control achievable with CFR technology can translate to significant savings in time and costs and can have a favorable safety and environmental impact. Furthermore, the small-reaction volume, broad operating pressure and temperature ranges, and mixing efficiencies of flow reactors extends the repertoire of chemistries beyond that of the safety and technical limitations of batch reactors. The capital investment for CFR technology is also substantially less as is the footprint required in the plant than a similar capacity batch-reactor system. However, even though the potential advantages of CFR technology can be significant, the technology is currently not applicable or practical in all situations. 

Adapting CFR technology to early-stage development projects has significant merit, but also significant challenges. CMOs work with numerous sponsor clients, diverse chemistries, and projects in all stages of development. Many of the projects CMOs encounter are very early stage with the development candidate being licensed out of an academic laboratory or coming directly from the sponsor company's discovery laboratories. These early-stage projects more often than not require various degrees of process research and/or process development to make the discovery synthesis amenable to current good manufacturing practice (cGMP) scale-up. Also, to receive additional funding or secure a development partner, the sponsor company has a strong sense of urgency to enter the clinic and achieve proof-of-concept as soon as possible. This puts pressure on the CMO to rapidly develop a scalable process to meet the near-term active pharmaceutical ingredient (API) goals of the sponsor company and at the same time enable the process to further scale-up to meet later stage API demands.   

Small-molecule drug development processes are typically in the range of six to eight synthetic steps. Given the time constraints and level of technical challenge, the design of an initial six to eight step totally continuous-flow process for an early-stage drug development project is generally not practical and is typically reserved for established commercial processes. CFR technology, however, does offer the distinct advantage of broader scaling capabilities for chemistries not suitable to batch scale-up. This scalability feature of CFRs is appealing for circumventing nonscaling problematic chemistries in a timely fashion. It is not uncommon for there to be one or more steps in an initial discovery synthesis that is not amenable to batch processing. When this occurs, significant time, effort, and money have to be invested in process research and/or development to resolve the chemistry or retool the synthesis. CFR technology, on the other hand, offers the potential to scale the existing problematic chemistry to overcome the bottleneck. For example, Johnson and Johnson (New Brunswick, NJ) demonstrated the utility of CFR technology for rapidly scaling gram to kilogram quantities of early-stage clinical trial API where batch processing was a concern (4). Several classes of reactions that presented safety or hazardous concerns for batch manufacturing were shown to scale efficiently, safely, and with shorter process research times. The reaction classes reported by the Johnson and Johnson group included exothermic reactions, reactions at elevated temperatures, reactions with unstable intermediates, and reactions involving hazardous reagents (4). Implementing CFR technology in an otherwise batch process to resolve early scalable issues provides an attractive strategy for expediting early-stage process development. Under this mixed "batch-CFR" paradigm, the problematic step(s) can be optimized to a CFR early on in the process allowing the chemistry to be readily scaled from grams to kilograms. Manufacturers of continuous CFRs such as Corning (Corning, NY) make smaller scale reactors that can be used for optimizing the continuous-flow chemistry on a small scale and employing the smaller reactor to make the desired product on a scale of grams to about a kilogram. When larger-scale production is required, the chemistry is readily transferred to an identical larger reactor simplifying the technology transfer process from laboratory scale to plant scale. Consequently, the "Batch-CFR" approach has the potential to be more expedient and cost effective as it takes advantage of CFR technology's ability to scale existing chemistry that is not suitable or safe for larger-scale batch processing. CFR technology may also allow the CMO to scale reactions beyond the capacity of their fixed reactors as an alternative to doing a technology transfer to another facility with larger fixed reactors. 

The contract manufacture will still likely use fixed equipment to process the continuous-flow reaction maelstrom. Although significant gains have been made in in-process monitoring and continuous crystallization, at the present time, it is more expedient for early-stage continuous flow reactions to be worked-up using traditional methodology such as filtration, extraction, solvent removal, and crystallization in fixed equipment. If the project moves to commercialization, particularly in the hands of a large pharmaceutical company, the process is more likely to become a fully optimized continuous process from start to finish. With a "Batch-CFR" process, this transition should be facilitated since the more challenging chemistry has already been adapted to CFR technology. 

The decision by a CMO to implement CFR technology to resolve a process scale-up issue is a critical risk decision requiring buy-in from the sponsor client. The technology holds significant promise for efficient and cost-effective development of early-stage cGMP processes. The "Batch-CFR" approach provides a much greater probability for scaling the initial discovery synthesis directly, thereby requiring significantly less process research and development work. CFR technology, however, requires different strategic thinking and technical expertise compared with classical batch manufacturing. Because most drug-development professionals are classically trained, there is likely to be some natural resistance to implementing CFR technology in early-drug development. This mindset has been referred to as "batch mentality (5). However, with FDA and the pharmaceutical industry encouraging the shift to CFR technology, contract manufacturers are likely to follow suit.   

, is vice-president of business development at Ash Stevens, 18655 Krause Street, Riverview, MI 48193, tel. 734. 282.3370 Ext. 1144, 

 2.  B. Trout and W. Bisson, "Continuous Manufacturing      of Small Molecule Pharmaceuticals: The Ultra-Lean Way       of Manufacturing," 2009 MIT Global Operations     Conference, Dec. 2, 2009, 

http://ilp-www.mit.edu/images/conferencemedia/trout.pdf

Beilstein J. Org. Chem.     Thematic Series 4

 (15), A. Kirschning, Guest Ed.,      Apr. 29, 2009, 

http://www.beilstein-journals.org/bjoc/browse/singleSeries.htm?sn=4

 4. X. Zhang, S. Stefanick, and Frank J. Villani,

www.pharmamanufacturing.com/articles/2010/088.html

The current trend in the pharmaceutical industry for the manufacture of small-molecule therapeutic agents is moving toward continuous flow processes. This article is part of a special issue on APIs.

Contract Manufacturing and Continuous Flow Reactor Technology for Early-Stage Drug Development

Continuous chromatography using the simulated moving bed (SMB) process has been used in the pharmaceutical industry for the past 15 years, mainly for the purification of enantiomers (1–3). This technique is well established and accepted as a unit operation to achieve high enantiomeric purity at a competitive price compared with other techniques such as classical resolution or dynamic kinetic resolution. The need for high purity at a low cost is a major reason for the pharmaceutical industry to evaluate new tools or apply existing tools in new applications for achieving an economical process. Continuous chromatography can provide economical solutions to a broad range of purification problems.   

The US Food and Drug Administration and other regulatory agencies encourage the pharmaceutical industry to develop drugs with fewer side effects for the benefit of the end user. Better understanding of the mode of action of an active pharmaceutical ingredient (API), as well as tragedies such as the thalidomide-related birth defects in the 1960s, drove the need to achieve chiral purity. Enantiomeric purity can be achieved in two ways. The desired enantiomer can be synthesized directly by using either naturally occurring chiral building blocks as starting materials or by asymmetric synthesis through chemocatalytic or biocatalytic methods. Asymmetric synthesis is often considered the most elegant solution by chemists (4). It is an attractive option, but it may require large development efforts and associated costs.  

Another method is to prepare the racemate and separate the desired enantiomer from the unwanted enantiomer. This approach has the advantage of producing both enantiomers during early development, which allows each enantiomer to be analyzed in toxicology studies and to be used to generate reference standards for analytical purposes. The chiral separation can be achieved either by salt resolution, enzymatic resolution, or chiral chromatography. Salt resolution is common, but it involves a three-step process: salt formation, resolution, and product recovery. This process requires large amounts of solvents and generates the equivalent amount of waste. Enzymatic resolution can be efficient, but its success relies on the identification of the best enzyme for the process. Sometimes several generations of enzymes need to be engineered before an optimal biocatalytic route can be developed. Chiral chromatography quickly provides a solution that can be cost effective. In two to three weeks, several chiral stationary phases (CSPs) can be screened with various mobile-phase compositions to identify separation conditions. At this point, either a batch or a continuous chromatographic method can be used. Typically, for small quantities, a batch preparative column (1–8 cm in diameter) is easy to set up and can provide the desired amount of product in a short period of time with a minimum investment in CSPs and solvents. When quantity requirements are larger, a continuous process such an SMB can be considered. Only a few more data points are usually required to develop the SMB process. Ultimately, a demonstration can be performed on a benchtop unit equipped with small columns to obtain the actual productivity of the separation and generate data for the scale-up. The total development time for a SMB process is approximately six weeks. After this initial work, the process can be demonstrated at any scale without additional development. 

The scale-up of chromatographic processes follows a simple linear rule based on the square diameter of the columns. All the parameters gathered at small scale are sufficient to calculate the process throughput and quality at any other scale. As a result, the development time for an SMB process is short. In a matter of weeks, one can have an idea of the performance of the process. Scale-up to commercial scale is straightforward and usually limited only by the availability of the feed material to be separated or by the availability of the equipment. Because of the cost of the CSP as well as the quantity of solvent involved, small-scale separations can be relatively expensive even though they may not be the most efficient. These considerations are normally balanced by the short period of time needed for development compared with other methods. Once the process reaches commercial scale, the CSP is usually amortized over a large amount of product, so the contribution of the CSP to the final product is small. AMPAC Fine Chemicals (AFC, Rancho Cordova, CA) has operated two large-scale SMB units for the same product using the same packing material for more than 10 years in one unit and for five years for the second unit (see Figure 1). During that time, the amount of product processed was more than 2500 metric tons of racemic feed using only about 400 kg of CSP. Additionally, the solvent used for the process can be integrally recycled. SMB is an isocratic process that operates under mild conditions. Unless volatile impurities in the product build up in the solvent and eventually affect the process, typically more than 99% of the solvent is recycled without difficulties. In the first stage, 65–85% of the solvent is stripped from the product in falling-film evaporators. This solvent is directly recycled to the eluent tank. The remaining solvent is recovered from the drying process (see Figure 2). This solvent is returned after appropriate quality controls to the eluent tank or to a make-up tank. As a result, the solvent consumption at commercial scale is low. The 5 X 1000 mm SMB unit uses about 38,000 gallons of solvent per day, but only three to six 55-gallon drums of solvent per month are used to make up the inevitable losses from the process. In 2007, AFC received the Pollution Prevention Recognition Award from the Chemical Industry Council of California and the Department of Toxic Substance of California for implementing recycling in its commercial-scale SMB units. 

Figure 1: A simulated moving-bed chromatography unit (5 x 1000 mm) at AMPAC Fine Chemicals' Rancho Cordova, California, facility. (FIGURE IS COURTESY OF THE AUTHOR)			

The fate of the unwanted enantiomer is an important factor. Because 50% of the manufactured product is to be discarded, it is important to try to conduct the separation as early as possible in the synthetic scheme to avoid carrying the dead weight throughout the process. It may be more economical, however, to conduct the chiral separation at a further downstream intermediate stage where the unwanted enantiomer can be recycled (i.e., racemized or sold as a side product). Under these conditions, the economics of the process drastically improve. 

Figure 2: Simulated moving-bed (SMB) chromatographic process for a chiral separation with eluent recycling and unwanted enantiomer revalorization. (FIGURE IS COURTESY OF THE AUTHOR)			

During the past five years, interest in continuous processes for the pharmaceutical industry has increased. FDA is in favor of continuous processes because they are compatible with the agency's quality-by-design (QbD) principles and are amenable to process analytical technologies (PAT). The pharmaceutical industry is interested in continuous processes because they are more efficient, cleaner, and safer than batch processes. They are also less demanding in terms of a manufacturing footprint and manpower. In short, they are more cost effective (5). Because continuous processes are amenable to QbD and PAT, there is less batch-to-batch variability, which results in a lower risk of batch rejection for failure to meet specifications and therefore better process economics. Continuous processes have been used for many decades in other industries. Almost all of the batch-unit operations in pharmaceutical manufacturing can be performed continuously, and these processes can be easily applied to pharmaceutical manufacturing. To successfully implement continuous processes, however, the conventional approach to process development needs to change. Evaluation of the kinetics and mass transfer is required for successful modeling and simulation of any unit operation. This assessment results in a better definition and understanding of the design space. It allows for the identification of critical parameters and their effect on product quality. A better process can be developed and implemented, thereby resulting in a more economical manufacturing process.  

To design and operate an SMB unit, it is necessary to understand the process and how its output evolves with changes in flow rates, temperature, or solvent composition (6, 7). Once the critical process parameters are identified and studied, the process can be designed and controlled efficiently. During normal operations, all parameters involved in an SMB operation can be controlled accurately using modern instrumentation and analytical tools. If these parameters are maintained efficiently and accurately within their desired range, the output of the process will consistently be within specifications. Regular sampling or on-line testing is performed to monitor the SMB output and ensure compliance. Recently, the University of Zurich and the equipment manufacturing unit of Novasep (Pompey, France) developed a controller that can automatically adjust the SMB parameters to maintain the product quality and the optimum throughput based on a regular sampling of the SMB output streams (8). This kind of smart automation has not yet been implemented at a commercial scale, but it is an improvement that should find its way to the production floor soon. 

 SMB is well established as a binary process that combines the performance of chromatography with the economical benefits of a continuous process. This technique is successfully applied in the pharmaceutical industry for the chiral separation of APIs and intermediates. Chiral separations are only a few of the processes that can benefit from SMB. A few years ago, the purification of crude paclitaxel, a natural high-potency product, was implemented using an SMB process (9). The separation was complex due to a large number of impurities. This process was turned into a binary separation where the troublesome impurities such as impurities not efficiently removed by crystallizations were eluted together in one SMB stream while the purified product was eluted in the other stream. As a result, a crude product with overall purity of approximately 75% was increased to a purity of more than 95% with a recovery greater than 98% before the final crystallization. 

 The latest application of SMB is the purification of large molecules for the biopharmaceutical industry. Chromatography (i.e., ion exchange and size exclusion) is used to purify the expensive molecules produced from bioreactors and fermenters. These processes usually require large amounts of water-based mobile phases. An increasing number of scientific publications addresses the conversion of these inefficient batch processes into continuous processes (10, 11). Because these batch separations usually require several steps (i.e., loading, elution, and regeneration), the basic set-up of an SMB unit needs to be modified to apply this technique to these separations. SMB units with five zones or more have been designed. These design variations may make the process more complicated, but nevertheless improve throughput and solvent consumption. Other difficult separation problems can also be solved using SMB technology. A few examples, recently developed at AFC, are described below and show how SMB can be efficiently used in API manufacturing.  

SMB modifications for increased throughput.

 SMB provides a significant advantage over batch chromatography when the selectivity of the separation is rather low.  In the case of high selectivity, batch chromatography may outperform SMB because of flow and operating pressure constraints. In an SMB unit, the flow rate in the first zone of columns pushes out the most retained product. For a long retention time, it takes a high flow rate to push everything out of the column before the column switch occurs. Because all the zones of the SMB are connected, if one zone is operated at a very high flow rate, then the other zones must be operated at a lower flow rate. This zone manipulation is necessary to manage operations below the maximum operating pressure of the system. As a result, the production rate is reduced. AFC developed a simple modification to the process (see Figure 3) that alleviates the pressure constraint by decoupling the first zone of the SMB from the other zones of the SMB unit (12). This additional zone allows for a rapid wash of the column with the mobile phase at maximum operating pressure without affecting the pressure in the other zone. As a result, the rest of the separation can be conducted at a higher flow rate and therefore at a higher throughput.  

Figure 3: Comparison between traditional four-zone simulated moving-bed (SMB) and the modified SMB system for separations with large selectivity or increasing retention time. (FIGURE IS COURTESY OF THE AUTHOR)			

SMB for chiral separations and  impurity removal.

 Ideally, racemic feeds only contain the two enantiomers.  Unfortunately,  in most cases, a few impurities that are closely related to the product also are present in the mixture. These impurities are usually either leftover starting material or side products from previous reactions. In either case, they might be difficult to remove during downstream processing without sacrificing yield. The chiral SMB separation can potentially be used to purify the product as the enantiomers are separated. Many publications describe the SMB process, but they rarely address impurities (6, 7, 13). If an impurity is present in the racemic product, it can potentially be doubled after the separation because approximately 50% of the mass of the feed is removed. Therefore, it is important to know the fate of the impurity during the SMB separation.  

Five major cases can be identified, and Figure 4 shows some examples of the removal of an impurity with a chiral separation. The first case is when the impurity elutes with the desired compound (see Figure 4a). The only way to address this case is to change the separation conditions. The second case is when the impurity elutes with the unwanted enantiomer. This is a good case because the impurity will be completely removed (see Figure 4a). If the second enantiomer is to be recycled by racemization, one must ensure that the impurity is addressed in the recycle step to avoid accumulation over time. For the third case, the impurity is eluted between the two enantiomers (see Figure 4b). This case is more difficult but can usually be solved with the existing separation method. The fourth and fifth cases are when the impurity is eluted much later or earlier than the enantiomers (see Figure 4c). Under these conditions, the impurity is usually distributed evenly in both the extract and the raffinate streams. By adjusting certain flow rates, it is possible to control the ratio of the impurity in the outlet streams. 

Figure 4: Separation of impurity(ies) during a chiral resolution by chromatography shown with simulated chromatograms. The red graphs represents an overall chromatogram, and the blue graph denotes the impurity(ies). Figure 4(a) is an impurity eluting with one of the enantiomers. Figure 4(b) is an  impurity eluting between the two enantiomers. Figure 4(c) shows impurities eluting much earlier or later than the enantiomer. (FIGURE IS COURTESY OF THE AUTHOR)  			

 During the past few years, there has been a lot of interest in the identification and removal of genotoxic or carcinogenic impurities to very low levels in APIs. This removal is usually difficult to do by traditional crystallization techniques without losing significant amounts of product in the mother liquor. Chromatography is one technique that can achieve very high purity while maintaining a high recovery of product (i.e., greater than 95%). The removal of a toxic impurity is a binary separation and can be done by SMB. These separations can normally be developed on normal-phase packing materials (i.e., bare silica or silica functionalized with a cyano or amino group, for example). These phases are not as expensive as chiral phases and provide larger loading capacity, thereby resulting in high throughput.  

AFC recently developed an SMB process to solve an impurity problem that was originally performed using crystallization to remove an impurity from about 1% to 10 ppm. The purification was performed using crystallization and required two to three crystallizations with an 85% yield for each step, thereby bringing the overall yield to 61–72%. As an example, the processing of 50 metric tons of this intermediate using crystallization would result in only 30.7 metric tons of pure product after three crystallizations. Assuming that each crystallization adds a cost of $30/kg to the product and that the crude feed costs $1000/kg, the crystallization process increased the pure-product cost to $53.3 million or $1736/kg. Despite a relatively cheap crystallization process, the overall cost of the product is drastically increased because a significant amount of product is lost to the mother liquors. Alternatively, if the purification is done by SMB and the estimated cost for the SMB separation is $50/kg, then the associated manufacturing cost for the pure product is only $52.4 million or $1104/kg with a total of 47.5 metric tons of pure product recovered. The lower cost of the SMB process is mostly due to the high recovery of product because it is not lost in the mother liquors as in the crystallization process. In this example, a 95% recovery was estimated; however, at commercial scale, typical yields of > 98% are realized. This difference in cost between the two methods can significantly increase when the price of the material to purify increases. 

 It is not unusual for a chemical synthesis to require more than five steps of chemistry, and every manufacturer is looking to improve the overall yield as much as possible by fine-tuning every unit operation involved in the process. Once the chemistry has been optimized to provide the best possible conversion and the best yield, a major loss of product can happen during the final crystallization and subsequent product washes.  Ideally, these steps (i.e., crystallization and washes ) are conducted with a solvent that can solubilize the impurities but not the product. Unfortunately, the product is always slightly soluble in the crystallization solvent and the wash solvent. As a result, 5-20% of the valuable product can be lost to the mother liquor and the cake washes. It is very difficult to recover the product from these effluents because of the level of impurities is significantly higher. Additional crystallization will only result in marginal product recovery and is usually not economical.   

AFC recently developed a process to reclaim the product from these effluents by using continuous chromatography.  In one specific case, the mother liquor contained about 30% of the desired product and two major impurities that prevented further product recovery by classical crystallization. AFC developed a chromatographic separation process that allows the product to elute away from the main impurities.  This separation becomes a binary-like separation that can be processed on an SMB unit. Once the purified product is recovered from the SMB, it can be crystallized using the normal crystallization method. Because the crystallization process has an 87% recovery, the 13% product loss was reclaimed in the SMB with a 95% recovery. This material is crystallized with an 85% yield, corresponding to a recovery of 10.5% of the original quantity. By adding these two steps, the total yield of the process increases from 87% to 97.5%.  The additional SMB and crystallizations steps, however, add cost to the final product. In this example, however, the savings in the raw material were significant.  

Continuous chromatography can provide a step-change in process economics. SMB technology was developed more than 50 years ago and is intensively used in the food and petroleum industry to achieve low manufacturing costs.  This technology also has been implemented successfully in highly regulated environments for the manufacturing of pure chiral APIs. The justified interest in continuous processes and the push by regulatory agencies for more efficient, controlled, and robust processes are major reasons to implement continuous chromatography in manufacturing operations. High purity with high yield at a low cost is achievable. The technology, the experience, and the know-how are available to perform these operations at all scales.   

 PhD, is director of process technologies, AMPAC Fine Chemicals, PO Box 1718, Rancho Cordova, CA 95741, tel. 916.357.6242, 

 6. M. Schulte et al., "Process Concepts" in 

, Henner Schmidt-Traub, Ed. (Wiley–VCH Verlag GmbH & Co. KGaA, Weinheim, Germany (2005), pp. 173–214. 

 7. A. Susanto et al., "Model Based Design and Optimization" in 

, Henner Schmidt-Traub, Ed. (Wiley–VCH Weinheim, Germany, 2005), pp. 215–369. 

 12. O. Dapremont,  "Simulated Moving Bed Chromatography for Strongly Retained Compounds," US Patent 7,618,539 B2, Nov. 2009. 

The author presents recent developments in simulated moving-bed chromatography in production of active pharmaceutical ingredients and intermediates. This article is part of a special issue on APIs.

Evolution of Continuous Chromatography: Moving Beyond Chiral Separations

Verification of an excipient's pedigree and comprehensive incoming inspection data are important elements of supply-chain security. Without adequate implementation of both components, a pharmaceutical company can be exposed to nefarious activities comparable to a computer user whose Internet activities are unprotected by a firewall and antivirus software. As demonstrated by recent global supply-chain breaches, excipients are vulnerable to contamination, counterfeiting, and adulteration.  

In May 2010, the International Pharmaceutical Excipient Council (IPEC) published criteria for excipient pedigrees (1). Pedigree criteria is based on good distribution practice (GDP) guides from the World Health Organization, IPEC, and the Product Quality Group (PQG), and cover auditing, Certificate of Analysis (CoA) data, distribution and holding, and more. The specific criteria can be implemented using the checklist for supply-chain security (see sidebar, "Checklist for supply-chain security"), and can be supported by the supply-chain security flow diagram shown in Figure 1. Use of these materials can help industry confirm that a purchased excipient arriving at the receiving dock has been produced in substantial conformance to excipient good manufacturing practice (GMP) and minimizes risk that the material has been tampered with or otherwise adulterated en-route. 

The first task in establishing excipient-pedigree authenticity is to identify the path from receipt of material back to the original excipient manufacturer. Unless the excipient is shipped directly from the manufacturer, the excipient user must trace the material's path from the final shipping point upstream to the manufacturer. This process can involve several stops along the distribution supply chain. At each stop, the pharmaceutical user should confirm through review of the shipping papers (i.e., papers included in the US Bill of Lading or Airway Bill) that the excipient lot in question was handled by the distributor and is traceable upstream to the previous stop. The path ends when the excipient manufacturer's shipping papers are identified, thus confirming the identity of the manufacturer and the full supply chain. 

Figure 1: Supply-chain security flow diagram. GMP is good manufacturing practice; GDP is good distribution practice; CoA is Certificate of Analysis. (FIGURE IS COURTESY OF THE AUTHOR)			

				 The second step in implementing the checklist involves performing an assessment of the manufacturer to confirm that the excipient was produced using an excipient GMP compliant quality system (2). In addition, each stop in the distribution supply chain must be assessed to confirm that the excipient was handled in compliance with applicable GMP and GDP requirements (3). 			

Industry best practice is to visit and audit the original excipient manufacturing site. Relying solely on responses from questionnaires no longer meets regulatory expectations under current GMP for supplier qualification. In a recent conference presentation, FDA announced that pharmaceutical users may soon be expected to audit their excipient suppliers themselves or to use a qualified third-party auditor (4). The pharmaceutical user should assess the third-party provider and confirm that it is qualified. At the conference, FDA said pharmaceutical manufacturers would be expected to audit their suppliers or use an accredited third party or qualified third party to do so. The American National Standards Institute (ANSI) has accredited an organization to provide certification to excipient GMPs that is accepted by FDA.   

Before any on-site audit, it is advisable to send the supplier a pre-audit questionnaire that includes a request for the manufacturer to list the applicable quality system under which the excipient was manufactured. The pre-audit questionnaire can also facilitate the site audit by providing applicable background information. The questionnaire should identify the scope of operations conducted at the site. For the manufacturer, the response should identify contract operations, which also require auditing.  

For the distributor, the response to the pre-audit questionnaire must identify the scope of its operation and whether other on-site operations might affect excipient quality. For example, the distributor may package bulk excipient or repackage excipient into smaller packages. The pharmaceutical manufacturer also must confirm that the distributor samples and tests the excipient to confirm there has been no contamination or degradation of the material. Once the pre-audit questionnaire is completed, the pharmaceutical user can finalize an audit plan and schedule the on-site audit.  

A secure supply chain can be achieved when all parties are confirmed to be in compliance with excipient GMP and GDP requirements. It is also crucial to establish procedures to ensure the quality of the excipient upon receipt. Current industry practice for approving/accepting an excipient from a qualified supplier is to confirm the quality of the excipient based on the CoA and identification testing. Industry best practice is to expand this approach to include confirmation that the excipient has not been tampered with at any stage of its distribution cycle.  

A tamper-evident seal for each excipient package can help provide such assurance. However the individual responsible for receiving an excipient often must deal with different seals because each supplier should use a unique seal. An authentic photograph from each excipient supplier showing the tamper-evident seal should be available to the receiver so that he can confirm that the package's original seal has remained in place while en-route. Authentic photographs of both the excipient package and label can provide additional assurance that the excipient was not repackaged.  

Overall, receipt of excipients involves satisfactory completion of the following steps: 

1. Confirmation according to shipping papers that the excipient came from the approved supplier 

2. Verification that the package has not been tampered with by comparing the package and its seal with authentic photographs and packaging descriptions. This step includes determining whether:  

  a. The excipient was received in the approved packaging (contact packaging and secondary containers) 

  b. The authentic tamper-evident seal is in place 

3. Scientifically justified sampling of the excipient packages and confirmation that the excipient passes appropriate identification testing. 

4. Verification that the CoA demonstrates that the excipient meets the compendial monograph or appropriate specification. 

Periodically, the pharmaceutical user also should verify that the qualified supplier produced the excipient and that the CoA is authentic. Confirmation of the manufacturer can be accomplished by using shipping papers to trace the supply chain. CoA authentication can be achieved by sending the CoA to the excipient manufacturer to verify that it is unaltered. 

Recent incidents have sensitized the pharmaceutical industry to economically motivated adulteration and excipient vulnerability. Many presentations and papers have addressed supply-chain security, but the practice of receiving and approving excipients must be strengthened to fully ensure drug product safety.  

 is vice-president and chief operating officer of International Pharmaceutical Excipients Auditing (IPEA), a subsidiary of the International Pharmaceutical Excipients Council (IPEC), tel. 732.463.8710, 

 2. IPEC–PQG, Joint IPEC–PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients (2005). 

 3. IPEC, Good Distribution Practices Guide for Pharmaceutical Excipients (2006). 

 4. B. Hasselbalch, "Public Health Challenges for the Quality of Human Drugs," presented at FDA–Xavier University Global Outsourcing Conference (Cincinati, June 2010). 

The author explains the background behind the excipient pedigree and how to implement its use.

Excipient Pedigree Verification

Pharmaceutical and fine-chemical production is dominated by batch processes, which enable many kinds of reactions and can handle multiphase systems in multipurpose plants. Operators can arrange vessels in various configurations to establish several reaction routes and even certain work-up steps such as distillation or extraction. Production quantities of pharmaceutical intermediates or active pharmaceutical ingredients (APIs) vary from a few grams in the first medicinal studies to several hundred tons per year for successful pharmaceutical products. This wide production range demands various manufacturing devices at several scales for process transfer.  

The first laboratory studies work with just a few grams of reagents in glass flasks, but continuous-flow devices with integrated microchannels also produce these quantities (1). Process development leads from small-scale production, to sample production at pilot scale, to large-scale production (2). Often, during the scale-up of the chemical process, a wide range of stirred vessels is used to perform the reaction. Heat transfer and mixing rate, however, are often limited in stirred vessels, which need high dilution, long operation or dosing times, and sometimes do not permit highly exothermic reactions. One solution is to combine the versatility of batch vessels with the safety, reproducibility, and high transport capabilities of continuous-flow microstructured equipment. 

Microstructured devices with small internal volumes and high surface-to-volume ratios offer transport capabilities for rapid mixing, enhanced heat transfer for good temperature control, and intensified mass transfer (3). The proper control of these often harsh conditions is not only essential for the safe operation of chemical equipment, but also necessary to enable an economical chemical process. Harsh conditions with an unusual range of temperature, pressure, concentration, mixing time, and residence time make new process windows and process routes available, and enable the manufacture of new chemical intermediates. These conditions and routes are not feasible in batch vessels or cannot be maintained during process scale-up (4–6). But harsh reaction conditions can be handled safely in closed systems with small internal volumes.  

Microstructured devices operate under continuous flow conditions. Generally, continuous processes offer many advantages ranging from controlled process conditions to high flow rates and mass throughput. Continuous operation enables bulk-chemistry processes to have high production capacities. Fluid dynamics determine the characteristics of continuous-flow equipment such as pressure loss, residence time, heat-transfer characteristics, and mixing time. The combination of continuous-flow processes with microstructured devices brings benefits to the laboratory and production environments. This article discusses microreactors with a single rectangular channel, typical diameters from 0.2 to 2.0 mm and higher, moderate flow rates (e.g., 10–300 mL/min), and Reynolds numbers in the transitional regime (i.e., 100–3000) from straight laminar to turbulent flow. The authors describe process design and related issues with generic examples, as well as with real chemical examples from Lonza's (Basel) experience.  

Equipment design for single-channel microreactors

Lonza designed a small, compact plate device called the LabPlate reactor to visualize the flow inside the microstructured channel. The device enables personnel to design reactor channels and develop processes with low flow rates when reagent availability is limited. Process conditions are similar to those in capillary chemistry, as well as in larger reactor devices, with the advantage that the reaction zone can be inspected and viewed. Multiphase reactions can be observed with phase distribution, as can the precipitation of metastable intermediates. 

The fluid entering the microchannel within the reactor plate passes through the entrance, contacting element, and several mixing- and residence-channel elements, each with its own design (see Figure 1). The entire LabPlate reactor consists of a cooling block with cover plate, microstructured plate, view glass, and flange housing (see Figure 2). The fluids are sealed against the external environment by conventional O-rings; the reagents and heat-exchange medium are separated by metal walls. The modular setup allows the integration of several microstructured plates, as well as the integration of the reactor into other flow equipment. The entire device can be integrated into a modular microreactor system (MMRS, Ehrfeld Mikrotechnik BTS, Wendelsheim, Germany) (7). 

Figure 1: (Left) A LabPlate reactor (Lonza, Basel) with microstructured channels and thermal fluid and reagent connections. (Top right) A typical mixing channel with nozzle-type contacting element and tangential mixing elements. (Bottom right) A single mixing channel during a gasâliquid test reaction in the LabPlate microreactor. (IMAGE IS COURTESY OF LONZA)			

Lonza developed a plate stack reactor for reactions that typically take minutes to complete (see Figure 2) (8). The reactor is based on the multiscale approach, which adapts plates of various sizes to the reaction needs. For example, operators may use a tiny channel at the start of the reaction, when heat generation is strong, and gradually increase the size of the plates to accommodate slower reaction rates (i.e., less heat evolution). This design optimizes heat transfer, minimizes pressure drop, and greatly increases volume (i.e., by as much as several mL). In addition, the reactor may be combined with conventional heat exchangers and tube equipment to gain several liters of volume and several minutes of residence time. Lonza manufactures and distributes the reactor in cooperation with Ehrfeld Mikrotechnik BTS (7). 

Figure 2: A microreactor (LabPlate, Lonza, Basel) for development purposes, including a microstructured plate with heat-exchange block and connections for the heat-exchange medium (left) and a typical plate-stack reactor setup with A6 or A5 size (right). (IMAGE IS COURTESY OF LONZA)			

The microstructured reactor plates are made from corrosion-resistant material and can perform various tasks in a modular setup. Plates are designed for mixing and heat exchange. Mixing plates include a mixing channel as well as wider channel elements to provide sufficient reactor volume for heat exchange and appropriate residence time. In an effort to standardize Lonza's proprietary MicroReactor design, the company chose production-plate sizes based on the European A4, A5, and A6 standard paper sizes. Each size features a plate area double that of the previous size, thus doubling the heat-exchange area and reactor volume. The sizes enable scale-up, which is related to the reaction's kinetics (9). Thus, for rapid reactions with typical reaction times of less than 1 s (i.e., mixing controlled, Type A), the aims are the following:  					

To ensure sufficient cooling between the reactor plates and mixing channel

To provide short mixing times in tiny, complex channels with a comparable high-pressure drop.

For rapid reactions with typical reaction time between several seconds and 10 min. (i.e., kinetically controlled, Type B), the aims are the following: 									

To maintain volume for sufficient residence time for the reaction and the same area-to-volume ratio for enhanced heat transfer

To optimize mixing quality by choosing a pressure drop as low as possible.

Slow reactions with a characteristic time of more than approximately 10 min. (i.e., Type C) can be performed in conventional equipment such as static mixers or tube reactors. However, for rapid reactions, all the reactor plates are microstructured because mixing and heat exchange are the dominant factors. For intermediate reactions, the same plate depth is used for the various plate formats, thereby keeping the surface-to-volume ratio constant. The gradual size increase of reactor plates (i.e., the multiscale approach) and appropriate channel geometry allow the MicroReactor to operate at flow rates as high as 600 mL/min. 

The modularity and versatility of the single channel and plate-in-series approach allow the development of plates appropriate to a multitude of applications. Lonza designed, manufactured, and applied plates for rapid mixing, gas–liquid dispersions, and multi-injection applications in various projects, thus demonstrating the technology's suitability for various purposes. The right side of Figure 2 shows the individual reactor plates made from Hastelloy C-22 sandwiched between aluminum plates with high thermal conductivity, a design that yields a compact reactor. In this way, the thermal fluid layer is not directly fixed onto the reactor plates, thus allowing for cost-effective manufacturing, as well as quick and easy adaptation to various reaction conditions. The overall reactor is robust, allows high flow rates of the heat exchange fluid, and can sustain pressures higher than 100 bar on the reaction side. 

In many reactions, especially with viscous systems and low-temperature applications, the pressure drop may become important at high flow rates. In addition, the mixing zone often is the plate section that consumes the largest pressure drop. Consequently, an enlargement of mixer elements at higher flow rates drastically reduces the overall pressure drop. In general, no loss of performance is observed as long as the same energy-dissipation rate in the mixing zone is maintained. Thus, the mixing zone is the only scaled factor that is considered in this reactor technology, and it must be properly designed and adapted. It is essential to operate a microreactor with one single channel and completely avoid device parallelization to scale up processes successfully from laboratory to pilot scale. 

The stepwise scale-up of the plates is accompanied by a stepwise scale-up of the channel cross section, leading to a scaling factor of approximately 1.4 between each two steps. For example, the typical hydraulic diameters of the mixing channel in the A6 reactor plate are 0.35 and 0.5 mm. The A5 reactor plate therefore contains mixing-channel structures with typical diameters of 0.7 and 1.0 mm. Larger plates are scaled up accordingly, thus creating comparable mixing conditions. To gain residence time, the heat-transfer area and internal volume are increased in corresponding steps of connected plates in series. These measures result in a consistent, versatile, and flexible scale-up strategy that completely avoids parallelization over a wide range of flow rates (10). 

In addition to reactor size, the operational conditions are changed accordingly. Small reactors such as the LabPlate and A6 Lonza MicroReactor are well suited for projects in process development. They fulfill the needs of early-phase studies in a consistent and straightforward manner. Larger A5 MicroReactors are suitable for small-scale and pilot-production campaigns. 

Project approach for continuous-flow processes

The main goal in laboratory development is to achieve a robust process because chemical systems are often metastable and tend to form deposits that are more or less stable over time. Precipitation or fouling within the channels creates unpredictable pressure drop behavior over the reactor. The reactor technology must facilitate timely and flexible process development and minimize the need to consider chemical engineering during process development. Thus, the use of one single channel, together with robust, pulsation-free high-pressure pumps, ensures correct feed balance and stoichiometry, as well as the ability to clean the reactor during and after operation. 

The MicroReactor concept also indicates a certain project-management strategy for converting a batch protocol into a continuous-flow process. The base is a detailed mass balance with stoichiometry, including all starting materials, intermediates, and products, as well as major side products. A preliminary short feasibility study with a LabPlate or A6 MicroReactor indicates the potential advantages of performing a given chemistry in a continuous-flow process. Typical parameters such as concentration and mixing ratios, mixing and residence times, reactor temperature, and pressure can be tested. A decision at the end of each step allows good project control and shortens the time needed to make a decision.  

If results are positive, operators can perform a parameter-optimization study to develop a robust process with sufficiently high yield and selectivity. A flexible and modular reactor setup with pumps, sensors, control system, and residence-time loops allows the investigation of a wide range of process parameters and will give a huge amount of data from kinetics and chemistry. These data are important for the design of the final production process. A long run of several hours in the laboratory at the end of the optimization step ensures the achievement of a robust and reliable process that can be scaled up to pilot scale.  

The production campaign on pilot or large scale can be performed with the same reactor equipment used in the laboratory, but with longer operation times and appropriate peripheral equipment. The high flow rates typical of production can be tested in the laboratory for a short period to guarantee appropriate reactor performance. This approach enables operators to avoid a parallelization of reactor equipment, including in production campaigns. The approach also provides flexibility and manageable cost scenarios and time limits. In additionally, it avoids the risk of a technology jump from laboratory to production scales. 

All reactor types displayed in Figure 2 are used frequently in Lonza's laboratories and production environment. A real-case example of a two-step organometallic reaction (i.e., lithium–hydrogen exchange and coupling) demonstrates the scale-up of microreactors. The reaction had three feeds: Feed-1 with substrate, Feed-2 with the first reagent, and Feed-3 with the second reagent. The reaction was stoichiometric and operated at two temperature levels. Feed-1 and Feed-2 were precooled to the cryogenic reactor temperature (i.e., –35 °C), and the second reaction was performed without cooling at room temperature. The flow diagram and reaction scheme are depicted in Figure 3. 

Figure 3: Reaction scheme of a two-step reaction, corresponding process scheme with two reactors, and image of the plant setup in a pilot-plant environment. Three feed lines and the MicroReactor (Lonza, Basel) with iced surface (â35 Â°C reactor temperature) are visible. (IMAGE IS COURTESY OF LONZA)			

The first reaction was of Type A with an adiabatic temperature rise of more than 75 °C. This reaction was performed in four units: a static mixer, a glass microreactor, and the Lonza A6 and A5 MicroReactors. The second reaction was of Type B and less demanding in terms of heat exchange (Δ

 < 25 °C) and mixing. A microreactor and static mixer performed equally well.  

Personnel observed no adequate temperature control within the static mixer for the first reaction. Roughly the entire adiabatic temperature rise was detected at a medium flow rate (i.e., 148 g/min). Many unwanted side products were formed, and yield dropped visibly compared with that at lower flow rates (i.e., 84% versus 89% on average).  

The glass microreactor showed a loss of temperature control at high flow rates, but it was not reflected in the product yield. The short residence time also was important for this process.  

Lonza's smaller (i.e., A6) and larger (i.e., A5) MicroReactor technology showed equivalent performance. It was possible to operate the A5 reactor at a speed of 237 g/min with a total flow rate higher than 700 g/min for the second reaction by keeping the pressure drop well controlled. A yield of 88% was achieved. A pilot campaign produced 700 kg of isolated material, thus yielding more than 10 m

  of processed solution through the reactor setup. A second campaign was performed to produce more than 2 tons of isolated material. Both campaigns demonstrated the long-term robustness of the process and the reliability of the installed reactor equipment. Further chemical examples from Lonza's experience demonstrate the versatility of the reactor toolbox described with various kinds of chemistry such as phosgene, ketene or diketene, ozone, or the production of nitrogen-containing compounds (5, 10). 

After more than a decade of microstructured devices in chemical production, the implementation of microreactors is essentially understood. The interaction of chemistry, reaction kinetics, involved phases, and transport phenomena plays the crucial role in appropriate reactor and plant design. It is important to determine the limiting steps in time scales and heat management. It is possible to run continuous processes in microstructured devices at the laboratory scale, and these processes can be scaled up to pilot and production scale with low risk. This multiscale production potential from grams to tons allows a high flexibility and offers short time-to-decision in a project.  

The Lonza MicroReactor technology represents a consistent and comprehensive scale-up approach and has benefits for the process research and development and manufacturing departments of fine-chemical and pharmaceutical companies. The technology illuminates a clear path from laboratory chemistries to large-scale manufacturing processes, and it completely avoids the parallelization strategies that may result in technical problems. This reactor platform supports rapid process development and production under continuous-flow conditions using microstructured elements. The developed reactor technology is modular, robust, multipurpose, and scalable and has already been tested for several products and processed tons of material during a campaign of a few weeks. 

 is responsible for business development, all at Lonza, CH-3930 Visp, Switzerland, tel. +41 0 27 948 50 27, fax +41 0 27 947 50 27, 

*To whom all correspondence should be addressed. 

 1. K. Geyer, J.D.C. Codée, and P. Seeberger, 

Transport Phenomena in Micro Process Engineering,

 (Wiley-VCH, Weinheim, Germany, 1st ed., 2008). 

 6. H. Pennemann, V. Hessel, and H. Löwe, 

The authors discuss a continuous-flow reactor that avoids parallel channels and enables economic plant setup. This article is part of a special issue on API Development, Formulation, Synthesis and Manufacturing.

Microstructured Reactors for Rapid Process Development and Scale-Up

Enantiomers of chiral compounds can have dramatically different pharmacological activities, thereby making the ability to assess and isolate pure enantiomers vitally important to pharmaceutical developers. Chiral chromatography is traditionally used as the stereoselective separation technique, with polysaccharide-based chiral-stationary phases (CSP) as the media of choice for more than 20 years.  

Although these CSPs have unparalleled application range and versatility, their main limitation has been the inability to tolerate certain solvents. Traditionally, chromatographers have needed to exercise extreme caution to avoid even small quantities of incompatible solvents that can rapidly degrade or destroy a column.  

Novel CSPs, based on proprietary immobilization technologies, were recently developed to safely accommodate virtually any organic solvent as a mobile phase or mobile-phase component. The CSPs derived using these technologies exhibit stability, separation reproducibility, and durability when used in normal-phase, reversed-phase, and supercritical fluid chromatography modes. 

The ability to use an expanded range of solvents for mobile-phase components and solvent dissolutions, as well as elevated temperatures, offers new possibilities for investigating conditions for obtaining separations that could not be achieved on solvent-restricted columns. These new capabilities demand a new approach to method development.  

 Immobilization technology was used to manufacture three types of columns, referenced here as Column 1, Column 2, and Column 3.  

Column 1 has an immobilized CSP with a tris-3,5-dimethylphenylcarbamate derivative of amylose.

Column 2 has an immobilized CSP with a tris-3,5-dimethylphenylcarbamate derivative of cellulose.

Column 3 has an immobilized CSP with a tris-3,5-dichlorophenylcarbamate derivative of cellulose that includes a unique chiral selector.

A statistical evaluation of a large number of chiral compounds indicated that, when used for screening, the three columns will separate 95% of chiral components. Using only a few mobile phases in the screening process delivers separations with exceptionally high success rates.  

The immobilized columns were thoroughly tested for stability to most common organic solvents, particularly those in which the chiral selector is soluble. These tests indicate complete stability to these solvents. For convenience, a limited range of solvents is recommended for initial screening, but ultimately, there are no restrictions on the solvents that can be used as mobile-phase components.  

Using immobilized technology effectively requires a new approach for method development. Table I lists a number of the primary solvents that may be used in a screening process to provide successful separations. Conventionally, the process is begun by using one of the mobile phases listed in Table I.  

Table I: First set of solvents for mobile-phase selection. 

Following analysis of the results, a weaker or stronger solvent composition is used to adjust retention of chiral compounds to achieve reasonable analysis time. For example, if the compounds are eluted too quickly, a weaker mobile phase should be used. Note that dichloromethane (DCM) and methyl-

-butyl ether (MTBE) will destroy conventional, coated polysaccharide-based chiral columns and should only be used with the new immobilized columns. 

The solvents in Table II can be used in those cases where resolution is not obtained using the primary screening solvents in Table I. Note, again, that the extended-range solvents will destroy conventional, coated chiral columns and should only be used with immobilized columns. 

Table II: Second set of solvents for method development. 

In the reversed-phase mode, the columns should not be operated below pH = 2 or above pH = 7. The upper range of Column 1 and Column 3 operations can only be extended to pH = 9, provided that a borate buffer and ammonium bicarbonate buffer are used, and that the guard column is changed at least once every 200 injections at this pH.   

Sample solubility is a key consideration in enantioselective high-performance liquid chromatography (HPLC) separations when scaling up from analytical, through semipreparative, to preparative columns. A wider variety of sample dissolution solvents can be used with a greater likelihood that sufficient sample solubility can be realized, thereby enabling higher sample loads. Chlorinated solvents, which are often preferred because they dissolve most organic compounds, are safe to use with the immobilized CSPs. 

Studies have confirmed that chloroform, tetrahydrofuran, ethyl acetate, DCM, MTBE and acetone can be safely and effectively used as mobile phases and sample diluents with the immobilized CSPs. Dimethylsulfoxide can be used as sample solvent with a slight loss of column efficiency. Column 1 can be readily regenerated by flushing with dimethylformamide. Columns 2 and 3 can be regenerated using any solvent from the extended range listed in Table II.   

The narrow temperature range tolerated by coated polysaccharide CSPs does not typically allow temperature to be used as a variable to control a separation. The immobilized CSPs are stable to at least 80 °C, giving an expanded temperature range, which makes temperature a variable worth investigating. 

The effect of temperature on chromatographic separations is fairly well established. In general, increasing temperature increases column efficiency but decreases both retention and enantioselectivity. The decrease in selectivity will vary between compounds, and the rate of decrease depends on the difference in binding enthalpies of the enantiomers. 

The effect of temperature on column efficiency depends on changes in mobile-phase viscosity, diffusion rates in the stationary phase, and kinetics of desorption. Some separations are improved using subambient temperature where the increased selectivity is sufficient to offset the loss in column efficiency. 

Traditionally, diethylamine (DEA) is recommended as an amine additive for the analysis of basic compounds on polysaccharide phases. Studies conducted on Column 2 have shown that ethylenediamine, ethanolamine, and butylamine are likely to enhance the resolution and peak shape of basic compounds separated on this column when compared with the resolution obtained with the DEA additive. These additives provide enhanced compound resolution on Columns 1 and 3 only in specific cases where the compounds are relatively strong bases.  

The robust immobilization technology for chiral-compound resolution provides, for the first time, the ability to use virtually any organic solvent as a mobile phase or mobile-phase component. 

The ability to use a much wider variety of mobile-phase components, temperatures, and solvents for sample dissolution opens up new possibilities for investigating conditions to accomplish separations that cannot be obtained with coated CSPs. The indestructible qualities of the immobilized CSPs eliminate the need to take extreme precautions to avoid solvents that damage or destroy conventional columns. 

 is senior manager of sales operations, both at Chiral Technologies, 800 North Five Points Road, West Chester, PA 19380, tel. 610.594.2100, fax 610.594.2325, 

*To whom all correspondence should be addressed.  

The authors discuss the capabilities of immobilization technologies and the ability to use an expanded range of solvents for mobile-phase components and solvent dissolutions. This article is part of a special issue on APIs.

Method Development for Analysis and Isolation of Chiral Compounds Using Immobilized Stationary-Phase Technology

The Handbook of Pharmaceutical Excipients lists several generally regarded as safe (GRAS) polymers that have been used in the pharmaceutical industry for decades in a variety of applications. More recently, these polymers have been used in solid-dispersion technology to enhance the solubility of active pharmaceutical ingredients (APIs) to increase bioavailability. These polymers have been used for various purposes, including as binders, fillers, and disintegrants in tablet formulations, enteric coatings, and controlled- and sustained-release matrix systems. Ample stability and safety data demonstrate that these polymers are ideal for solid-dispersion formulations. Further research during the past decade in solid-dispersion technology and process technology has established that stable solid dispersions that enhance solubility can be prepared at commercial scale through spray drying and melt extrusion. This article reviews seven classes of polymers that can be used to prepare solid-dispersion-based formulations. When properly formulated and processed, the result is a polymer-drug matrix, which has excellent shelf-life stability and can improve drug solubility and bioavailability. 

These seven polymer types can be grouped into two categories: nonenteric polymers and enteric polymers. Although several of these polymers can increase the dissolution rate of APIs, careful consideration of API permeability properties is necessary when choosing the appropriate polymer. For example, enteric polymers may not be considered useful for APIs with a narrow permeability window, for example. An improperly formulated solid dispersion may enhance the apparent API solubility but not significantly improve API bioavailability. 

Three nonenteric polymers are commonly studied for solid-dispersion technology: copovidone, povidone, and hypromellose. Because these polymers are highly compactable and used at high levels in solid-dispersion, it is often necessary to use disintegrants in the final dosage form to decrease solid-dispersion disintegration times and to prepare immediate-release solid dosage formulations. 

Copovidone is a synthetic polymer of 1-vinyl 2-pyrrolidone and vinyl acetate in a 60:40 ratio. Copovidone has been used in pharmaceutical formulations for decades as a tablet binder and film former. Most commonly, copovidone is used as a binder in direct compression and dry granulation applications. Copovidone is chemically compatible with most organic and inorganic pharmaceutical ingredients (1). For solid-dispersion applications, both monomer units are capable of accepting hydrogen bonds stabilized through carbonyl acetate groups and carbonyl pyrrolidinone groups. 

Figure 1: Copovidone (FIGURE IS COURTESY OF ISP) 

Copovidone is readily soluble in multiple organic solvents, including acetone, dichloromethane, methanol, ethanol, and mixtures, thereby making it ideal for preparing spray-dried dispersions. This copolymer remains chemically and physically stable in various organic solutions for several days. For spray-drying applications, the relatively high glass-transition temperature of copovidone (106 °C) aids in producing desired particle size and bulk-density powders with good product yield. Furthermore, the lower glass-transition temperature of the material as compared with the homopolymer povidone makes it ideal for melt-extrusion processing. Copovidone has been processed in melt-extrusion application at temperatures in excess of 180 °C without visual degradation (2). Typically, plasticizers are not necessary for melt-extruding solid solutions with copovidone but they can be used if necessary. One limitation of copovidone is its hygroscopicity, which can weaken solid-solution stability in humid environments. This concern, however, can be overcome with proper packaging and storage. 

The solubility parameter (δ) of copovidone has been calculated using the Hansen method, the van Krevelen and Hoftyzer method, and the Hoy method at 26.1 MPa½, 21.6 MPa½, 21.9 MPa½, respectively (3). The solubility parameter of the polymer can be compared with the solubility parameter of APIs to determine miscibility for solid dispersion or solid-solution application. 

Table i. Glass-transition temperatures of excipients commonly used in preparing solid dispersions. 

 Povidone is a synthetic linear polymer of 1-vinyl-2-pyrrolidinone groups that contains varying degrees of polymerization that result in polymers with various molecular weights. The different grades of povidone are distinguished by K-value, a measure of specific viscosity which correlates to molecular weight. Commercial grades of povidone range in K-value from K-12 to K-90. Povidone has been used for decades as a dissolution enhancer, suspending agent, and tablet binder. Most commonly, povidone is used as a binder in wet-granulation application. Lower molecular weight povidones such as K-12 and K-17 are regarded as safe for parenteral formulations and as solubility enhancers for liquid-filled soft-gelatin capsules. The K-30 polymer can be used in ophthalmic formulations and all povidones can be used in oral formulations. Povidone is chemically compatible with most organic and inorganic pharmaceutical ingredients (1). For solid-dispersion applications, the 1-vinyl-2-pyrrolidinone group is capable of accepting hydrogen bonds that are stabilized through carbonyl pyrrolidinone groups.  

Povidone also is readily soluble in multiple organic solutions including acetone, dichloromethane, methanol, ethanol, and mixtures thereof, which make it ideal for preparing spray-dried dispersions. Povidone remains chemically and physically stable in various organic solutions for several days. The glass-transition temperatures of povidones increase with increasing molecular weight (120–174 °C /from K-12–K-90). As a result, using melt-extrusion technology without plasticizers makes it difficult to process high molecular weight povidones. In spray-drying applications, however, the high glass-transition temperatures of these polymers aids in producing desired particle size and bulk-density powders with good product yield. One limitation of povidone is its hygroscopicity, which can weaken solid solution stability in humid environments. This challenge can be overcome with proper packaging and storage. 

Figure 2: Povidone. (FIGURE IS COURTESY OF ISP) 

The solubility parameter (δ) of povidone has been calculated using the Hansen method, the van Krevelen and Hoftyzer method, and the Hoy method at 23.1 MPa½, 22.2 MPa½, 22.9 MPa½, respectively (3).  

Hypromellose is a natural cellulose that  is synthetically modified to produce partly O-methylated and O-(2-hydroxypropylated) cellulose. It is available in several grades that vary in viscosity and extent of substitution. Hypromellose also has been used for decades as a bio-adhesive material, coating agent, dispersing agent, dissolution enhancer, emulsifying agent, emulsion stabilizer, foaming agent, modified-release agent, solubilizing agent, stabilizing agent, tablet binder, and thickening agent. In oral formulations, hypromellose can be used as a tablet binder for wet- and dry-granulation processes, a film coating agent, and as a matrix in extended-release formulations (1). For solid-dispersion applications, the aliphatic–hydroxyl groups of the natural cellulose and the synthetic 2-hydroxypropoxyl groups are capable of donating hydrogen bond to APIs with hydrogen-bond accepting groups. The synthetic aliphatic methoxyl groups are comparably weak hydrogen-bond acceptors. In most cases, hypromellose is compatible with APIs with hydrogen-bond accepting groups.  

Hypromellose has limited solubility with various organic solvents. The polymer is insoluble in dichloromethane, ethanol, acetone, and ether but remain soluble in mixtures of methanol and dichloromethane. Certain grades of hypromellose are soluble in aqueous organic solutions (1). The limited solubility of hypromellose in organic solvents makes it difficult to use in spray-dried dispersions. 

Table ii. Solubility of excipients commonly used in preparing spray-dried dispersions. 

Various grades of hypromellose have glass-transition temperatures ranging between 160 °C and 210 °C but they show significant degradation at temperatures in excess of 250 °C (4). Hypromellose is challenging to melt extrude because of its high glass-transition temperature and low degradation temperature. As a result, the polymer has a narrow processing window for hot-melt extrusion. Typically, at least 30% by weight of a plasticizer is required to melt extrude hypromellose (4). However, high levels of plasticizer can help to reduce amorphous solid solution stability. Hypromellose-based solid solutions are also susceptible to high humidity environments (1). 

Several enteric polymers have been studied for solid-dispersion application, including hypromellose acetate succinates, hypromellose phthalates, cellulose acetate phthalates, and polymethacrylates. Low amounts of these polymers are typically used as coating agents for pharmaceutical application, but manufacturers are conducting extensive toxicology studies to make them suitable for solid-dispersion application. Following compression, these polymers show faster disintegration properties than nonenteric polymers but the API dissolution of these solid-dispersions can be highly pH dependent, thereby affecting permeability and bioavailability. 

Hypromellose acetate succinates (HPMCASs). 

HPMCASs are synthetically modified mixtures of acetic acid and monosuccinic acid esters of hypromellose. HPMCASs are available in three grades (L, M, and H) which correspond to pH-dependent release profiles of low (pH~5), medium (pH~5.5), and high (pH~6.5) pH (5). These synthetically modified natural products are traditionally used as controlled-release agents, enteric-coating agents, film-forming agents, sustained-release agents, and more recently, as solubility enhancing agents. HPMCASs are incompatible with acids, peroxides, and other oxidizing materials (1). In solid-dispersion applications, the aliphatic hydroxyl groups of the natural cellulose and the synthetic 2-hydroxypropoxyl groups are able to donate hydrogen bond to APIs with hydrogen- bond accepting groups. The acetyl and succinyl groups can accept hydrogen bonds from APIs to stabilize the solid dispersion.  

HPMCASs are practically insoluble in all organic solvents, but they can form a clear or turbid viscous solution with the addition of acetone, or a mixture of ethanol and dichloromethane (1). The viscous solution is difficult to maneuver in spray-drying applications at the commercial scale, but the process can work with proper solution preparation and spray-drying parameters. HPMCAS polymers have glass-transition temperatures ranging between 120 °C and 135 °C (6). Limited information is available on onset degradation temperatures. Plasticization by APIs may be necessary to safely melt extrude HPMCAS-based solid dispersions. In spray-drying applications, the high glass-transition temperatures of these polymers aids in producing desired particle size and bulk density powders with good product yield.  

Hypromellose phthalates are natural cellulose that is synthetically modified to produce partly methyl ethers, 2-hydroxypropyl ethers, and phthalyl esters. Although several different types of hypromellose phthalates are commercially available with molecular weights ranging between 20,000 and 200,000 Da, only two materials (HP-50 and HP-55, where 50 and 55 indicate solubility at pH 5 and 5.5, respectively) are typically used in solid-dispersion technology. Hypromellose phthalates are typically used in oral pharmaceutical formulations as enteric coating materials for tablets, beads, or granules. These polymers are characteristically insoluble in gastric fluid but are swellable and rapidly soluble in the upper intestine. Hypromellose phthalates can be used as coating agents because they do not require the addition of plasticizer or other film formers to produce coatings for oral formulations (1).  

For solid-dispersion applications, the aromatic carboxylic acids in the phthalyl ester substituent groups are capable of donating strong hydrogen bonds to APIs with hydrogen-bond accepting groups. Hydrogen bond donating of the aromatic-carboxylic acid can be further stabilized with an aromatic ring and the ester functionality. Like hypromellose and HPMCASs, the aliphatic–hydroxyl groups of the natural cellulose and the synthetic 2-hydroxypropoxyl groups can also donate hydrogen bond to APIs with hydrogen-bond accepting groups. These hydrogen bonds, however, are not as strong as the aromatic stabilized hydrogen bonds from the phthalyl–ester substituent groups. The ester groups in the phthalyl–ester substituent groups are capable of accepting hydrogen bonds from APIs to stabilize the solid dispersion. The hydrogen-bond accepting carbonyl group of the ester can resonance stabilize the carboxylic acid hydrogen bond donating group through the aromatic phthalate. The hydrogen-bond donating and accepting properties of hypromellose phthalates make these polymers useful for several API functional groups. 

Hypromellose phthalates are insoluble in dichlormethane, methanol, isopropanol, ethyl acetate, and ethanol but demonstrates desired solubility in acetone, tetrahydrofuran, mixtures of dichloromethane and methanol, mixtures of dichloromethane and ethanol, and mixtures of acetone and methanol (1). The insolubility of hypromellose phthalate in single-solvent systems makes it challenging to conduct simple drug-compatibility studies and spray-drying applications. However, solvent mixtures can be effectively prepared for commercial spray drying by using proper spray-drying optimization. 

HP-50 and HP-55 have glass-transition temperatures of 150 and 145 °C, respectively (6). Hypromellose phthalates remain chemically and physically stable at room temperature for several years but are susceptible to hydrolysis under elevated temperature and humidity conditions (1). Limited information is available regarding hypromellose-phthalate stability during hot-melt extrusion under high shear or high temperature. A plasticizer or an API with plasticizing attributes may be necessary to effectively melt extrude hypromellose phthalates.  

 Cellulose acetate phthalate (CAP) is a natural cellulose that is synthetically modified. Half of the CAP hydroxyl groups are acetylated and approximately one quarter are esterified (one of the two acid groups is phthalic and the other acid group remains free). CAP is used in oral pharmaceutical formulations as an enteric coating material. CAP concentrations in oral formulations are typically limited to 0.5 to 0.9% of tablet core weight (1). Much higher concentrations are typically required to prepare stable solid dispersions. 

CAP is practically insoluble in water, alcohols, and chlorinated and nonchloronated hydrocarbons. CAP, however, demonstrates good solubility in acetone, methanol, ethanol, and several solvent mixtures, including acetone and water, acetone and ethanol, acetone and isopropanol, acetone and methanol, acetone and dichloromethane, dichloromethane and ethanol, ethyl acetate and ethanol, and ethyl acetate and isopropanol (1). 

CAP has a glass-transition temperature of 175 °C but is reportedly compatible with various plasticizers, including acetylated monoglyceride, butyl phthalybutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalylethyl glycolate, glycerin, propylene glycol, triacetin, triacetin citrate and tripropionin  (7). A 20% (w/w) addition of diethyl phthalate, triacetin, or acetylated monoglyceride reduces the glass-transition temperature of the CAP to 100 °C, 95 °C, and 163 °C, respectively (7). CAP, like other phthalates, is susceptible to hydrolysis under high temperature and high humidity (1). The high glass transition temperature and chemical instability of the polymer makes plasticizing necessary for hot-melt extruding the material. Limited information is available on hot-melt extrusion conditions for CAP.  

Figure 3: Hypromellose, hypromellose phthalates, hypromellose acetate succinates, and celluloseacetate phthalates.

Polymethacrylates are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Polymethacrylates are commercially available for use as film forming agents, tablet binders, and tablet diluents (1). Four of these polymers have been studied for solid-dispersion technology, including: cationic methacrylate, methacrylic acid copolymer Type A, Type B, and Type C.  

Cationic methacrylate is a cationic copolymer of dimethylaminoethyl methacrylate, methacrylate methylester, and methacrylate butylester. Cationic methacrylate is soluble in gastric fluid as well as weakly acidic buffer solutions up to pH 5 (8). The cationic dimethylaminoethyl methacrylate substituent group can provide a unique ionic interaction with APIs for solid-dispersion technology. This ionic interaction is believed to further stabilize solid solutions beyond hydrogen bonding and steric interactions. The methacrylate ester groups are considered to be good hydrogen-bond accepting groups for hydrogen-bond donating APIs. However, the strong cationic interaction can be detrimental to drug stability when the drug is susceptible to common cation catalyzed reactions. 

Cationic methacrylate is soluble in methanol, ethanol, isopropanol, acetone, dichloromethane, ethyl acetate and various other solvents making it a suitable solvent for spray-drying application (8). The low glass-transition temperature of the polymer (48 °C) makes it difficult to use in spray-drying applications but makes it ideal for use in hot-melt extrusion processing.   

Methacrylic acid copolymers Type A and Type B are anionic copolymers of methacrylic acid and methyl methacrylate. The Type A copolymer has a ratio of 1:1 of each monomer unit whereas the Type B copolymer has a ratio of 1:2 of the methacrylic acid monomer to the methyl methacrylate monomer. The Type A copolymer is reportedly soluble/permeable in intestinal fluid from pH 6 and higher; whereas, the Type B copolymer is reportedly soluble/permeable in intestinal fluid from pH 7 and higher (8). The methacrylic acid monomer unit in these copolymers is capable of donating hydrogen bonds to APIs with hydrogen bond accepting groups. The methyl methacrylate monomer unit is capable of accepting hydrogen bonds from APIs with hydrogen bond donating groups. These hydrogen bond donating and hydrogen bond accepting properties make methacrylic acid copolymers versatile for solid dispersion technology. However, the strong anionic interactions can be detrimental to drug stability if the API is susceptible to anion catalyzed reactions. 

The Type A and Type B anionic copolymers remain soluble in methanol, ethanol, isopropanol, and acetone. This solubility makes them suitable for solvent-based spray drying (8). It is not possible to determine the glass-transition temperatures of Type A and B copolymers because the functional groups become damaged at temperatures greater than 150 °C (8). Plasticizers must be used to successfully melt extrude these polymers and barrel temperatures must be effectively controlled to prevent polymer degradation. Triethyl citrates, polyethylene glycols, acetyl triethyl citrate, some butyl citrates, polysorbates, dibutyl sebacate, triacetin, and 1,2-propylene glycol can be used to plasticize these copolymers (8). For spray- drying application, these polymers' high glass-transition temperatures aids in producing good particle size with good product yield.  

Methacrylic acid copolymer Type C is an anionic copolymer of methacrylic acid and ethyl acrylate in a 1:1 ratio, that also contains 0.7% sodium lauryl sufate and 2.3% polysorbate 80, as emulsifiers (9). This copolymer mixture is reportedly soluble/permeable in intestinal fluid at pH ranges of 5.5 and higher (8). Similar to Type A and B copolymers, the Type C copolymer is capable of donating hydrogen bonds through the methacrylic acid monomer unit and can also accept hydrogen bonds through the ethyl acrylate monomer unit. These anionic interactions, however, can be detrimental to drugs that are susceptible to anion catalyzed reactions. 

The Type C anionic copolymers are soluble in ethanol, methanol, isopropanol, and acetone but insoluble in dichloromethane  (8). These solvents are also suitable in spray-drying applications. Their lower glass-transition temperature (110 °C) makes the copolymer mixture ideal for spray-drying application and melt-extrusion processing. If necessary, plasticizers such as those compatible with Type A and Type B copolymers can be added to increase melt-extrusion throughput. 

When developing solid-dispersion formulations of poorly soluble APIs, one must do the following: compare the API functional groups with the polymer functional groups, compare the API solubility parameters with polymer solubility parameters, and analyze the expected permeability of the API to determine which polymers to evaluate for solid-dispersion technology. The most soluble or most stable formulation should not necessarily always be chosen for further process development because many factors (e.g., API permeability window, polymer supply, polymer toxicology, physical product characteristics, and processing yields) can have a substantial impact on the final product. These issues must be considered before moving forward with product development. 

 is a project leader/solid-dispersion scientist, both at International Specialty Products (ISP), tel. 410.910.7414, 

 1.  R.C. Rowe, P.J. Sheskey, and M.E. Quinn, Handbook of Pharmaceutical Excipients, 6th ed. (Pharmaceutical Press, Grayslake, IL, 2009) 

, Norgwyn Montgomery Software, Version 6.2.5 

The authors review seven polymer classes that can be used to prepare solid-dispersion formulations.

Pharmaceutical Technology-09-01-2010