Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

	The majority of pharmaceutical drugs are still produced as solid dosage forms because of the acceptability and convenience of the oral route as well as the good patient compliance it offers in general. As solid dosage forms do not require sterile manufacturing conditions, the overall production costs are less expensive. Moreover, the pharmaceutical industry has years of experience developing solid dosage forms with well-defined and known processes, equipment, and technologies.

	To gauge emerging trends in solid dosage manufacturing, 

 spoke with Randy Wald, senior research fellow at Bend Research, part of Capsugel Dosage Form Solutions about key drivers shaping the pharmaceutical drug development and manufacturing landscape.  

 How has the manufacture of solid dosage forms changed over the past decade?

 The manufacture of solid dosage forms continues to evolve, with key drivers including functional improvements, safety, and overall cost of development and commercial manufacture.

	Several key trends can be noted, all of which continue and include increased partnership of CDMO/CMO with pharmaceutical companies, increased demand for specialized dosage forms (pediatric/geriatric, abuse-deterrent, fixed dose combinations), higher potency APIs in the development pipeline and in commercial production, the maturation of solubility-enhancing technologies, increasing prevalence of continuous manufacturing processing displacing legacy batch processing, and continued advances in excipients including ready-to-use and co-processed.

	The outsourcing of pharmaceutical development and/or manufacturing to CDMO/CMOs has become mainstream given the continued trends of pharmaceutical company downsizing and focusing on molecule discovery and marketing functions, the increasing role of small/virtual pharmaceutical companies in drug discovery and development, and the demand for increasingly innovative drugs using specialized technologies.

	Continuous processing, where multiple continuous unit operations are coupled into an integrated system, improves overall productivity and costs of production and is complimentary with ICH and other quality-by-design paradigms. Continuous processing, such as continuous coating, has been implemented in immediate-release capsules and tablets (initially in the health & nutrition segment and, in past few years, there has been fast growth in Rx/OTC). It will continue to find applications in the pharmaceutical segment inclusive of more specialized areas such as extended-release drug products.

	We are also seeing functional improvements using existing pharmaceutically approved excipients. Given the prohibitive cost of developing and gaining approval for a new excipient, suppliers have coupled processing advances for the development of innovative dosage forms. Several examples can be cited:

		Coupling of processing and polymer chemistry to greater effect, e.g., melt-spray-congeal processing to encapsulate API in a lipid matrix, the architecture of which is tailored to meet the functionality required whether it is bioavailability enhancement, controlled release, and/or taste masking.

		Use of functional capsules incorporating approved enteric polymers to eliminate previously required coating steps to provide gastric resistance or fully enteric protection for solid oral dosage forms. The elimination of functional coating can speed up and de-risk the development process for actives requiring enteric protection and/or targeted release in the upper GI tract.

		Use of existing excipients and processing to provide abuse resistance for opioids and other often-abused drugs, which is increasingly required by regulatory authorities. By understanding the typical routes of abuse, resistance is being built into drug products using a range of excipient functionality inclusive of thickening agents, waxy or high melting point excipients and taste modifiers.

		Additional functionality built into existing excipients, e.g., additional grades of pharmaceutically approved excipients to provide more tailored functionality and/or improved supply-chain performance such as shelf life. Examples include new polymer grades for hot-melt extrusion and spray dry dispersion processing (e.g., more molecular weight and viscosity grades for cellulosic polymers). Co-processing of approved excipients for greater functionality and simpler manufacturing is another trend.

		Drug design and manufacture for specialized populations including pediatric and geriatric applications where patient compliance is a challenge. Reducing the number of medications and/or dosing frequency, coupled with improving the ease of swallowing, is increasingly factored in and drives more fixed dose combinations, extended release, and multiparticulate formulations.

 Excipients make the bulk of a solid dosage form and they play an important role in properties of the finished formulation, such as its stability, drug release, bioavailability, taste, and texture. When it comes to formulation development, what are the key considerations when selecting your excipient for a solid dosage form?

: Functional excipients form the foundation of most solid oral dosage forms and as such, careful consideration must be taken in their selection. The possible consequences of sub-optimized excipient selection can include reduced bioavailability, compromised stability, manufacturing complications, and increased chance of side effects, which affect the overall commercial success of the drug. We have developed decision trees and models, based on more than a thousand compounds, to guide the choice of appropriate technology and excipients for key challenges such as bioavailability and controlled release.

	Key technological considerations include:

		The product’s desired pharmacokinetic performance (PK modeling)

		Functional excipients for enhanced absorption, controlled or modified release, API stability, etc.

	Commercial considerations are also factored in, such as the desired finished dose presentation. This process greatly narrows the choice of excipients preferred for the technology and manufacturing processing.

 In terms of excipients for solid dosage forms, what are the key advances that have significantly impacted the formulation development and manufacturing process of solid dosage forms?

: Excipient suppliers continue to respond to both regulatory and industry trends by providing additional grades of existing excipients as well as new and/or co-processed excipients. Key requirements include enhanced excipient functionality and range to assist in repositioning existing compounds for greater efficacy and/or new indications. For preclinical evaluations, speed, and de-risking are key considerations. And simplified formulation and processing approaches are increasingly important. A few examples are listed in the following:

		Additional grades of hypromellose acetate succinate (HPMCAS) have been developed to expand the range and applicability of spray dry dispersion technology for addressing low solubility.

		Lipid multiparticulate (LMP) technology has been developed to provide the functionality of lipid-based formulations and the benefits of the multiparticulate format-an example of leveraging lipid-based formulation and melt-spray congeal processing know-how to achieve innovation with existing excipients.

		New polymers and grades have been developed specifically for hot melt extrusion processing, based on increased understanding of the process and requirements.

		Dry dispersion formats of existing polymers have been developed for ease of processing and reduced costs.

		Functional capsule technology developed to intrinsically provide enteric protection, eliminating the need for functional coatings and the complexity and risk associated with their application.

		Co-processing to provide multi-functionality and/or improved functionality using a single excipient for early stage development through commercial production.

 Do you see a need for novel excipients and if so, what excipients?

 Continued advances-not necessarily novel excipients-in excipient formulation and processing technology are required to keep pace with the increasing challenges in drug product formulation and production. As an example, the drug pipeline challenge continues with an increasing percentage of poorly soluble and higher molecular weight molecule candidates. Thus, excipient functionality that provides both enhanced absorption and extended release is a promising area. Another example is the move towards continuous processing. Excipient vendors will increasingly need to supply excipient types and grades amenable to new processing versus historic batch processing.

Articles

Randy Wald, senior research fellow at Bend Research, part of Capsugel Dosage Form Solutions shares insights on trends shaping the evolving solid dosage manufacturing landscape, including advances in excipients and the impact on formulation development and manufacturing processes.

Key Considerations in Excipients Selection for Solid Dosage Forms

Poor solubility is an ongoing challenge in pharmaceutical development. A drug must be in solution form for it to be absorbed regardless of the route of administration. The solubility of an API, therefore, plays a crucial role in bioavailability given that drug absorption is a function of solubility and permeability.

	Modern drug discovery techniques, with advances in combinatorial chemistry and high throughput screening, continue to fill drug-development pipelines with a high number of poorly soluble new chemical entities (NCEs). “Estimates have varied over the years, but it is reported that 40%–70% of NCEs are poorly water-soluble,” observes Sampada Upadhye, PhD, technology platform leader for bioavailability enhancement & OptiMelt, Catalent Pharma Solutions. “There has been a tremendous amount of research going on in the industry to overcome the challenges in bringing poorly soluble drugs to the market.”


	Selecting a suitable drug-delivery approach for these challenging NCEs depends on various parameters, explains Praveen Raheja, associate director, Formulations, at Dr Reddy’s CPS, “for example, the drug solubility, chemical composition, melting point, absorption site, physical characteristics, pharmacokinetic behavior, dose, route of administration, and intended therapeutic concentration, to name a few.” An analysis of all these parameters is required to determine the most appropriate method of drug delivery, he says.

	According to Marshall Crew, PhD, vice-president, Global PDS Scientific Excellence, Patheon, there are two aspects that must be understood in a comprehensive way before proceeding toward the best solubilization technology-the drug molecule and the target product profile. “The dosage form, dosage, and other requirements for the drug product must be taken into consideration, along with the molecular properties and profile of the API,” he says. “Modern pre-formulation approaches begin by understanding the target product attribute space, and leverage modeling to more fully characterize and understand the molecule.” Crew explains that this approach enables solubilization formulation scientists to know the starting point and direction of the process from the earliest stage to formulation design and optimization.

	“Once the drug product requirements have been understood and the API characterized, solubilization technologies can be screened to identify the best fit for the particular drug and desired outcome,” Crew adds. After the technology has been identified, the next step is to conduct experiments involving a range of excipient/polymer models in combination with the drug. Crew advocates the use of computational screening, which allows a greater number of options to be explored more efficiently, thereby increasing the likelihood of identifying the best approach.

	Dan Dobry, vice-president, Bend Research, a division of Capsugel Dosage Form Solutions, also recommends a mechanistic, model-based approach. “Simple modeling and characterization tools can relate physicochemical aspects of the compound and therapy to potential delivery challenges,” he notes. “The models are often not quantitative in early development, but give context to experiments, 

, to help shape the problem statement and pair the right delivery technology.”

	Mastering multiple delivery technologies, from formulation through to scale-up and manufacturing, reduces bias for a particular technology, says Dobry, and allows each technology’s sweet spot to be exploited, rather than trying to force fit a technology to a problem statement. He further adds that integrating appropriate enabling technologies into lead selection (instead of using them in a rescue mission during mid-development, when it may already be too late), can streamline the process and help identify the most effective combination of molecule and drug-delivery technology.

	Dieter Lubda, PhD, director, Process Chemical Solutions R&D Franchise Formulation, Merck Millipore KGaA, Darmstadt, Germany, finds that conventional solubilization approaches such as physical modifications of APIs, micronization, or nano-milling tend to have limited results. “The formulation of new drugs often needs new technologies and excipients that can induce specific solubility- and bioavailability-enhancing properties,” he says. However, Lubda stresses that the interaction of new technologies and the excipients used is a far more complex scenario. Instead of focusing on one technique, it is important to consider how a range of excipients or approaches could work best for the poorly soluble API under development. “This helps increase the success rate of selecting suitable drug-delivery solutions,” he asserts.


	When considering solubility, Dobry says the industry has a range of commercial solutions to choose from, such as size reduction, and the use of lipids or amorphous dispersions. These proven approaches can be selected based on the individual drug’s properties and specific problem statement.

	Each method, however, has its limitations and may pose new formulation challenges, notes Upadhye. Strategies such as polymorphism, salt formation, co-crystal formation, and the addition of excipients may marginally increase drug solubility, but often have limited success in increasing bioavailability, according to her. In some cases, they can even increase drug toxicity, resulting in negative side effects, she says.

	Although particle size reduction may be a safe way to increase drug solubility, it does not alter the solid-state properties of the drug particles, Upadhye observes. In addition, solid dispersions, solid solutions, amorphous generation, and lipid-based formulations each has its own set of challenges that can affect drug stability and drug loading capacity, she adds.

	One of the greatest formulation challenges today, according to Dobry, is the fact that poorly soluble compounds often present other problems, such as metabolism or permeability challenges, drug-to-drug interactions in a combination dosage form, or the need to modify pharmacokinetics (e.g., blunting the maximum concentration [C

] or extending drug release). “These challenges rapidly increase as the dose increases and desire for dosage form burden comes down,” Dobry notes.

	According to Stephen Tindal, director, Scientific Affairs, Softgel R&D, Catalent Pharma Solutions, dose is the number one problem. “Unless you can get significant increases in bioavailability, the patient has to take multiple large unit doses whether they’re tablets, capsules, or softgels,” states Tindal. Another problem is because APIs are not designed with enabling technologies in mind, there can be a suboptimal fit between the API and the dosage form.

	Lubda explains that the first key consideration in formulation development is the route of administration. “The main question here is where the API needs to go in the body and how the drug can best be formulated to reach this targeted location,” he continues. “In this challenge, the prerequisite for API bioavailability is to increase its solubility and permeability. These parameters must be optimized to achieve optimal release properties and the desired plasma profile within the required therapeutic window.”

	“Depending on the properties of the API, we have to assess if the drug can be formulated with standard formulation technologies or whether we need to explore non-conventional approaches,” Lubda expands further. “Developing a good formulation is not easy 

. The excipients used could interfere with the drug during the formulation process (e.g., a pH shift during wet granulation) and result in a lower therapeutic effect.”


	According to Raheja and Lubda, the main challenges encountered during the development of oral formulations for poorly soluble drugs are:

		ensuring the stability of the formulation during processing and in the gastrointestinal (GI) tract (e.g., avoiding precipitation of the drug in gastric fluids)

		achieving consistent drug release rates

		considering food effects, such as different levels of drug absorption during fed or fasted states

		taking into account the presence of p-glycoprotein and cytochrome P450 (CYP) enzymes.

	A common problem, as Raheja highlights, is determining the combination of suitable excipients and the enabling technology that increases solubility, as well as determining the appropriate tool to predict the solubility 

	Lubda emphasizes the importance of choosing the best excipients for the formulation, adding that process conditions such as heat or moisture during drug development are also crucial. “In the end, it comes down to: How can we cost-effectively formulate APIs with good content uniformity?” he asserts and highlights some key questions that should considered:

		Can we simplify complex formulations (requiring large number of excipients) that can lead to unexpected excipients interactions and limited drug stability?

		How can we influence the recrystallization of amorphous APIs and what are the pH effects on their stability?

	Lubda sums up that the ultimate goal is to achieve a robust manufacturing process that takes into account disintegration and dissolution of the oral dosage form, hardness, content uniformity, waste, and productivity with high tableting speed.

	According to Crew, developing a customized formulation for poorly soluble drugs requires achieving the best balance of dose, polymer, and API loading to allow the final drug product to have the required stability, manufacturability, and performance. “To accomplish this type of local optimization within a global context, using a modern approach is essential,” he notes. Crew recommends a systematic methodology, employing rigorous scientific practices, and then performing extensive 

 simulations. “Fortunately, the computational intensity of this type of exploration and analysis is now feasible,” he adds.

Choosing a suitable solubilization strategy


	When selecting a solubilization strategy, a number of considerations, such as the physicochemical and physiological properties of the drug, should be taken into account. Lubda lists the following key factors to consider:

		mode of action (e.g., oral local or oral systemic for fungal drugs)

		physicochemical properties of the API (i.e., pH-dependent solubility, pKa value(s), log P, temperature sensitivity, shear sensitivity, solubility in suitable solvents, known undesirable interactions with excipients, polymorphs, properties of crystalline state vs amorphous state)

		suitability of the manufacturing process for the API

		differences in performance during feasibility studies and screenings

		availability of necessary equipment for process and method used

		stability of the final formulation and shelf life

		intellectual property and licensing considerations.

	Raheja offers a real-world example. “If a compound has an acidic or basic functional group and the log P is between 1.0 to 3.0, one could explore buffer systems to solubilize it,” he says. However, he notes some possible drawbacks-a buffer-based system could result in precipitation in the GI. In such cases, anti-nucleating polymers could be used to overcome this problem. “These agents maintain a high degree of supersaturation and help improve bioavailability,” Raheja explains. “Other solubilization techniques such as complexation and solid dispersions can also be considered for compounds with a log P in the range of 1.0 to 3.0. For compounds with a log P of 5, it is better to explore lipid-based systems.”

	Each solubilization technique has its pros and cons, Upadhye observes, and only a careful consideration of the API’s physical, chemical, and thermal properties as well as its mechanical properties, will allow the best solubilization technique to be selected.

	While most experts would agree on the list of key factors guiding a solubilization strategy, Dobry stresses the importance of having a framework or model that puts method selection into a broader context that also considers the mechanism of dissolution and absorption, and allows for problem statement definition, risk assessment, and sensitivity analysis. “In this context, it is important to have basic pharmacokinetic data of the crystalline drug in animal models to guide initial model development,” he continues. “We find this aspect to be so important that we have developed discovery stage formulation tools to generate pharmacokinetic/pharmacodynamic data in animals, even for poorly-soluble actives.”

	While the drug molecule plays the key role in the decision, Crew adds that other crucial considerations include the amount of API available at the earliest stage of development and the drug product’s goals. “In some instances, the initial assessment and process development can employ one technology, and then, when the formulation design has been completed, another technology can come into play,” he says. Crew provides an example: creating an amorphous solid dispersion, for which either spray drying or hot-melt extrusion (HME) might be used. In this case, the API dictates the options available, he explains, and the decision tree includes such factors as:

		solubility of API in solvent or polymer

	These are only some of the factors, but they can only be derived from a thorough characterization of the molecule, Crew points out. Because the amount of API required for early formulation using spray drying is significantly less than what is required for HME, an early feasibility study might be done using that technology, if the API lends itself to HME (i.e., if its melting point does not exceed 200 °C–225 °C).”

Weighing up the different solubility-enhancement approaches


	“Several technologies are available to overcome solubility challenges,” states Lubda. “One approach is to influence the surface area of the API particles using micronization, nanonization, co-grinding, or precipitation from supercritical fluids. The other alternative is to increase the solubility with solubilizers (polymers, surfactants, or cyclodextrins), lipid-based formulations (e.g., self-emulsifying or self-micro-emulsifying drug delivery systems [SEDDS/SMEDDS]), polymorphs, salt formation, or co-crystals.” He notes that some newer solubilization techniques attempt to address both the surface area and solubility through the formation of liquid and solid dispersions or porous inorganic carriers such as mesoporous silica. “The overall goal is to improve API solubility and achieve a higher dissolution rate, which facilitates faster drug absorption,” he says.

	According to Lubda, micronization of API is challenging, especially at production scale. “Batch-to-batch homogeneity is poor,” he observes, further highlighting the potential stability problems that could occur due to the high energy input, apart from the difficulty in achieving content uniformity in the solid dosage form. “Surfactants can be seen as a straightforward approach to influence API solubility,” he adds. “But because they are not inert excipients, surfactants can interact with APIs and other excipients. Their effects are hard to predict and surfactants potentially have an influence on biological membranes as well as possible side effects.” Lubda views porous inorganic carriers (e.g., silica) as well as liquid and solid dispersions as promising technologies to solve solubility challenges.

	Poor solubility is clearly a problem that will continue to challenge drug developers. As Crew points out, the number of insoluble molecules continues to rise. “During the decade of the 1970s, only 0.6% of FDA-approved molecules had been solubilized,” Crew observes. “The next two decades showed increases, and by the 2000s, this category accounted for more than 10% of approved drugs.”

	According to Crew, Patheon analyzed the number of drugs approved by FDA between 1970 and 2013, which used diverse solubilization platforms (including lipids, amorphous solid dispersions, nanocrystals, and other alternative technologies). While lipid systems were the most widely used in the 1980s, and continue to be favored today, Crew says that solid dispersions saw a steep increase in the mid-2000s, and continue on a rapid growth rate even today. Findings from Patheon’s study show that lipids dominated with a 50% share, solid dispersions took second place with 30%, ahead of the next closest technologies at less than 10%. Catalent’s softgel expert Tindal concurs that lipid-based formulations have a historic advantage over solid dispersions, but notes that use of solid dispersions is increasing.

Solid dispersions continue to show broad applicability


	Solid dispersions are widely used as a solubilization technique. Kevin O’Donnell, PhD, and William Porter III, PhD, who are bothâ¨associate research scientists at Dow Pharma & Food Solutions, attribute it to the ability of solid dispersions to drastically improve the solubility of most APIs. “While solid dispersions present their own challenges, they eliminate the issues associated with traditional techniques,” O’Donnell observes. “Non-ionizable APIs or those that do not fit in complexing agents can now find success.”

	“Owing to its simplicity from both manufacturing and process scalability standpoints, solid dispersion has become one of the most active and promising research areas and is therefore of great interest to pharmaceutical companies,” comments Upadhye. “The term ‘solid dispersion’ refers to solid-state mixtures, prepared through the dispersion, typically by solvent evaporation or melt mixing, of one or more active ingredients in an inert carrier matrix. In these dispersions, the drug can be present in a fully crystalline state (in the form of coarse drug particles), in a semi-crystalline state, or in fully amorphous state (in the form of a fine particle dispersion, or molecularly distributed within the carrier). Such systems prove to be very effective for enhancing the dissolution rate of low solubility drugs.”

	Dobry says that the approach is broadly applicable because of its mechanism of stabilization and dissolution, as well as a scalable, precedented process. “The most prominent advantage of solid dispersions is the purely physical change of the active compound (mainly from the crystalline to the amorphous state). If the change is performed in a controlled manner, you don’t have to deal with concerns about undesired effects from chemical changes of the compound,” Lubda adds.

	According to O’Donnell, until recently, the number of methods available to a formulator to generate an amorphous solid dispersion was limited. “However, recent growth in the techniques capable of generating an amorphous solid dispersion-such as spray drying, HME, precipitation methods, co-milling, KinetiSol dispersing, cryogenic methods, and others-has created processing flexibility, allowing almost any API to be formulated into a solid dispersion,” he notes.

	Spray drying and HME are currently the most commonly used methods to produce solid dispersions. “Spray drying is highly effective at generating the amorphous form of an API and can be used for APIs that have low degradation temperatures,” Porter observes, adding that selecting the appropriate polymer and solvent will ensure the resulting product is homogenous.

	HME, on the other hand, is a versatile process that does not require solvent. “Moreover, because it is a continuous process with narrowly defined output quality attributes, HME represents an ideal manufacturing platform for the implementation of process analytical technology (PAT),” Upadhye says.

	For amorphous solid dispersions, a primary challenge is the stability of the amorphous drug, according to O’Donnell. “Improperly formulated systems may recrystallize into more thermodynamically stable and less soluble forms, resulting in dramatic changes in the dissolution, absorption, and therapeutic effect of the API,” he points out. “The stability of crystalline formulations is also of great concern if a high-energy polymorph is selected, due to the risk of polymorphic transformations that can have negative effects."

	“Another challenge consistently observed is that many poorly soluble drugs require delivering a high dose of the API to the patient,” Porter notes. “This issue creates complexity in designing adequately sized dosage forms and can result in adverse drug effects and poor patient compliance.” Porter explains that while amorphous solid dispersions may reduce the required dose circumventing this issue, a high drug load lowers the amount of stabilizing polymer present in the formulation, which can result in the aforementioned stability concerns.

	Raheja sees great potential in solid dispersions citing a growing number of commercial products and those in development. “In the past decade, a lot of understanding on formulation components, analytical tools, and scale-up challenges have improved,” he states. “Our own experience with this technology has brought products into different clinical and commercial stages.”

While simple solid dispersions will continue to be a cornerstone technology for enhanced bioavailability, we need to continue to innovate,” says Dobry. “This will include the evolution and combination of the best aspects of multiple technologies, such as combining manufacturability and solid state stability of amorphous dispersions with rapid dissolution and permeability enhancement of lipid formulations.”


	According to Lubda, the use of silica has been gaining traction since it was first used as a drug carrier in the 1980s. Most research has focused on the use of ordered mesoporous silica. “Materials such as SBA-15 (Santa Barbara Amorphous-15) or MCM-41 (Mobile Composition of Matter-41) are pure silicon dioxide particles with an ordered mesoporous structure but remain on scientific production levels. Silica materials with unordered mesopores are most widely used because their manufacturing process is easily scalable and the pore structures are known to be pressure resistant,” he elaborates.

	These mesoporous silica particles are inert and have a large internal surface area (potentially exceeding 1000 m²/g) that provides space for the drug molecule to be absorbed, which is crucial for drug loading capacity, Lubda says. The challenge, however, will be making this surface area accessible to the drug molecule.

	Different silica carriers can be used for drug delivery, Lubda explains, but it is important that they are monograph-compliant and have GRAS (generally regarded as safe) status. The underlying solubilization technology is to impregnate an amorphous drug form into the pores, with the help of an organic solvent in a pre-formulation step, and to prevent recrystallization during dissolution in the body, Lubda says. The result after drying and removal of the solvent is an intermediate, in powder form, of silica with the API. In most cases, he notes, such intermediates enhance the solubility (by supersaturation), dissolution rate, and stability of the poorly soluble small molecules. “This solubilization approach is applicable to a broad range of drugs, as the API only needs to be soluble in a volatile organic solvent,” says Lubda, adding that the final formulation can easily be compressed into a tablet and the process is scalable.


	Given the range of solubilization technologies available, poor solubility does not necessarily prevent a drug from reaching the market anymore, notes Lubda. Research promises to expand the range of technologies available in the future.

	“There is an increasing focus on understanding solubility and more importantly, the bioavailability of drugs in general,” Lubda remarks. Experts notice the increasing collaboration between pharmaceutical manufacturers and academic research groups to develop more appropriate, better fitting test systems for 

 studies that will help provide deeper insights into drug properties and further the understanding of solubilization strategies. “The ability to model both molecules and excipients separately and then in combination 

 allows access to a broader solution space, and also significantly increases the predictability of solubilized outcomes,” Crew adds.

Modern methods and modeling offer a better way to understand solubility issues and solve today’s complex formulation challenges.

Solving Poor Solubility to Unlock a Drug's Potential

Oral formulations, which are still the most widely used dosage forms, can be designed to release the drug at specific sites of the gastrointestinal (GI) tract. Today, the colon is becoming a more attractive target, not only for treating diseases of the colon such as Crohn’s disease, ulcerative colitis, and colorectal cancer, but also for GI therapies in general. For example, colon targeting can be used to systemically deliver proteins and peptides that are susceptible to enzymatic degradation in the stomach or small intestine. This approach has been found to provide safe and effective therapy with proven bioavailability enhancement as well as a lower incidence of drug toxicity and unwanted side effects.  

	Colon-specific drug delivery exploits the differences in anatomical and physiological features of the upper and lower segments of the gut. Research has shown that the colon is more responsive to absorption enhancers, protease inhibitors, and bioadhesive and biodegrable polymers compared with other regions of the gut (1). The challenge, however, comes in ensuring that the drugs are intact when they eventually reach the colon, which is often a problem with traditional oral dosage forms. A number of different approaches are being used to target drug release in the colon. This article will summarize key trends, including the use of prodrugs, pH- and time-dependent systems, as well as newer approaches based on osmotic-controlled drug delivery.

 The prodrug strategy exploits the presence of the colonic microflora, which is in the order of 10

 colony-forming unit (CFU) per mL in the colon, compared with 10

 CFU/mL in the stomach and small intestine (2). To form the pharmacologically inactive prodrug, the parent drug is attached to a chemical group, and enzymatic degradation by the bacteria in the colon then frees the active drug molecule. Linkages such as azo, amide, glucuronide, and glycosidic bonds are often used in prodrug formation for colon-specific drug delivery. Ruiz et al. reported on the development of a double prodrug system for colon targeting of benzenesulfonamide cyclo-oxygenase-2 (COX-2) inhibitors (3). The prodrug was first activated by azoreductases followed by cyclization to release the active drug. According to the researchers, the prodrug demonstrated good stability in human intestinal extracts and was only activated under specific conditions of the colon, hence achieving targeted drug release.

pH- and time-dependent drug-delivery systems.

 In this approach, drug release is triggered by a change in pH as the dosage form passes through the gut. It is generally accepted that the pH of the GI tract progressively increases from the stomach (pH 1–2 in fasted state and pH 4 during digestion) to the small intestine (pH 6–8). The important thing is for the formulation to remain intact until it reaches the colon. Such formulations typically incorporate polymer coatings that are insoluble in an acidic environment but become soluble as the pH increases. Commonly used pH-sensitive polymers include Eudragit L and S, polyvinyl acetate phthalate, hydroxyl propyl methyl cellulose phthalate, and cellulose acetate, to name a few.

	Time-dependent systems take a different approach by delaying drug release after a specific period of time. Taking into account gastric emptying and intestinal transit times, swellable systems that incorporate different combinations of hydrophilic and hydrophobic polymers as the coating material are used to adjust the time lag. Recent approaches often combine both pH- and time-dependent systems to achieve more targeted drug delivery to the colon. Ofokansi and Kenechukwu, for example, prepared ibuprofen tablets using Eudragit EL 100 and chitosan to form interpolyelectrolyte complexes (4). The formulation showed pH-dependent swelling properties and prolonged drug release 

 (4). The electrostatic interaction between the carbonyl (-CO-) group of Eudragit RL 100 and the amino (-NH

) group of chitosan was thought to prevent drug release in the stomach and small intestine, facilitating colon-targeted drug delivery.

 Osmotic systems are commonly used for controlled-release purposes but the concept can be applied in colon drug delivery as well. The system consists of the drug, an osmotic agent, and a semi-permeable membrane with an orifice for drug release. An additional enteric coating is applied on top of the membrane to prevent drug release in the stomach and upper GI tract. As the dosage form enters the small intestine, the increase in pH causes the enteric coating to dissolve, exposing the semi-permeable membrane. Water enters the drug core and the expanding volume forces the drug out the osmotic system through the orifice.

	A number of research groups are working on the development of innovative osmotic tablets for the treatment of inflammatory bowel disease. Chaudhary et al., for example, developed microporous bilayer osmotic tablets of dicyclomine hydrochloride and diclofenac potassium for colon targeting (5). The bilayer coating consisted of a microporous semipermeable membrane and an enteric polymer. The tablets showed acid resistance and time release in 

dissolution studies, demonstrating the potential for colon-specific drug delivery to treat irritable bowel syndrome.

	Nath et al. incorporated Sterculia gum, which is a polysaccharide, into osmotic tablets for colon-specific drug delivery of azathioprine (6). Sterculia gum is digested by the colonic enterobacteria and swelling of the polysaccharide forces the drug out of the tablet core. To ensure that drug release does not occur in the upper GI regions, a double-layer coating of chitosan/Eudragit RLPO (ammonio-methacrylate copolymer) and enteric polymers is used to impart acid- and intestinal-resistant properties to the tablet.

	In short, the colon offers an alternative drug-delivery approach for acid-labile drugs such as proteins and peptides, drugs that degrade in the stomach and small intestine or undergo extensive first pass metabolism, as well as for topical treatment of inflammatory diseases of the colon. While progress is being made in achieving more specific targeting of drugs to the colon, the complexity of these drug-delivery systems will require validated dissolution methods and establishing 

 24 (1) 63–92 (2007).
	2. V.R. Sinha and R. Kumria, 

 18 (5) 557–564 (2001).
	3. J.F. Ruiz et al., 

 21 (22) 6636–6640 (2011).
	4. K.C. Ofokansi and F.C. Kenechukwu, 

 online, DOI: 10.1155/2013/838403, Aug. 6, 2013.
	5. A. Chaudhary et al., 

 78 (1) 134–140 (2011).
	6. Nath et al., 

 When referring to this article, please cite it as A. Siew, "Mission Possible: Targeting Drugs to the Colon," 

Prodrugs and drug-delivery systems controlled by time, pH, and osmosis, are being used to prevent drug degradation in the stomach and large intestine and ensure drug release in the colon.

Mission Possible: Targeting Drugs to the Colon

	It’s the last day at ACHEMA! With a few more hours left before the show draws to a close, here’s a brief summary of the key trends observed during the week.
	
	Gone are the days of the blockbusters. The pharmaceutical industry is definitely moving towards personalized medicines. As therapies become more targeted to a specific population, batch sizes are getting smaller.  And pharmaceutical manufacturers are consequently looking for flexibility in their production lines, such as short changover times, easy cleaning of equipment and machinery, and process automation to name a few. The industry is beginning to recognize the advantages of modular production plants. The personalized medicines era is also driving up the number of highly potent drug products, resulting in a demand for containment solutions and isolators.  
	
	In bioprocesssing, single use has no doubt made significant in roads, more so upstream than downstream. Single use suppliers now have a good understanding of their materials, hence the risk of extractables and leachables isn’t so much of an issue as before. Of course, challenges still exist, such as the lack of standardization and guidance from regulators.
	
	Not only is pharmaceutical manufacturing is advancing but there is significant progress observed in bioprocessing as well. It is all because of the innovators who are constantly finding solutions to common problems. ACHEMA has indeed provided a platform for the process industry to showcase its technologies. So as we say goodbye to the show, and as exhibitors pack up and go their separate ways, here’s to all the engineers and scientists who have made a difference in the industry.

It’s the last day at ACHEMA! With a few more hours left before the show draws to a close, here’s a brief summary of the key trends observed during the week.

ACHEMA in Short

	In cell culture, contamination of cells is a major problem. In most cases, the incubator could be the source of contamination with people opening and closing the door to put in or remove their cells. It could also be due to the outside air coming into contact with the medium and cells either from splashing or inadvertent removal of lid. “One solution to minimize the risk of contamination is to disinfect the incubator routinely,” said Jessica Wagener, PhD, field application specialist, Cell Handling, Eppendorf, at the company’s laboratory tour during the ACHEMA show. Other key pointers include filing consumables one by one and using flasks with a screw cap instead of dishes with a loose lid, for example, for maintenance of stock cultures or when frequent transportation of the cultures is required. Wagener added that Eppendorf offers solutions such as an easy to clean incubator with high temperature disinfection mode; SplashProtect ring in dishes to avoid splashes and bridging of medium with the outside environment; corrugated handling ring of cell culture dishes for safe transportation; and flasks with optimized geometry.
	
	Another frequent problem in cell culture is the non homogenous cell growth, noted Tanja Musiol, PhD, project leader, Customer Workflows, Eppendorf. “When using multiwall plates, you often find that the distribution of cells in the edge wells is not homogenous,” explained Musiol, adding that there is higher evaporation rate in the edge wells. Temperature variations during incubation and variations in chamber atmosphere due to door opening of the incubator could also contribute to the problem. “One way to minimize this [non homogenous cell growth] is to avoid using the edge wells,” continued Musiol. And then, picking up an Eppendorf cell culture plate, Musiol showed how the peripheral moat helps minimize the edge effect. Wagener went on to highlight Eppendorf’s Galaxy CO

 incubator, which has split inner doors on each shelf to allow stable cell growth conditions.
	
	Cell adhesion can also be non homogenous, as Musiol pointed out. “You can have variations in seeding cell numbers, or formation of air bubbles during the seeding process, which all lead to the uneven distribution of cells,” she said. A possible solution is to regularly re-suspend the cells during seeding. Manual movement of consumable after seeding can also help minimize the risk of uneven cell adhesion. Eppendorf’s Multipette and Combitips enable fast seeding operation, according to Musiol. “The dispension steps avoid air bubbles from being inserted,” she added.
	
	Moving on to single use in cell culture, Matthias Korsten, director service and support, Bioprocess, Eppendorf, stressed that despite the benefits it offers, there can be issues related to extractables and leachables and product characteristics may be altered as a result. For this reason, it is important that extractables studies are performed to identify and quantify potentially harmful compounds. Korsten showed one of Eppendorf’s offerings, which is a single use vessel produced from monolayer injection-molded plastic. “The materials used comply with USP Class VI,” said Korsten. “These are virgin materials, which are sourced directly by Eppendorf.”
	
	One thing you will notice at ACHEMA is that there are solutions for most of the challenges encountered in the process industry. In every hall, exhibitors are passionately talking about their innovative products, and Eppendorf is no exception. The company-guided tour runs daily in Hall 4.1, Booth D36. Visitors are invited to experience the Eppendorf lab workflow and learn about the company's product solutions for common problems in the bioprocessing/cell culture lab.

Experts at Eppendorf discuss common challenges in cell culture and share insights on possible solutions.

A visit to Eppendorf’s cell culture lab at ACHEMA

	With drug development trends shifting towards personalized medicines, new technologies are needed for the manufacture of these highly sensitive drug products. Lyophilization is widely used to preserve biopharmaceuticals. The process involves three steps: freezing, primary drying, and secondary drying. The challenge, however, is in process optimization and reducing cycle time, said Stephan Reuter, managing director of Optima, at the Optima O! talks session. Sharing insights on lyophilization process technology, Reuter stressed the importance of ensuring that each vial in the freeze dryer is subject to the same condition, which means the shelves must have homogenous temperature distribution. Reuter also explained that the freezing step determines the texture of the ice crystals. This is where controlled nucleation can help optimize freezing of the product. "You get better quality product with controlled nucleation and shorter drying times," said Reuter. Controlled nucleation, however, is not yet widely implemented in the industry, according to Reuter, partly because the technology is still considered to be in its infancy.
	 
	In aseptic processing, isolator technology is increasingly being chosen over cleanrooms, mostly driven by the need to minimize downtime. One of the advantages with isolator technology is the short change over times. "Isolators offer high flexibility and have better sterility levels than RABS," said Marc Bechler, sales manager, Metall+Plastic, Optima, when speaking on trends in barrier Systems during the Optima O! talks. Bechler provided an overview of how a catalytic converter, which can be easily retrofitted to an isolator, enables the reduction of cycle time by 50%. According to him, the cycle beginning from leak detection and dehumidification to decontamination with hydrogen peroxide and aeration takes approximately two hours.
	 
	At ACHEMA, it is evident that the process industry is striving to understand every aspect of a particular process so that it can be further optimized. It’s all about reducing run times and cutting down on costs without affecting product quality – and that’s what you call process optimization.

With drug development trends shifting towards personalized medicines, new technologies are needed for the manufacture of these highly sensitive drug products.