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

Adeline Siew, PhD

Orally disintegrating tablets (ODTs) are designed to dissolve in the mouth within seconds without the need for water. Because of this convenience and ease of administration, ODTs have gained recognition as one of the most user-friendly oral dosage forms. “For people with an aversion to, or fear of, swallowing tablets, ODTs present an acceptable method of drug delivery that not only aids compliance but also greatly reduces the risk of choking,” says Mathias Bayru, group product manager, Catalent Advanced Delivery Technologies. Moreover, because of the quick dissolution, one can be sure that the medicine has been taken, which is a clear advantage for children, the elderly, and patients with mental disorders, adds Philippe Lefevre, global technical application specialist at Roquette. Bayru concurs that ODTs reduce the risk of patients successfully disguising swallowing by hiding the medication in their mouth and removing it later--a practice known as “cheeking.”

	ODTs are stable formulations with good shelf lives, according to Rosie McLaughlin, director of scientific affairs, Zydis, Catalent Pharma Solutions. “They do not require refrigerated storage, making the products easy to store and transport,” she says. For pharmaceutical companies, ODTs can be part of a lifecycle management strategy, Lefevre highlights. ODTs are innovative dosage forms that can also be used to create new brands and product differentiation.

	“Today, the most promising development of ODTs is in the pediatric field,” says Lefevre. Orodispersible minitablets (ODMTs), which have a maximum diameter of 3 mm, are currently one of the most studied pediatric dosage forms, he notes. Studies have shown that ODMTs are well adapted and well accepted by children. “For newborns, ODMTs can be dispersed in water prior to use,” explains Lefevre, “whereas for children who are six months old and above, ODMTs can be taken in single or multiple units based on the child’s weight and age.”

 spoke to industry experts from Roquette and Catalent about the development of ODTs.

 What drugs are suitable candidates for formulation into an ODT?

 An obvious answer is drugs that people want to take immediately wherever they are and drugs targeting patients for which ODTs or ODMTs are considered useful. Unfortunately, there are technical restrictions on the type of drugs that can be concretely formulated into ODTs. Due to the specificity of the oral tablet, some constraints on drug taste and drug dosage are inevitable. Bad taste is the first hurdle to ODT development because the quick disintegration in the mouth intensifies the disagreeable taste feeling by the patient, but there are various taste-masking strategies available to tackle this challenge, such as encapsulation or molecular inclusion in cyclodextrins.

	The ideal candidate for ODTs would be a drug with low dosage and neutral taste, with no side effects. Highly potent APIs (i.e., those with a low dosage in the final form) are easier to formulate as ODTs. The API will have less effect on the physical properties of the tablets.

 ODTs are most suited for drugs that require rapid onset of action, such as pain management, allergy relief, and treatments for diarrhea and constipation. Formulations targeted at specific population groups are also typical candidates for ODTs, such as those with pediatric or geriatric applications, as well as anti-psychotics where ODTs can help overcome swallowing issues, and indeed resistance to swallowing.

 What are the ideal characteristics of ODTs?

 Typically, the characteristics would be a tablet weight below 500 mg with physical and chemical stability. Other ideal characteristics include disintegration of the tablet in less than 30 seconds with no adverse taste or residual texture in the mouth and no throat burn.

 A short disintegration time in the mouth is an essential prerequisite for ODTs, but patients will also appreciate pleasant taste and texture--these two characteristics will play a key role in keeping a patient loyal to a particular brand.

	There is an optimum speed of disintegration. Disintegrations that are too quick are often associated with total drying of the mouth, which may create discomfort to the patient, or a suffocating feel. The important thing to remember is that ODTs have to be formulated to avoid any need for drinking water. The best sensation for the patient is when the disintegration starts quickly and ideally lasts 30 seconds or a maximum of 45 seconds. 
	After disintegration, the optimal texture is one that gives the patient a feeling that the tablet has turned into syrup. Soluble excipients have to dissolve quickly after tablet disintegration and the insoluble ingredients have to be as small as possible to avoid a sandy feeling in the mouth. Finally, ODTs must have a sweet and pleasant taste.

 The main challenge in developing ODT formulations is achieving a short disintegration time upon contact with saliva. This specific property of ODTs requires specific excipients compared with other oral tablets.

	The first, and perhaps inevitable, excipient in ODTs is mannitol. Mannitol has a unique behavior--although it is soluble, it presents a delay of dissolution when in contact with saliva. This property is essential because it maximizes the action of disintegrants and gives access to short disintegration time. In the first few seconds, mannitol does not interact with water, so all the water (from the saliva) is available for the action of the disintegrant, which can be a super-disintegrant or a starch. Mannitol then dissolves slowly and gives a pleasant taste as well as other properties such as sweetness, a cooling effect, and palatability.

	The second excipient is the super-disintegrant. For standard to large tablets, crosspovidone is the first choice because its action requires the smallest amount of water. For small ODTs, all super-disintegrants can be used.

	To simplify and accelerate the development of ODTs, formulators may benefit from compounds that combine mannitol and a super-disintegrant or compounds that combine mannitol and starch. The composition of these compounds, however, has been optimized to address ODT formulation challenges. For example, when using a super-disintegrant, short disintegration time requires high tablet porosity and consequently low tablet hardness. Pearlitol Flash, which is made of mannitol and starch, has been developed to solve this disintegration/hardness antagonism. This compound gives fast oral disintegration time independently of the hardness of the tablet, and ODT friability is no longer a concern. Formulators will also benefit from the neutral taste of starch in comparison to super-disintegrants. Pearlitol Flash is designed to facilitate optimization of the organoleptic properties of ODTs.

 The two major categories of ODTs are loosely compressed ODTs and lyophilized ODTs. For loosely compressed tablets, there are three main functional ingredients that help achieve rapid disintegration--super-disintegrants; effervescent agents; and highly water-soluble materials, either alone or in combination. Examples of super-disintegrants include croscarmellose sodium, crospovidone, and sodium starch glycolate. On exposure to water (i.e., saliva), the super-disintegrants either swell or ‘wick up’ the liquid, thus disrupting the tablet and aiding dispersion. Effervescent agents include, for example, sodium bicarbonate in combination with an organic acid such as citric or tartaric acid. On contact with water, the materials will effervesce and disrupt the tablet, aiding disintegration. Soluble agents include, for example, mannitol or xylitol, and their solubility contributes to the overall disintegration of the tablet.

	There are some commercially available blended excipients that are ‘ready to use’ for loosely compressed ODTs, for example, BASF’s Ludiflash (a mixture of mannitol, crospovidone, and polyvinyl acetate) and Fuji’s F-MELT (a combination of inorganic excipients and disintegrants in a carbohydrate complex). In addition to these functional excipients that aid disintegration, other excipients related to the direct compression process, such as binder, lubricant, or fillers may also be used, as well as flavors, sweeteners, and colors.

	Lyophilized ODTs such as Catalent’s Zydis technology do not rely on super-disintegrants to achieve rapid dispersion. Instead, the rapid-disintegration properties are related to both the formulation excipients and the manufacturing process. In the case of Zydis technology, gelatin is used as the polymeric structure-former in combination with mannitol to provide increased robustness and an elegant appearance. Both gelatin and mannitol will readily dissolve in saliva, contributing to the rapid disintegration and ‘melt-in-the-mouth’ experience. The structure imparted to ODTs manufactured by lyophilization is also a key component in achieving rapid disintegration. During lyophilization, ice crystals are sublimed to leave behind a multitude of air pockets within the ODT’s structure when it is freeze-dried. This approach results in a highly porous structure that ‘wicks up’ saliva and assists disintegration of the tablet.

	During the freeze-drying process, it is important to ensure that all of the mannitol is crystalline in the finished product, so as to prevent collapse during storage. Freezing conditions are also critical because too rapid freezing will lead to the build-up of small ice crystals, thus reducing porosity and disintegration.

	From a processing perspective, the key parameter for loosely compressed ODTs is compression force. Too low a compression force may improve disintegration but lead to a very friable product that is not robust when handled. Conversely, a higher compression force will result in a more robust ODT but at the cost of disintegration. In this respect, the use of compressible excipients is also a key consideration.

 Can you describe the different technologies used to produce ODTs and how they compare with each other?

 The two most common forms of ODTs are produced by lyophilization, which Catalent uses for its Zydis formulations, and low compaction or loose compression (as discussed in the previous section). There are also molded forms of ODT and, more recently, printed ODTs have appeared.

	There are variations in molding techniques, but the principle is that the drug/excipient blend is moistened with a solvent (usually water or ethanol) and then molded into a tablet (usually by low compression). There is then a heat- or air- treatment step to remove excess solvent and/or promote solid-state excipient phase-transformation, thus increasing tablet hardness. A new technology to the market alongside these three approaches is 3D printing, and there is one ODT currently on the market that uses this technique--Aprecia’s ZipDose technology.

 Today, the majority of ODTs are made by direct compression. Wet granulation is commonly used in Japan where there is a history of sophisticated ODTs made using that process. Processes using a melting step have been developed to produce new textures that reach short disintegration times. But this approach adds complexity to the manufacturing of ODTs and creates some concerns about long-time stability. Such heating processes generate amorphous or unstable crystalline forms of ingredients--drugs or excipients--that could potentially evolve over time.

	Among all the processes used to make ODTs, freeze-drying is the most efficient with regard to the disintegration properties of the final product. ‘Lyocs’ have high porosity compared to tablets obtained by tableting, and this porosity enables the high speed of saliva adsorption and the quick collapse of the dosage form on the tongue. Nevertheless, the development of lyocs has been constrained by the high cost of production.

 What advances have you seen in the development and manufacture of ODT formulations? What areas are still lacking? 

 In the past years, directly compressible compounds specifically developed for that application have demonstrated real benefits in the formulation of ODTs. Mannitol/disintegrant (super-disintegrant or starch) compounds ease the formulation and manufacturing of ODTs with regards to tablet cohesion and disintegration. They also help to improve taste and texture. Nonetheless, drugs having a bad taste are still a problem when formulating an ODT. This issue is, in fact, the most common cause of failure in the development of an ODT. Any solution to this problem will be appreciated, whether it is based on the improvement of existing systems such as film- or lipid-coating, or new approaches involving the use of specific additives that modify taste perception.

	During ODT formulation, disintegration times are measured using the standard disintegration tests recommended in pharmacopeias. Studies have demonstrated that there is no correlation between this in-vitro test (using 800 mL of water) and the effective in-vivo disintegration in the mouth with only a few mL of saliva. Specific in-vitro tests have been described and evaluated. Having a real predictive and validated in-vitro test will simplify and accelerate excipient selection in formulation development.

 In the case of loosely compressed ODTs, excipients have been developed that are especially designed for this type of dose form, for example, highly compressible excipients and excipient-blends to aid disintegration, such as Ludiflash and F-MELT. There have been several advances in the application of lyophilized ODTs, for example:

		To provide greater taste-masking capabilities, up to 400 mg of API, such as with Zydis Ultra technology 

		To produce room temperature stable peptide or vaccine formulations, such as with Catalent’s Zydis BIO platform

		To optimize lyophilized ODTs by incorporating nanoparticles to achieve improved bioavailability.

	Thin film strips have been positioned as alternatives to the more established ODT, but still have limited applicability due to a maximum dose load of between 20-50 mg of API.

	When referring to this article, please cite as A. Siew, "A Case for Orally Disintegrating Tablets," 

Articles

Industry experts discuss key considerations in the development of orally disintegrating tablets.

A Case for Orally Disintegrating Tablets

Poor solubility is one of the major problems hindering a molecule from progressing through the drug development pipeline. Approximately 70% of new chemical entities (NCEs) have been reported to be poorly soluble (1), which is not surprising given that modern drug-discovery techniques select compounds based on their binding affinities to target receptors. The most promising candidates are often highly lipophilic, hence, leading to solubility and bioavailability issues. Even for marketed drugs, it is estimated that 40% consists of APIs that fall into class II (low solubility, high permeability) or class IV (low solubility, low permeability) categories of the biopharmaceutics classification system (BCS) (2). Of 45 NCEs approved in 2016, 32 were small molecules and a significantly large number of them were poorly soluble (3).

	Various approaches have been used to tackle solubility challenges from particle size reduction, salt formation, and the use of cosolvents or cyclodextrins to formulation into solid dispersions or lipid-based drug-delivery systems among others. Of all the solubility enhancement strategies available, a study conducted by Patheon analyzing the drug products approved by FDA between 1970 and 2013 revealed that lipid systems were the most widely used solubilization platform, followed by solid dispersions (4). Both of these approaches involve the use of polymers.

	Over the years, polymers have played a key role as solubilizing excipients in many types of formulations, including liquid, semisolid, and solid-dosage forms. Typically, formulations that contain BCS class II and IV compounds will require the use of solubilizing polymers, observes William W. Porter III, research scientist at Dow Pharma Solutions.

	The choice of polymers used will depend on the drug properties and route of administration, according to Ian Barker, principal scientist at Juniper Pharma Services. “For oral formulations, such as self-emulsifying and self-microemulsifying drug delivery systems (SEDDS and SMEDDS) and amorphous solid dispersions, solubilizing polymers have found widespread applications, have proven effective in increasing the solubility and consequently, the bioavailability of poorly soluble drugs,” he says. Robert Harris, chief technical officer at Juniper Pharma Services continues, “For topical products, polyethoxylated surfactants and co-block polymers such as poloxamers (e.g., Kolliphor P188 and P407) are often incorporated to achieve drug solubility in the vehicle.”


	The industry has begun to pay closer attention to the polymers’ structures and functionalities in recognition that the physicochemical properties of polymers aid in the selection of appropriate excipients for the desired formulation, notes Andreas Gryczke, global technical marketing manager, Solubilization, BASF Pharma Solutions. Solubilizing polymers are amphiphilic in nature. “The hydrophilic and hydrophobic characteristics are crucial because they provide sites for intermolecular interactions (e.g., hydrophobic van der Waal’s and hydrogen bonding) with the lipophilic drug,” Gryczke explains. “Non-amphiphilic polymers are often used in combination with a surfactant to maintain the drug in supersaturated solution after its being released from the dosage form.”

	“A good solubilizing excipient will depend upon the affinity of the drug with the polymer,” Harris points out. “In particular, hydrogen-bonding between drug and polymer plays a key role in maintaining the drug in a dissolved state and promoting miscibility and stability of the formulation.”

	Gryczke adds that when using polymer-surfactant combinations, attributes such as wettability, surface active properties, and hydrophilic lipophilic balance (HLB) are also important in drug solubilization to ensure that the molecule remains encapsulated in the polymeric assemblies as nanoparticles, micelles, or emulsion/microemulsion. Polymer chain length and molecular weight can also have an effect on the dosage form’s performances by leveraging the stronger drug-polymer entanglements, which are crucial for stability of the solubilized drug and for maintaining supersaturation of drug without precipitation or nucleation, says Gryczke.

	According to Barker, generally when reference is made to use of polymers to aid drug solubility, it is usually associated with amorphous solid dispersions. The most commonly used excipients in solid dispersions are cellulose-based polymers (e.g., hydroxypropyl methylcellulose [HPMC], hydroxypropyl methylcellulose acetate succinate [HPMCAS]), vinyl pyrrolidones and their co-polymers (e.g., Kollidon VA64), and methacrylates (e.g., Eudragit, Kollicoat MAE). “Within each of these classes, there are multiple polymer chemistries that are used in this application space,” adds Kevin P. O’Donnell, research scientist at Dow Pharma Solutions. “Some of the useful properties of these polymers include having a molecular weight significantly higher than that of the drug, sufficiently high glass transition temperature to promote amorphous physical stability, and the ability to have hydrogen bonding interactions with the drug in the solid-state and in solution.”

	“Polymers enhance solubility of the poorly soluble drug by increasing the degree of API distribution or by even changing the crystalline structure of the active to an amorphous higher energy state,” explains Firouz Asgarzadeh, Evonik’s director of technical service for North America. According to Asgarzadeh, maintaining the solubility enhancement effect requires the long-term stabilization of the amorphous structure via molecular interactions (i.e., ionic and/or hydrogen bonding) and by minimizing the molecular mobility below the glass transition temperature of the polymer. He further points out that the selection of polymers through a systematic approach of estimating miscibility levels based on the structures of polymers and actives can significantly accelerate the formulation development. In the following roundtable discussion, industry experts provide insight on the factors that influence polymer selection and the importance of screening studies in formulation development.

 How do the physicochemical properties of the polymer and API affect performance of the formulation?

 According to the organic/polymer chemistry’s rule of thumb ‘like dissolves like,’ the miscibility of polymer and API will influence the processing conditions and stabilization of the resulting amorphous solid solutions and dispersions. Polymers and APIs with similar solubility parameters and potential for hydrogen bonding and ionic interactions are expected to be more stable and easier to process. Such interactions may allow for the formation of amorphous solid dispersions at temperatures well below the melt temperature of the API. When the intermolecular bonding forces of the polymer and drug in amorphous solid dispersions are stronger than the intramolecular forces, combined with the glassy state of the polymer, recrystallization is inhibited, which can improve storage stability.

 The fact that polymers can be used to formulate drugs into a dosage form has to do with the polymer’s physicochemical properties, physics, and chemical constitution. In respect to physical properties, we have to take into consideration the polymer’s melting point and glass transition temperature, melt and/or solution viscosity, and the overall rheological behavior as these properties also determine a polymer’s suitability when being used, say for example, as a binder in melt or wet granulation process.

	In terms of formulation development for poorly soluble drugs, the different features of polymers have proven useful. For example, polymers are often used to serve as a matrix for a drug to be (molecularly) dispersed in it. In this case, the drug’s crystal lattice energy is overcome already, meaning that the drug has been dissolved and the polymer controls its release later. The drug release rate is not just determined by the chemical composition but also the molecular weight of the polymer.

	Polymers can consist of different monomers with different chemical functionalities. Nowadays, we have available a variety of polymers with different functional groups such as carbonyl, hydroxyl, and amino- moieties; hence, for many drug molecules, a suitable polymer that stabilizes the drug in its dispersed state can be found.

	In respect to the manufacturing process of a drug product, polymers play a decisive role in term of compressibility, elasticity, rheology, and many other parameters. The glass transition temperature is a good example as this parameter is considered when making a decision on the manufacturing of a solid dispersion. Overall, the polymer’s physicochemical properties have to match the requirements for the drug molecule and the available processing technology.

Barker and Harris (Juniper Pharma Services):

 The physiochemical properties of the drug and polymer are critical when assessing the most appropriate formulation route.  Generally, both drug and polymer have to be stable to processing.  In addition, the polymer has to sustain long-term stability of the drug with regards to properties such as recrystallization. An example is hot-melt extrusion (HME) where high heat and shear can cause degradation of not only the API, but the polymer as well. Advances are being made in producing polymeric materials for HME applications, with notable examples being the tri-block co-polymers and cellulosic materials with wider HME processing windows.

 The physiochemical properties of the API will direct polymer selection.  The polymer will be selected to improve critical API attributes and allow for downstream processing of the amorphous solid dispersion. For example, an API with a low glass transition temperature will require a polymer with a suitably high glass transition temperature to allow for physical stability of the dispersion. Similarly, if the dispersion is manufactured using a solvent-based process, the polymer must dissolve in a solvent that is also compatible with the API. In addition, if the dispersion is manufactured via a thermal process, the polymer and API must be thermally stable at reasonable processing temperatures. Finally, the API and polymer interactions need to be sufficient to promote both solid-state stability of the dispersion as well as sustained supersaturation upon dissolution.

 How do you decide which polymers to use? What are the key considerations in excipient selection?

 In solid amorphous molecular dispersions, polymer choice is often dictated by pre-formulation screening work, which aims to match an excipient to the API being formulated. It is, therefore, critical that polymers amenable to industrially viable processing techniques (e.g., HME or spray drying) are used from the outset. Typically, such polymers have a high amount of polar groups capable of hydrogen bonding, are stable to heat, soluble in a wide range of solvents including water and are widely available from numerous pharmaceutical excipient suppliers.

 Polymers for solid dispersions are typically selected based on the physiochemical properties of the API. A key consideration is the intended method of production because HME and spray drying will have different critical quality attributes for the polymer. For example, spray drying requires a polymer that is soluble in organic solutions while maintaining a low solution viscosity for atomization. Alternatively, HME requires a polymer with a moderate softening temperature and adequate melt viscosity over a broad processing window.

 To begin with, there are several aspects that need to be considered, such as the drug release site, the desired release rate, the desired dosage form, the required dose per dosage form, and the available manufacturing technologies. All these factors will influence the decision on which polymer can be used in solid dispersions. 

	There are many polymers available on the market, for example, polymers that release the drug independent of pH such as Kollidon VA64, and polymers that serve as both a matrix polymer as well as a solubilizer such as Soluplus. There are also polymers proven to have good properties in inhibiting drug precipitation after being released such as povidone K30 (Kollidon 30) and HPMC.

	Polymers are selected based on their parameters such as melting point (if there is one), glass transition temperature, melt viscosity, hygroscopicity, chemical nature, available in-house process technology, and the available experience and know-how, all to match the requirements of a drug molecule.

 When selecting polymers for the development of pharmaceutical formulations with enhanced solubility, one of the most important criteria is the regulatory compliance of the polymer (compendial status) and established use in existing oral drug products.

	The quality attributes will depend on the process that is used to manufacture the solid dispersion. For polymers used in a melt process (e.g., HME), the selection criteria typically includes a glass transition temperature that is moderately higher than the desired storage temperature while possessing conditions with sufficient thermal stability. A glass transition temperature or melt temperature that is too high may require HME process temperatures that could accelerate drug and/or polymer degradation. On the contrary, a glass transition temperature or melt temperature that is too low may cause product instability and premature recrystallization.

	For a spray-drying dispersion process, polymers with high solubility in organic solvents are necessary to minimize solution preparation and spray times. Actives with stability problems at higher temperatures are more suitable for spray drying than HME techniques. In both spray drying and HME processes, the miscibility of the active and polymer is necessary. The presence of appropriate hydrogen-bond donor or acceptor groups, and in the case of ionic actives, the presence of appropriate counter-ions on the polymer and active will ease the formation of solid solutions and the inhibition of crystal growth. 

 Can you tell us more about the importance of screening studies when developing a formulation for a poorly soluble drug? What screening tools are typically used to reduce trial and error?

 Screening studies are necessary to guide formulation toward the optimal polymer. High throughput supersaturation screening and thermal screening tools are frequently used to identify the best polymer candidates and starting drug loads. A secondary screening can be performed by small-scale spray drying or HME to verify the initial screening and provide processing guidance for scale up. Combined, these methods reduce trial and error and minimize the amount of API needed for early formulation development work.

 The rational selection of formulation ingredients for solid solution formation leads to a significant reduction in the number of experiments and hence speeds up formulation development. A first screening study using solubility parameters of the polymer and active is essential when investigating the solubility issues with a systematic approach rather than a random mixing and matching empirical approach. A tool developed by Evonik is MemFis (Melt Extrusion Modeling and Formulation and Information System). We have stories of clients who had already started an empirical development approach with no acceptable results and MemFis proved useful in identifying polymer-drug combinations that were overlooked in the original screening studies. Once appropriate combinations with potential miscibility are identified, a quick evaluation using film casting, spray drying, or HME at a very small scale can further confirm the formation of stable solid solutions with enhanced solubility. The application of MemFis not only enhances formulation development but also saves drug substance, which may be expensive and/or limited in supply, especially at the early stages of development.

 The screening we recommend involves several phases, aimed to achieve the decision for a lead formulation in a fast manner. It begins with the in-situ phase where the chemical requirements of the drugs are matched with polymers, which is based on computer simulations and miscibility estimations to reduce the set of polymers in the next phase of conduction experiment. Following that, small-scale screening tests are conducted to verify the computer simulation. This type of testing can be done manually or by high-throughput screening systems. BASF uses a combination of these approaches to understand the following three things:

		How to best bring the drug into supersaturated solution over an extended period (>4 hours)

		How to maintain the drug in supersaturated solution (depending on the surrounding medium), and how to inhibit drug precipitation to a level where sufficient absorption is expected

		How to stabilize the drug in the formulation until it is released.

	The use of design of experiments is important because it allows us to generate data to find a comprehensive solution with reasonable effort.

 With more than 80% of new chemical entities exhibiting poor solubility, screening studies form an important part of early development. Preclinical toxicology studies often require enhanced formulations to ensure suitable exposure is achieved. Screens focus on drug/polymer miscibility and stability and can be achieved using miniaturized techniques (e.g., film casting) where mg quantities of the drug and test polymer are used. The physicochemical analysis that accompanies these tests, such Raman spectroscopy, x-ray powder diffraction, differential scanning calorimetry, and optical microscopy provide crucial data to inform appropriate drug in polymer formulation routes. The process can be rapid and can include initial pharmacokinetics animal data.

, 4 (1) 3-17 (2014). 
	2. T. Loftsson and B.E. Brewster, 

, 62 (11) 1607-1621 (2010).
	3. L. M. Jarvis, 


	When referring to this article, please cite it as A. Siew, "Taking On Mission Insoluble with Polymers," 

Polymers have played a key role as solubilizing excipients. Industry experts explain why polymer structures and functionalities are important considerations in formulation development.

Taking On Mission Insoluble with Polymers

	Lipid-based drug delivery is increasingly being used to tackle oral bioavailability challenges resulting from poor solubility. This type of formulation exploits the body’s lipid disgestion and absorption pathways. 
	“Many poorly soluble drugs are associated with a positive food effect in that their bioavailability increases with food intake,” observes Kaspar van den Dries, senior director formulation sciences, solid dosage forms, and softgels at Patheon. “This endogenic effect of food makes lipid systems a suitable formulation option to enhance the bioavailability of poorly soluble drugs.”

	The development of lipid-based formulations, however, requires a multifaceted approach. “It is insufficient to just explore the API’s solubility in different lipid excipients and use this information to formulate a lipid system,” explains van den Dries. He recommends that aspects such as lipid digestions in simulated gastric and intestinal fluid, phase diagrams, and emulsification behavior should be covered as well as part of the formulation characterization. According to van den Dries, the number of excipients for lipid-based formulations has expanded over the years.

	“Besides the traditional medium and long-chain triglycerides (e.g., castor oil), there is a wide range of other excipients available to generate lipid-based formulations, from chemically modified glycerides to polar and non-polar surfactants and cosolvents,” he says. “Which excipients to select will depend on multiple factors, such as API solubility in these excipients, whether the excipients are sensitive to lipid digestion, and the emulsification behavior.”

	Van den Dries believes that lipid screening is an important aspect in the development of lipid-based formulations. “The solubility data in a sufficiently broad range of lipid excipients will provide an initial assessment of the excipients that can be used and the expected drug loading,” he explains. “However, combining the right excipients in the correct ratio and subsequently establishing the emulsification behavior in physiologically relevant media is essential to evaluate whether the formulation also provides the required emulsification behavior and could work in an in-vivo environment.” 

	The key for lipid solubility screening is to standardize the protocol for the screen, says van den Dries. These protocols should be designed to minimize drug usage and at the same time, perform a rapid screening. According to him, a general approach to developing lipid-based formulations should typically involve: 

		Rapid solubility screening in up to 20 lipid excipients with minimal API consumption 

		Formulation design using phase diagrams 

		In-vial stability program to assess chemical and physical stability prior to batch manufacturing to reduce risk and API consumption

		Formulation characterization to assess rheology and emulsification behavior

		Lipid digestion screening to predict in-vivo behavior of lead candidate formulations

		Prototype development for animal studies or GMP batches for human clinical studies with International Council for Harmonization (ICH) stability testing on prototypes

		Optional testing such as permeability studies and gastric intestinal model, among others.

	Along with the standard experimental work to screen lipid formulations, Patheon also uses in-silico modeling, van den Dries points out. “We employ modeling to provide estimates of the solubility of drug compounds in typical excipients used for lipid formulations. Modeling does not replace all experimental work, but these computational approaches significantly reduce the amount of up-front experiments that might otherwise be performed in the process of selecting and developing robust formulation approaches to overcome bioavailability challenges.”


	When referring to this article, please cite it as A. Siew, "The importance of lipid screening in the development of lipid-based formulations," sidebar to "Taking On Mission Insoluble with Polymers," 

Lipid-based drug delivery is increasingly being used to tackle oral bioavailability challenges resulting from poor solubility.

The importance of lipid screening in the development of lipid-based formulations

Parenteral formulations are increasingly capturing a bigger share of the pharmaceutical market, driven by the booming biologics sector. The production of these injectables is, nonetheless, complicated and requires specialized equipment and facilities. “The biggest challenge in aseptic processing is to maintain sterility,” says Sam de Costa, stabilization project manager at Nova Laboratories, “especially if the manufacturing process involves novel or complex steps.” He highlights that FDA, the European Medicines Agency (EMA), and the World Health Organization have laid out well-defined regulatory requirements for parenteral drug products. “The main focus is on ensuring product safety because parenteral preparations bypass the patient’s natural defense mechanisms,” de Costa explains. “Sterility assurance and control of pyrogens is, therefore, particularly important.”

	According to de Costa, terminal sterilization is the preferred approach in drug manufacture. “Unfortunately, many drug substances, particularly biologics, cannot withstand exposure to the elevated temperatures or irradiation required as part of a terminal sterilization process,” he notes. “In such cases, aseptic manufacture is the only available option.” In this article, de Costa speaks to 

 about aseptic spray drying as an alternative option for stabilizing parenteral formulations.

 Can you explain the concept of aseptic spray drying for parenteral formulations?

 Aseptic spray drying converts a liquid formulation into a dry powder suitable for parenteral applications without the need for terminal sterilization. The aseptic powder can then be filled into different presentations including vials or medical devices. Reliable spray drying systems adopted to operate under cGMP sterile conditions are essential within a robust manufacturing facility. In-depth knowledge in aseptic manufacturing techniques will be essential to successfully maintain such a facility. 
	
	

 Why is aseptic spray drying not traditionally used compared to lyophilization?

 Lyophilization has been the established technique and the method of choice for biologics manufacture for number of years. Most contract manufacturing organizations (CMOs) have freeze-drying capabilities, thus contributing to its popularity.

	The aseptic spray drying technology was pioneered by Nova Laboratories more than nine years ago. This technology has received positive response from regulators, with FDA and EMA approving, in 2015, the first aseptically spray-dried biologic, Raplixa (developed by ProFibrix BV). This drying methodology can be combined with gassed isolators to provide a reliable and continuous processing option for biologics.

	With the regulators’ acceptance of this technology, we are confident that the application of aseptic spray drying in biologics manufacture will increase in the coming years, making this approach a viable alternative to lyophilization.

 How does aseptic spray drying compare with lyophilization?

 Spray drying has number of advantages over lyophilization. Lyophilization is a batch process, therefore, the production batch size is limited by the capacity of the lyophilizer. In contrast, spray drying can be operated continuously, sometimes even over a number of days, to achieve the required quantities of product. This flexibility will ultimately help to reduce the batch cost, hence, driving down the unit cost of the finished biologic. Continuous processing is especially useful for commercial manufacturing of products required in high quantities, and this is one area where spray drying can be applied.

	When choosing a suitable drying method, the compatibility of the drug product needs to be assessed carefully. For example, the freezing step during lyophilization can sometimes affect the formulation in a negative way. Spray drying is a much gentler process, making it compatible with biologics manufacture.

	Moreover, the particle-engineering capability of spray drying is an advantage over freeze drying. Advances in liquid atomization and powder-collection technologies have enabled us to manufacture sterile powder with desired characteristics. For example, by manipulating the surface area or morphology of spray-dried particles, dissolution rates can be improved. This capability is, however, not available for a lyophilized product. If required, encapsulation or particle coating is another feature of spray drying that can facilitate different drug-release or dissolution profiles.

	A spray-dried product is by nature a powder. This characteristic allows the formulation to be powder-filled into final containers without further processing. A lyophilized product, on the other hand, will have to be milled or sieved first before undergoing the powder-filling step. Spray drying eliminates the need for an additional milling or sieving step, thus reducing manufacturing costs. Quality concerns such as product uniformity can also be solved by spray drying. Spray-dried powders can be engineered to have good flowability and compactability, which then enable easy filling into various containers including vials, pouches, and medical devices.

	Both lyophilization and spray drying are scalable technologies. Maintaining a consistent product quality across all production scales would be paramount for both technologies. An example is Nova’s experience in scaling up the manufacturing process for Raplixa, a spray-dried product. This process was initially converted from a low-bioburden spray-drying process to a fully aseptic spray-drying process. It was subsequently scaled up from clinical trial manufacturing scale to commercial scale at our facilities. As described previously, one of the main reasons for the cost difference is the mode of processing, (i.e., continuous processing helped to bring the unit cost down).

 How do you assess compatibility of a product to aseptic spray drying? 
	

 The suitability of a product to aseptic spray drying should be assessed at an early stage of the development program. At Nova, we conduct early stage feasibility studies to demonstrate compatibility of the technology to the biologic, but compatibility to other aspects of sterile manufacture will also be evaluated as part of this process.

	A range of biopharmaceutical products have been evaluated, from vaccines, monoclonal antibodies, and hormones to therapeutic peptides/proteins and live biologic platforms such as virus vectors. Some of these products were assumed to be extremely fragile and thermo-sensitive but proved to be compatible with spray-drying technology.

 Can thermo-sensitive biopharmaceuticals be spray dried successfully? What are the key considerations when spray drying a thermo-sensitive biologic formulation? 
	

 Yes, a range of biopharmaceuticals have been successfully evaluated before. Live viral or bacterial vectors have to be typically stored at -80 °C. The stabilized products, using spray drying, are stable at 2-8 °C or at room-temperature storage. This stability could be achieved because the drying method used was gentle to the product.

	During spray-drying process optimization, the drying temperature can be adjusted to suit the sensitivity of the product. Other process parameters such as drying gas rate, atomization pressure, and product holding temperatures should be optimized to yield best results.

 Why is there a misconception that thermo-sensitive biopharmaceuticals cannot be spray dried successfully?

 The misconception arises from the use of higher temperatures as part of the process compared to lyophilization. However, in reality, the product is not actually exposed to these temperatures during drying. As the atomized droplet evaporates within the drying chamber to create the powder, this step generates an evaporative cooling effect around the droplet/powder particle, resulting in a “cooler” environment around the product. This feature, in combination with the short resident time of a dried particle within a drying chamber, reduces the risk of the product being exposed to elevated temperatures. Similar to lyophilization, in most instances, bulking/stabilizing excipients can be added to the formulation for spray drying, which can further provide thermal protection during processing and storage.

 Can you provide an example of how aseptic spray drying is used as an enabling stabilizing technology?

 In our experience, Raplixa is the best example of explaining the concept of aseptic spray drying. Raplixa is a hemostat product consisting of fibrinogen and thrombin developed by Profibrix BV. Due to their natural states, fibrinogen and thrombin cannot be processed together in liquid format. The two biologics were, therefore, aseptically spray dried individually using optimum processing conditions. Particle engineering was applied to obtain suitable particle-size distributions, and the resulting powder was blended and powder-filled under sterile conditions. The ability to engineer the particles to suit the application enabled us to develop this novel pharmaceutical drug successfully. This ability to aseptically spray dry the biologic product avoided the need for terminal sterilization, offering a quality and cost advantage.


	When referring to this article, please cite it as A. Siew, “Exploring the Use of Aseptic Spray Drying in the Manufacture of Biopharmaceutical Injectables," 

Aseptic spray drying provides an alternative to lyophilization as an enabling stabilization technology for parenteral biologic formulations.

Exploring the Use of Aseptic Spray Drying in the Manufacture of Biopharmaceutical Injectables

Self-administration is fast becoming a trend in today’s healthcare as the pharmaceutical industry continues to tap into the potential of autoinjectors as a drug-delivery solution that can offer improved patient experience and compliance. As a result, the market for autoinjectors is expanding rapidly, driven primarily by two factors, says Kevin Deane, medical device expert at PA Consulting Group, “the proliferation of biologic compounds, which are filling pharma’s pipelines, and the need to move drug administration away from clinics and hospitals into home use and self-administration.” Deane notes that Humira (adalimumab) and Enbrel (etanercept), which are among the top five best-selling drugs, are self-administered by patients using autoinjectors.

	“The autoinjector market grows because pharmaceutical and biologic companies are constantly looking to differentiate their drug-device offerings and provide intellectual-property (IP) protection against competition,” highlight Oli Gould, design team manager, R&D, and Gareth Walker, human factors specialist, both from Owen Mumford. It is crucial that product differentiation goes beyond the molecule, especially when facing the patent cliff. According to Gould and Walker, custom-developed autoinjectors can provide opportunities for patented product differentiation, thereby, helping companies to maintain their margins and market share.

	In this article, Deane, Gould, and Walker discuss the different aspects involved in developing an autoinjector, including the importance of human factor engineering.

 Can you discuss the challenges of developing an autoinjector? 

 The key challenges encountered in the development of an autoinjector are the competing requirements, which include size, cost, and mass. With design freedom in these parameters, one can be confident of achieving any reasonable requirement. But this is seldom the case. At a minimum, size and mass can directly influence usability and therefore combination product efficacy.

	Ensuring user safety is, of course, the primary concern. Being intelligent in how one achieves that level of safety, or indeed, exceeding established safety benchmarks will benefit the end-user and can set one apart from the competition.

	Efficacy is, generally, a close second in priority and, dependent upon the treatment, may be inseparable from safety. Efficacy broadly groups accuracy, reliability, and usability. Some of the greatest challenges in autoinjector development come from doing more to achieve excellence in safety and efficacy (particularly in usability) whilst maintaining a cost-effective product solution.

	Time to market is always an important factor in product-based organizations. Driven by more stringent regulation and increased expectations of pharmaceutical partners, the rigor in developmental investigations, in combination with increasing complexity of device solutions, puts a strain on project timescales.

 The key challenges in developing an autoinjector are cost of goods, drug viscosity, and freedom within a crowded IP landscape. The requirement to minimize the cost of goods drives the designer to minimize the number of parts in the device. This is most effectively achieved by placing multiple functions on each part, but this adds to the complexity and increases the importance of design for manufacture and assembly activities.

	Drug viscosity can prove a challenge both at high and low viscosities. At high viscosity, a high power source is required to ensure the injection time is acceptably short for the user. Retaining such high loads throughout the shelf life of the device and ensuring the device still functions, are challenging and require extensive modeling and accelerated aging to simulate high stress and long life. At low viscosity, the challenge is lengthening the injection time to avoid pain, but at the same time, avoiding device stall as friction loads dominate the injection. Both of these aspects can be partially solved by modification of the needle size, but this change is not available to the designer.

	The IP landscape for autoinjectors is crowded, particularly in the space offering the simplest and most reliable device architecture. A sleeve actuated autoinjector, which is becoming the standard embodiment, is not a complex device. The function can be fulfilled with a small number of parts, and thus, there are a limited number of mechanisms that will provide the functionality. As a result, there are limited opportunities to innovate without infringing existing IP. To overcome this design constraint and avoid the need to license, the designer is driven to move to less elegant design solutions, typically introducing additional parts or suboptimal mechanisms, with a knock-on impact on molding and assembly complexity as well as the inevitable impact on cost of goods.

 How can prefilled syringes and cartridges be effectively integrated into an autoinjector?

 The prefilled syringe was never designed to be mounted within an automated delivery device such as an autoinjector. As a result, the geometry and emptying force are poorly defined and controlled. Unlike a person, an autoinjector cannot adapt to this variability and thus, the user is exposed to inconsistent injection depths and variable injection times. Moreover, there is a risk of damaging the syringe, presenting a safety risk to the user. The designer can solve some of these problems with complex mechanisms (e.g., electromechanical closed-loop feedback systems), but to effectively integrate the syringe requires extensive testing and characterization. The characterization is complicated by the lack of access to multiple syringe manufacturing batches (both unfilled and filled) and the difficulty of capturing the force to expel the drug.

	Access to multiple batches can be impossible if the drug is in development, and filling is not representative of the production fill. Even in later stages, getting hold of multiple batches to assess process variability is difficult due to the mismatch in syringe and autoinjector production volumes. This issue necessitates that characterization activities continue throughout the development.

	Capturing the force to expel the drug is challenging as the typical autoinjector power source, a spring, generates a decaying force during the delivery of the dose. Some theoretical modeling is possible, but limited in its validity. Empirical testing presents its own challenge as standard test equipment does not exist. Dynamic force testers are available but have limited functionality. Thus, typically a combination of constant force, constant velocity, and device power pack testing is used to measure the force to expel the drug.

	Cartridges require the same force characterization, but the geometry specification is much tighter. The additional challenge of the cartridge is designing the interface with the needle. In its simplest form, this design can be user applied (which has associated usability challenges and user safety risks). In the more complex form, the device must automatically couple the needle to the cartridge, piercing the septum as part of the injection process.

 The resistance from the stopper to movement within the container (from friction), strength of the container, resistance of the needle shield to removal, and general geometry (including relative position of the stopper in particular) are key parameter considerations when integrating prefilled syringes and containers into an autoinjector. However, what may be an even more important consideration than the nominal state of these parameters is their natural manufacturing variations. For example, many autoinjectors make use of a compression or torsion spring to evacuate the container and thus, the force exerted decreases as the fluid is evacuated. Conversely, a stopper within a poorly lubricated container may increase its resistance as it reaches the end of evacuation. The design of the autoinjector must allow for this change, and any variation, within its design.

	The strength of a container is often a key consideration also. We’re seeing a trend in increasing formulation viscosities as drug technologies change and the frequency of injection reduces. These more viscous fluids require greater delivery loads and more stress on the container as a result. Well-engineered support for the container and control over impact velocities are necessary to maintain container integrity.

 Human factors are a key consideration when developing a drug delivery device, such as an autoinjector. What guidelines have regulators such as FDA and EMA provided on this aspect? 

 The development of medical devices is governed by a number of regulations that can sometimes be baffling in their complexity. Even within the realms of regulations relating to human factors, ease of comprehension is sometimes overlooked. To address this aspect and help manufacturers understand the regulatory requirements, a number of guidance documents have been created. Most recently, in April 2016, FDA published guidance on 

Applying Human Factors and Usability Engineering to Medical Devices

. This guidance in particular aims to provide clarity on the activities that should be undertaken during the development of medical devices, and how to adapt human factors to deal with the different challenges created by the various applications of drug-delivery devices. Such guidance allows manufacturers to understand the scope of activities expected by regulators, and what types of techniques should be adopted. The guidance has removed some of the uncertainty that previously existed about what bodies, such as FDA, would want to see in terms of human factors evidence.

	FDA has also highlighted the importance of human factors data for drug-delivery devices by putting autoinjectors on their list of highest priority devices for human factors review. This means any autoinjector going forward for FDA approval through the premarket submission route must provide FDA with a report summarizing the human factors processes they have followed, including any analyses and evaluation activities, along with the human factors validation testing performed, the results obtained, and the conclusions drawn.

	European regulatory bodies have approached the matter with a lighter touch, leaving more to the manufacturer’s discretion. However, regardless of which regulatory body you are engaging with, there is clear and strong emphasis placed on ensuring safe and effective use through the application of human factors to all medical devices.

 Can you discuss human factor engineering and how it can be integrated in the development of an autoinjector?

 Human factors work is most efficient and productive when planned from the start as part of an iterative development program. Initial research should be carried out to understand the intended users and how their capability might affect their interaction with an autoinjector; what the context of use would be and how that might affect the interaction with the device; and what training would be expected.

	For example, an autoinjector for rheumatoid arthritis may have two distinct user groups: healthcare professionals and lay users. The design of the device would need to consider their physical impairment (reduced hand strength and mobility) and the size of device (larger proportion of female patients, generally adults). Because people with rheumatoid arthritis are generally older adults, consideration would also be needed for age-related decline in visual acuity and hearing.

	The next stage is to incorporate human factors into risk management to identify foreseeable misuse scenarios and to identify which use steps are related to patient safety and the ability to deliver medication effectively. These so-called critical tasks help inform what usability testing should be done. During the design and development phase, formative usability testing helps inform and iterate the design as well as identifying unforeseeable misuse scenarios that would need to be tested during the final simulated use human factors validation study (previously known as a summative study).

	Formative testing during the design phase is generally with small groups (5-8 participants) and may be aimed to look at one aspect of the design, an early sketch model, or high fidelity prototype. These experiments are not preference studies but are aimed to uncover key usability and safety issues related to the design. Human factor validation studies need to be run like a repeatable scientific study, although they are generally not clinical studies. FDA recommends using a minimum of 15 participants per distinct user group. The tasks carried out in the human factors validation study should be linked to the tasks identified in the human factors risk assessment and be comprehensive in scope to represent generalized use.

	FDA has provided guidance on which aspects of an autoinjector should be tested, including:

		The ability of users to read and understand the autoinjector instructions

		The ability to set up the autoinjectors

		The ability to dispose of the injector.

 How do you verify and validate your autoinjector? What tests do you have to carry out?

 Verification of performance against functional specifications is a critical part of the regulatory approval process for autoinjectors. Verification planning begins early, in parallel with the development of functional specifications, and continues throughout the design process. Development test data are used to understand key risk areas for the design and highlight potential measurement challenges. A design verification matrix establishes full traceability between functional specifications and the planned set of verification tests, defining the scope of the verification test program.

	Wherever possible, test methods are based on automated measurement processes to effectively remove the operator contribution to gauge variability. A wide range of measurements, generally including delivered dose, needle depth, needle protection override force, and audible dose indicator performance, are all integrated into a single measurement sequence, streamlining the method validation and test processes.

	Acceptance criteria are derived in accordance with ISO 11608, combining accuracy (process mean and specification limits) and precision (process standard deviation) into a single, target tolerance-limit factor that defines a minimum required pass rate at a given confidence level. Analysis methodologies are fully defined before commencement of testing and are focused on assessment against the predefined acceptance criteria. Subtleties include taking into account the underlying distribution of the measurement data; for example, injection times for mechanical autoinjectors generally follow a log-normal distribution.

	Design validation uses inputs from regulatory guidance, risk analysis, formative user studies, client requirements, and verification results to design a user study with a representative end-user population. This design validation study comprehensively addresses the high-level product requirements identified with user needs and intended product uses, in addition to foreseeable misuse scenarios.

 Design verification is confirmation that design input requirements have been met. Thus, the types and means of verifying a design input are developed from the identified risks of the device failing to meet those requirements. This risk identification can be achieved though theoretical analysis but, more frequently, physical testing is employed to confirm alignment of output performance with input requirements.

	It is important that risk identification and assessment methods are undertaken to identify areas of investigation during development of the device. Significant effort should be employed to understand the effect of environment, time, and manufacturing on the expected device performance so as to design-out any concerns at an early stage.

	Several international standards (notably ISO 11608, parts 1 and

) describe test methods designed to tackle the majority of autoinjector functions. A typical range of tests undertaken includes:

		The time taken to deliver the required dose using a timing device and/or video

		The volume delivered, measured with mass and converted using density

		Correct operation of safety features (frequently, needle shielding)

	These tests will be undertaken following a range of pre-conditioning operations, which may include:

		Free-fall from 1 meter onto a steel plate

		Very high temperature exposure for a short period

		Very cold temperature exposure for a short period

		Cyclical operation (a lifetime’s operation)

	The tests are also undertaken under a range of operational conditions:


	When referring to this article, please cite it as A. Siew, " Building a Better Self-Injection Solution," 

Experts discuss the key considerations in the development of an autoinjector.

Building a Better Self-Injection Solution

	On 23 June 2016, the United Kingdom will hold a referendum to decide if it wants to remain as part of the European Union. The debate has caused quite a stir because the so-called Brexit, if it does happen, would have serious implications across the country and continent. 
	As one of the industries facing major repercussions, pharma has voiced strong opposition against Britain’s departure from the EU. A vote to leave would inevitably affect drug regulations and market access, and global pharma leaders have warned of the significant regulatory burdens and business upheaval that could follow. 
	The European Medicines Agency (EMA), for example, which is currently based in London, would have to relocate its headquarters to another city within the EU. R&D could be threatened, especially if the loss of funding dampens investment in the country. More importantly, patient access to innovative medicines could be jeopardized if launching new drugs in the UK no longer guarantees entrance to the larger European market. 
	A letter to the Observer, signed by Sir Andrew Witty, CEO of GlaxoSmithKline, and 92 other leading life-sciences figures pointed out that leaving the EU would bring added complexity and uncertainty whereas the UK’s continued membership offers stability and predictability. 
	Although polls, at the time of writing, indicate a narrow lead for the “Remain” campaign, there is still the possibility of a Brexit. And if that bridge must be crossed, it’s not the end of the world for pharma. After all, Switzerland is proof that the pharmaceutical industry can still thrive in a country that is not a member of the EU, but it all boils down to the negotiations between the UK and the EU regarding future relationships, and it is this unknown that pharma is wary of. 


	When referring to this article, please cite it as A. Siew, "Pharma Wary of Brexit," 

Pharma has voiced strong opposition against Britain’s departure from the EU.