Solubility Survival Guide. J u ly PharmTech.com

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1 Survival Guide J u ly sponsored by PharmTech.com

2 TOC Survival Guide Table of contents 4 to Unlock a Drug s By Adeline Siew, PhD 15 Dedicated Dialogue By Kaspar van den Dries, PhD & Martin Piest, PhD 21 with Amorphous Solid Dispersions By Adeline Siew, PhD Cover Image: Getty Images/VICTOR HABBICK VISIONS

3 Enhancement Services Welcome to getting solubility right the first time. Welcome to Phase Ahead Considering that 70% of drug candidates have solubility challenges, making sure your program is prepared for all phases of clinical trials is the fast way forward PATHEON patheon.com/solubilityenhancement 2016 Patheon. All rights reserved.

4 to Unlock a Drug s By Adeline Siew, PhD Click to view PDF Whitepaper How Broadening the Analysis of Compound Factors Allows for Predictive Solutions Modern methods and modeling offer a better way to understand solubility issues and solve today s complex formulation challenges 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 drugdevelopment 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 4 July 2016 PharmTech/Patheon ebook

5 of research going on in the industry to overcome the challenges in bringing poorly soluble drugs to the market. Improving drug development success rates 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, in vitro and in vivo, to help shape the problem statement and pair the right delivery technology. 5 July 2016 PharmTech/Patheon ebook

6 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 drugdelivery 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. Tackling solubility challenges 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 6 July 2016 PharmTech/Patheon ebook

7 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 [Cmax] 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 per se. 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. Developing an oral formulation 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 7 July 2016 PharmTech/Patheon ebook

8 well as determining the appropriate tool to predict the solubility in-vivo so that an in-vitro in-vivo correlation (IVIVC) can be established. 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 in-silico 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: dosage form administration route mode of action (e.g., oral local or oral systemic for fungal drugs) API dose per unit or API load 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) 8 July 2016 PharmTech/Patheon ebook

9 suitability of the manufacturing process for the API scalability of the formulation process 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 total cost of ownership 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 9 July 2016 PharmTech/Patheon ebook

10 used. In this case, the API dictates the options available, he explains, and the decision tree includes such factors as: the amount of API chemical properties log P melting point solubility of API in solvent or polymer size of molecule. 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 solubilityenhancement 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 selfmicro-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 10 July 2016 PharmTech/Patheon ebook

11 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 both 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. Nonionizable 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 semicrystalline 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 11 July 2016 PharmTech/Patheon ebook

12 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 12 July 2016 PharmTech/Patheon ebook

13 lot of understanding on formulation components, analytical tools, and scaleup 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. Mesoporous silica gains recognition 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 monographcompliant 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. Recent advances in the field Given the range of solubilization 13 July 2016 PharmTech/Patheon ebook

14 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 in-vitro and in-vivo 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 in silico allows access to a broader solution space, and also significantly increases the predictability of solubilized outcomes, Crew adds. Dobry notes that, during the past decade, significant advancements have been made in improving the stability, bioperformance, and manufacturability of NCEs that, in the past, might have been considered too insoluble to proceed into the next drug-development phase. An important advancement has been in solid-state characterization and stability prediction of amorphous dispersions, Dobry observes. Five to 10 years ago, this was seen as an Achilles heel. Now, it is one of several important aspects to address in a risk assessment, he says. Continued innovation will be needed in this area, as molecules and formulations become more complex. The ability to characterize dissolution mechanisms has been a major achievement, Dobry says, especially since today s formulation problems tend to transcend simple insolubility. In many cases, there is a need to incorporate enabling technology into the discovery interface, he explains. Integrating quality-by-design principles in development, for example, allows interaction between the process and formulation attributes to be identified, enabling the manufacturing space to be optimized, while allowing performance and stability targets to be met.v As formulations become increasingly complex, new approaches tackle the problems of solubility and bioavailability in different ways. The future promises to bring more solutions to what may once have been viewed as insoluble protblems. to Unlock a Drug s This article was originally published in Pharmaceutical Technology, July July 2016 PharmTech/Patheon ebook

15 Using Lipids to Enhance Oral Bioavailability Click to launch Infograpic Infographic Tale of Two Molecules Lipid-based drug delivery is increasingly being used to tackle oral bioavailability challenges resulting from poor solubility. Pharmaceutical Technology interviewed Kaspar van den Dries, Senior Director and Principle Scientist Solid Dose Development, from Patheon about the broad applications of lipids in bioavailability enhancement and importance of lipid screening during formulation development of these systems. PharmTech: Lipid-based drug delivery is not something new. Tell us about the role of lipids in bioavailability enhancement of poorly soluble drugs. van den Dries: Lipid systems make use of the body s lipid digestion mechanism. Many poorly soluble drugs are associated with a positive food effect (see Table I), in that their bioavailability increases with food intake. This endogenic effect of food makes lipid systems a very 15 July 2016 PharmTech/Patheon ebook

16 Table 1: Relationship between food effect on the extent of absorption (AUC) and BCS classification of compounds (adapted from reference 1). suitable formulation option to enhance bioavailability of poorly soluble drugs. The number of excipients for lipid formulation has expanded over the past decades. Besides the traditional medium and long-chain triglycerides (e.g., castor oil), there is a wide range of other excipients available for the development of lipid formulations, from chemically modified glycerides to polar and nonpolar surfactant and cosolvents. Also, the knowledge of the in-vivo behaviour of lipid formulations is increasing, mainly by fundamental research on lipid digestion studies and more understanding on digestion pathways such as lymphatic transport. PharmTech: What sets lipid-based drug delivery apart from other solubility/ bioavailability-enhancing approaches? van den Dries: The key advantage of lipid systems is that it makes use of the body s own digestion system. Moreover, because of the wide array of excipients available, the breadth of lipid formulations that can be used to overcome bioavailability challenges is larger compared to other approaches. However, the development of lipid formulations 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. Aspects such as lipid digestions in simulated gastric and intestinal fluid, phase diagrams, and emulsification behaviour should be covered as part of the formulation characterization. One other advantage that is usually overlooked is that once a proper formulation has been developed, the manufacturing of lipid formulations is relatively straightforward. Mixing of lipids is straightforward and when encapsulated into soft gelatin capsules, scale-up is less complex than many of the other technologies. In principle, bigger vessels can be used for mixing and the 16 July 2016 PharmTech/Patheon ebook

17 equipment can be run for a longer time period. Because softgel production is a semi-continuous process, small, pilot, and commercial-scale batches can be produced on the same encapsulation equipment. For other technologies, such as spray drying and hot-melt extrusion, more expensive equipment is required for manufacturing; and scale-up of spray drying requires investment in a range of different scale sizes. PharmTech: What type of drugs are most suitable for lipid-based drug delivery and why? van den Dries: The best class of molecules that are suitable for lipid-based drug delivery are the so-called BCS class II compounds, i.e., molecules with poor aqueous solubility and good intestinal membrane permeability. It is estimated that approximately 70% of the molecules currently in development are considered BCS class II compounds; therefore, lipid formulations are applicable for a wide range of APIs. In general, these molecules have a log P (a measure for the lipophilicity of a compound) between 2 and 5. However, even for extremely lipophilic compounds, i.e., those with a log P > 5 and very low aqueous solubility, lipid formulations can be explored. In these special cases, it is likely that the lymphatic transport system (2), which is also associated with the absorption of dietary lipids, is utilized, leading to an improved bioavailability. PharmTech: What are the key components and their functions in a lipid-based formulation and how do you decide which excipients to use? van den Dries: A wide range of excipients is available to generate lipid-based formulations, ranging from standard medium- or long-chain triglycerides and mixed triglycerides, to polar and non-polar surfactants and cosolvents. Which excipients to select will depend on multiple factors, such as API solubility in these excipients, whether the excipients are sensitive for lipid digestion, and the emulsification behaviour. Because a broad range of excipients, and therefore formulations are available, a classification system has been proposed to make a distinction between the different type of formulations. In summary four types of lipid formulation have been classified namely (3, 4): Type I systems are mixtures of lipid excipients that have no solubility in water. Medium- or long-chain triglycerides derived from vegetable oils are typically used, either individually or as a blend. Because they are derived from food, they are safe for oral ingestion, rapidly 17 July 2016 PharmTech/Patheon ebook

18 digested, and absorbed completely from the intestine. Type II formulations are formulated with oils, polar oils, and waterinsoluble surfactants. Type III formulations contain watersoluble surfactant and a significant mass of lipid component. These systems provide less stability when ingested. It is, therefore, important to verify the lipid digestion behaviour of these formulations to ensure that the drug does not precipitate during emulsion formation. Type IV systems are essentially pure surfactants or mixtures of surfactants and cosolvents, which are intrinsically unstable systems because drug tends to precipitate from these formulations in the gastrointestinal tract. Nevertheless, studies have shown that even in cases where precipitation occurs, improved bioavailability can be obtained; for example, in some specific cases, the drug precipitates in an amorphous or very fine crystalline form. Given these wide range of possibilities, it is recommended that a solubility screen is performed with sufficient database of excipients (20 or more) that are selected from the different type of formulations. This approach provides further direction on which formulation options are feasible. PharmTech: Can you tell us more about the importance of lipid solubility screening? What are the advantages to this capability? van den Dries: Lipid screening is an important aspect in the development of lipid 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. However, combining the right excipients in the correct ratio and subsequently establishing the emulsification behaviour in physiologically relevant media is essential to evaluate whether the formulation could work in an in-vivo environment. The key for lipid solubility screening is to standardize the protocol for the screen. These protocols should be designed to minimize drug usage and at the same time, perform rapid screening. A general approach to developing lipid formulations typically involves: 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 18 July 2016 PharmTech/Patheon ebook

19 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 ICH stability testing Optional testing such as permeability studies, gastric intestinal model, etc. PharmTech: Is there a way to be more predictive of the outcomes for lipid formulations? van den Dries: Along with the standard experimental work to screen lipid formulations, Patheon also uses in-silico modelling to support and enhance the selection of the right solubilization technologies. [reference 5] For lipid formulations we employ modelling to provide estimates of the solubility of drug compounds in typical excipients used for lipid formulations. Modelling does not replace all experimental work, but these computational approaches significantly reduce the amount of upfront experiments that might otherwise be performed in the process of selecting and developing robust formulation approaches to overcome bioavailability challenges. PharmTech: What are the main challenges when developing a lipidbased formulation? van den Dries: Because the purpose of lipid formulations is to obtain an improved bioavailability of a molecule, one important challenge is to be able to make informed decisions prior to doing actual animal or human studies, whether the formulations indeed show the preferred in-vivo effect. Given that pharmacokinetic studies are relatively expensive, it is usually not possible to screen a wide range of formulations in-vivo. It is, therefore, important that in-vitro testing should have some representation of the behaviour invivo. During the past decade, much improvement has been made on developing more clinically relevant in-vitro tests and establishing the link between these tests and in-vivo behaviour. The lipid digestion test, also known as lipolysis study, should be a standard screen when developing lipid-based formulations because it can provide valuable information on how the formulation could behave in-vivo (3). PharmTech: What are the manufacturing challenges for lipid-based formulations? 19 July 2016 PharmTech/Patheon ebook

20 van den Dries: Once a formulation has been developed, there are, in principle, two manufacturing options, liquid-filled hard gels and soft gelatin capsules. Soft gelatin encapsulation is the simpler and more robust process because no separate banding step is required for final sealing of capsules to prevent leaking. However, in cases where a small number (e.g., 100) of capsules are needed, it is sometimes beneficial to use liquid-filled hard-gel capsules as these can be hand filled. Scaling-up a softgel process is straightforward because the encapsulation line will just have to run longer, and dies and pumps with more cavities and plungers can be utilized. Both clinical and commercial materials can be produced on the same equipment. References (1) W.N. Charman et al., J Clin Pharmacol, 33, (1993). (2) N.L. Trevaskis, L.M. Kaminskas, and C.J. H. Porter, Nature Reviews, 14, (2015). (3) A. Müllertz et al., J Pharm Pharmacol, 62, (2010). (4) C.W. Pouton and C.J.H. Porter, Advanced Drug Delivery Reviews, 60, (2008). (5) Matt Wessel, Tom Reynolds, Sanjay Konagurthu, Marshall Crew, SOLUBILIZATION TECHNOLOGY; How to Choose the Right Solubilization Technology for Your API. Drug Development & Delivery, July 2016 PharmTech/Patheon ebook

21 with Amorphous Solid Dispersions By Adeline Siew, PhD Click to launch webinar Free Webinar Taking An Informed Approach To Technology Selection To Address Challenges In Early Development Weighing the pros and cons of hot-melt extrusion and spray drying. The oral route remains the most preferred method for delivering drugs. It offers good patient compliance due to its acceptability, convenience, and ease of administration. Moreover, the overall production costs for oral formulations are less expensive because they do not require sterile manufacturing conditions. The development of a successful and effective oral dosage form, however, is often faced with a number of challenges such as drug instability in the acid or alkaline environments of the gastrointestinal (GI) tract and unsatisfactory absorption of compounds with poor physicochemical properties., dissolution, and the ability of a drug molecule to permeate the GI membrane are fundamental parameters for effective delivery of oral formulations. Advances in combinatorial chemistry and high-throughput screening have led to an increasing number of poorly soluble drugs in the development pipeline and the need to develop 21 July 2016 PharmTech/Patheon ebook

22 technologies that address solubility issues has never been more crucial. One approach that is becoming increasingly popular is the use of amorphous solid dispersions because of their broad applicability, observes Kevin O Donnell, PhD, senior chemist at Dow Pharma & Food Solutions. Traditional methods rely on certain API properties to be successful, according to O Donnell. For example, salt formation requires the API to be ionizable and complexing agents such as cyclodextrins require the drug to fit within the complexing ring. For solid dispersions, it is a matter of rendering and maintaining the drug in the amorphous state and/or adequately dispersing it within a carrier matrix using one of many available technologies, O Donnell explains. While drug-carrier incompatibilities may exist, requiring careful excipient selection, there is no distinct property required of the API for formulation into a solid dispersion. In addition to this breadth, solid dispersions can often provide a significant increase in solubility compared to other formulation approaches. This advantage is largely due to the amorphous state of the API and to the hydrophilic nature of the surrounding matrix material that can aid in wetting once exposed to the aqueous biological media. Furthermore, solid dispersions allow for unique intellectual property to be obtained, thereby aiding in the lifecycle management of existing compounds and maximizing a drug s economic potential. The number of commercial products based on solid dispersion technologies is growing--for example, Kaletra (AbbVie) and Sporanox (Janssen)--which means that the technologies are becoming more established and the regulators are becoming more comfortable with such formulations, notes Ian Barker, PhD, project scientist at Molecular Profiles. The amorphous solid dispersion strategy for enhancing drug solubility is attractive for several reasons, he continues. The formulation is relatively simple, consisting of principally the drug and a polymer, and potentially suitable for a wide range of drug compounds and drug loadings. This approach is well suited for downstream processing into conventional oral dosage forms, such as capsules or tablets. Solid dispersions for solubility enhancement Amorphous solid dispersions can be produced with various technologies, such as hot-melt extrusion (HME) and spray drying, explains Min Park, group product manager, Advanced Delivery Technologies, Catalent Pharma Solutions. These amorphous technologies offer a lot of flexibility in terms of use of polymers/excipients and process parameters that suit the physicochemical properties of a particular water-insoluble 22 July 2016 PharmTech/Patheon ebook

23 API. HME and spray drying are also scalable technologies, meaning that they are ideally suited for use in the production of solid dispersions. Spray drying seems to be more popular and available than HME, observes Paul Titley, business development director of Aesica Pharmaceuticals, but time may even the score, he adds. Both technologies can produce the amorphous materials desired but they expose the API to very different processing conditions. HME applies more heat to the API than spray drying. The API in an extruder will be heated to high temperatures (approaching 200 C) and remain there for longer than in a spray drier. This is not a problem for robust APIs, but some will degrade at the high temperatures inside an HME. Titley points out that spray driers also operate at high temperatures, but the API exposure is for a fraction of the time in an HME. The physical forms of the amorphous products are very different, Titley explains. Spray drying creates a fine powder, whereas HME creates a granular crumb, and therefore, different dosage form options. But both approaches can produce tablets or capsules. Spray drying always requires a solvent, sometimes water, but often organic and even flammable organic solvents. Such solvents must be scrubbed from the exhaust gas (air or nitrogen) at not inconsiderable expense. Processing costs of HME center on the heating and cooling of the extrusion barrel. Ultimately, the physical size of the equipment will need to be addressed. A large spray drier is a significant installation (similar to installing a fluid bed drier), and they are not portable. A large HME is hardly portable but need not be as permanent a fixture. Both technologies are offered by CDMOs and concerns over installation can be outsourced. Key considerations in the method selection process The selection of a particular technology will mainly depend on the physicochemical characteristics of the given drug and the drug loading required for the formulation, says Park. The low solubility of the API in solvents, the melting point, and the glass transition temperature of the API (lower than 220 C) will dictate the use of HME technology in producing solid dispersions. The lipophilicity of the API is also an important factor in selecting the technology, as higher log P leads to lower drug loading in the formulation. According to O Donnell, HME is unlikely to be a successful option for drugs that display thermal and shear instabilities, and the formulator should consider an alternative technology such as spray drying. This may also be true 23 July 2016 PharmTech/Patheon ebook

24 for APIs with very high melting points as it may be difficult to process into a solid dispersion while operating at temperatures at which pharmaceutical polymers are stable, he adds. Conversely, drugs that are poorly soluble in solvent systems reasonable for use in the pharmaceutical industry are inappropriate for spray drying. In such a case, the solids load in the feed solution may be too low for the process to be economically viable or an undesirable solvent may be employed creating regulatory concerns. O Donnell notes that the limited quantities of API available in early development often leads formulators towards spray drying because laboratoryscale equipment consumes a minimal amount of product. However, he points out that recent advances by manufacturers to miniaturize hot-melt extruders are allowing formulators to utilize HME at much earlier stages in development and assess it as a potential path forward. The formulator s experience/expertise and in-house capabilities may directly influence which method is chosen, says O Donnell. Overall, the preferred method will be one that allows for successful formulation of the API into a commercial product. Barker explains that the initial screening exercise would typically focus on determining the miscibility and stability of the drug substance in a range of polymers, often using a filmcasting approach to prepare the samples (pre-dissolving drug and polymer in a common solvent and then evaporating off the solvent). This process is similar to what happens in a spray-drying process, so arguably spray-drying is always the first option evaluated. However, if a drug has relatively low melting point (< 180 C) and is chemically stable when heated to its melting point, then HME is considered as an alternative process for producing the amorphous drug/polymer intermediate. According to Barker, HME is often the favored option because it is a simple manufacturing process that is suitable for continuous processing and is therefore cost efficient. It produces a dense, granular material that is easily further processed into capsule or tablet dosage forms; and it involves no use of solvents. Weighing the pros and cons of each technology Spray drying is a physically gentle process but it involves the use of solvents, says Titley. The API must first be dissolved in the spray-drying solvent (usually organic), and the range of solvents available increases the likelihood that a solution can be produced. According to Titley, the expected dose and the amount of API available will influence the method selection. Spray drying can be carried 24 July 2016 PharmTech/Patheon ebook

25 out using extremely small amounts of API as low as 100 mg, whereas HME requires sufficient material to fill the extruder (even a small one) and consumes a few grams. HME, however, is a solvent-free process, and this attribute in itself is a huge advantage in formulation development and manufacturing. Being a solvent-free process not only allows formulators to work with APIs that are poorly soluble in pharmaceutical solvent systems but eliminates certain issues such as potential residual solvent in the final product, which can reduce the physical stability of an amorphous solid dispersion and may create regulatory concerns. Additionally, the removal of solvents from the process decreases costs and increases worker safety, O Donnell points out. Furthermore, it is a continuous process, which minimizes production downtime, decreases product variability, and lowers costs. HME is more flexible in terms of the final product as well as it can directly produce strands, pellets, films, tubes, core/shell systems, granules, and various shapes allowing the manufacture of a wide variety of dosage forms to deliver a solid dispersion, O Donnell continues. In HME, the API is dissolved or melted in the host polymer, explains Titley. The API may not withstand the heat and may not dissolve completely in the desired excipient. Therefore, in early development, where API is scarce and the number of experimental batches may be high, spray drying may be the only choice. In later development stages, however, if the API exposure conditions permit, HME has advantages of lower energy and lower waste costs. Moreover, the HME equipment occupies a much smaller footprint than equivalent spray driers. Park adds that HME offers a lot of flexibility with the use of excipients and process parameters to achieve the desired drug loading with good physical stability. One disadvantage with HME is the degradation of APIs that have a degradation profile close to their melting point, Park notes. At Catalent Pharma Solutions, our Optimelt platform is capable of dealing with the challenges presented by such APIs using a unique approach to the development of oral solid dosage forms, says Park. It encompasses integrating the preformulation characteristics of the API with melt extrusion process parameters through the help of key indicators, such as the specific mechanical energy input, the residence time distribution, and the degree of fill, among others. O Donnell agrees that the production of solid dispersions of thermally or shear-sensitive APIs is a problem with HME that spray drying does not have. The formulator will also see greater success using spray drying for drugs 25 July 2016 PharmTech/Patheon ebook

26 with high melting points as temperatures capable of generating the amorphous dispersions of these drugs may degrade the polymeric carrier or other formulation components, observes O Donnell. Additionally, spray-dried dispersions have a very small particle size, thereby increasing the surface area significantly, which greatly increases the dissolution rate of the formulation. Similar particle sizes may be obtained following HME through milling. However, this may induce recrystallization of the drug resulting in a detrimental change in the dissolution rate of the final formulation, he adds. Scale-up challenges Scale up of spray drying has the objective of maintaining the particle characteristics and maximizing the yield of the process, according to Titley. Spray driers can be constructed with either single-pass or closed-loop airflow. The practicalities of the process do not change--if nozzles didn t block at small scale, they should not block at larger scale. However, the distance between the nozzle and the collection chamber wall will be greater, hence the dried particle will also tend to be bigger. Titley explains that subtle changes to the processing conditions can be made following calculations of input temperature and air volume to reproduce the original (small-scale) drying or residence time of the droplets. The increased particle size may be marginal and the crucial test is the rate of dissolution, he points out. Residual solvents must be assayed and processing conditions adjusted to reduce them to a minimum. The large volumes of liquid, size of vessels, assembly/disassembly of a large spray drier, and safe collection of the powder need serious consideration. HME is an efficient and versatile process, observes Barker. Increasing the batch size is often simply a case of feeding more material into the extruder and running it for longer, he explains. In scaling up from development or pilot scale to commercial scale, consideration needs to be given to determining the required processing parameters (e.g., temperature and shear rate) on a larger extruder to produce satisfactory extrudate, according to Barker. O Donnell adds that the exposure to temperature in terms of residence time distribution and heat transfer (as well as mass transfer) must be well understood. Shear exposure is also crucial in regards to both dispersive and distributive mixing. Simplifying these, the former requires the same number of divisions per kilogram be maintained while the latter requires the same stress rate be applied, O Donnell says. Devolatilization must also be considered when scaling up to ensure proper removal of any off- 26 July 2016 PharmTech/Patheon ebook

27 gassed byproducts or water vapor. Each of these aspects presents a unique challenge to the formulator; however, adjustment based on scale can be made through empirical calculation with some assumptions being made. Recent advances in the manufacture of solid dispersions In recent years, the most notable advancement in pharmaceutical extrusion equipment has been the miniaturization of the systems, observes O Donnell. Prior to this, HME was limited in adoption at early stages of development due to the large quantity of API required for the trials, O Donnell comments. Today, new laboratory-scale extruders, such as the Leistritz Nano 16 and Nano 12, Thermo Pharma 11, and Steer OMicron 12, require significantly less material for individual trials, thereby allowing for rapid process and formulation development of early stage pipeline compounds. For Barker, the greatest progress in HME has been in the types of excipients available for the formulation development of solid dispersions. Whilst the principles of HME have remained relatively constant, considerable changes in the excipients used have been observed, Barker remarks. These excipients include AFFINISOL HPMC HME (Hypromellose) from The Dow Chemical Company and BASF s polyvinyl caprolacta-polyvinyl acetate-polyethylene glycol graft copolymer, Soluplus. Notably, the introduction of functional polymers has widened the pool of matrices available, providing a greater chemical tool kit to solve difficult formulation challenges, says Barker. The increased processability of these materials allows for extrusion over a broad range of operating conditions, facilitating solid dispersion manufacture for a wide variety of APIs, adds O Donnell. Quality by design As amorphous solid dispersions are often formulated for Biopharmaceutics Classification System (BCS) Class II and Class IV APIs, the critical quality attributes (CQAs) for a product in development are dissolution, bioavailability, and solidstate stability, explains O Donnell. The acceptable target for each CQA should be identified early in development to define what the final product will be in terms of ideal performance, O Donnell points out. Once identified, a design of experiments (DoE) can be employed to determine the influence of the process parameters on the CQAs. The understanding of the process variables on the CQAs allows the formulator to identify the design space acceptable for consistent product quality thereby implementing quality by design (QbD). The development of a spray-dried product is a relatively straightforward 27 July 2016 PharmTech/Patheon ebook

28 process that can be split into several distinct sections, according to Titley. This stepwise nature lends itself to a measured QbD approach, observes Titley. Once the solvent system and formulation is settled, the process can be examined using the following: Critical process parameters (CPPs): inlet temperature, solution flow, and gas flow (aspiration) rates. CQAs: particle size, moisture content, percent yield, and crystallinity. Titley refers to Kumar et al. who recorded these findings for their subject formulation by following a QbD protocol. The study identified inlet temperature as the only significant factor to affect dry powder particle size. Higher inlet temperatures caused drug surface melting and hence aggregation of the dried nanocrystalline powders. Aspiration and solution flow rates were identified as significant factors affecting yield. Higher yields were obtained at higher aspiration and lower solution flow rates (1). For HME processes, the main CPPs to be considered in the design space are screw speed, barrel temperature, and degree of fill, says Park. These scaleindependent process parameters affect the product quality attributes, such as residence time distribution, specific energy, and melt temperature, he adds. Process analytical technology (PAT) tools can be used for measuring residence time distribution to design experiments in the QbD space. A set of DoE studies are used to determine the process response parameters that are critical to product quality, as well as to define the optimal process parameters that will guide the long-term process development and prove to be necessary to establish a reproducible process. The determined link between process responses and quality attributes of a drug product will be useful, regardless of equipment scale or brand, Park concludes. Reference (1) S. Kumar et al., Int J Pharm 464 (1-2) (2014). 28 July 2016 PharmTech/Patheon ebook

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