Solving Poor Solubility to Unlock a Drug's Potential

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

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

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.”

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

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

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 the fact that poorly soluble compounds often present other problems, such as metabolism or permeability challenges, drug-to-drug interactions in a combination dosage form, or the need to modify pharmacokinetics (e.g., blunting the maximum concentration [C_max] 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 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)

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

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

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

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

Solid dispersions continue to show broad applicability
Solid dispersions are widely used as a solubilization technique. Kevin O’Donnell, PhD, and William Porter III, PhD, who are 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. “Non-ionizable APIs or those that do not fit in complexing agents can now find success.”

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

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

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

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

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

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

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

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

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

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

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

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

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 problems.

Article DetailsPharmaceutical Technology
Vol. 39, No. 7
Pages: 20–27

Citation: When referring to this article, please cite it as A. Siew, “Solving Poor Solubility to Unlock a Drug’s Potential,” Pharmaceutical Technology 39 (7) 20–27 (2015).