Posing the first question, I ask the panel what oral solid dosage (OSD) form manufacturing capabilities are customers asking for most? And what in the pipeline is driving then to your door? “Poorly water-soluble drugs remain a major issue throughout every phase of drug product development,” says Vincent Jannin, Associate Director, Capsules and Health Ingredients, Lonza.
“Clearing the hurdles of poor active pharmaceutical ingredient (API) solubility requires precise formulation approaches and technologies to help manage bioavailability and manufacturability for better therapeutic performance.”
“There are many common strategies available to improve the solubility and bioavailability of orally administered drugs in the gastrointestinal (GI) tract, including amorphous solid dispersions (ASDs), cosolvents, cocrystals, cyclodextrins, lipid-based formulations (LBFs) and other tactics such as particle-size reduction, salts and surfactants."
"Of the optimising methodologies available, LBFs and ASDs have emerged as the industry’s preferred solutions, with many leading drug developers and manufacturers seeing proven capabilities and significant commercial development.”
“Whether liquid or powder, encapsulating these formulations makes practical sense because capsules offer both a fundamental delivery mechanism that patients prefer, as well as a range of efficiencies related to commercial development and manufacturing. Advances in capsule-based drug delivery and capsule materials are now offering formulators even more effective drug delivery solutions that address solubility issues and help to solve them earlier in commercial development.”
Thomas B. “Brad” Gold, Vice President of Pharmaceutical Development at Metrics Contract Services, suggests that the most significant impact on the OSD market during the last decade has been the growth in the oncology sector; the number of clinical-stage cancer programmes has risen steeply and continues to dominate the landscape.
For example, at the end of 2020, there were more than 2000 oncology drugs at various stages of the development pipeline. Infectious disease therapies were next with less than half that amount.1 The knock-on effect is that roughly one quarter of drugs currently in development worldwide are categorised as highly potent, which is having a notable impact on the contract (CDMO) space.
“The growing need for smaller scale and contained manufacturing processes poses a challenge for much of pharma’s installed capacity,” he says: “Many companies with candidates in these areas do not have the facilities needed to take a product from development to market.”
“Larger contract manufacturers often sell higher production volumes and multisite capabilities, but the trend has been towards specialist CDMOs as they often offer better continuity from development through to commercial requirements. Depth of specific expertise in applicable technologies is also imperative as it can often accelerate timelines and provide higher quality outcomes. This is critical in a market in which getting it right faster is typically far more valuable to sponsors than saving money on a per line item basis.”
“At Recipharm,” adds Torkel Gren, Senior Director, Technology Officer and Strategic Investments, Recipharm, “we have a wide range of diverse capabilities in OSD forms, which is an important reason why customers come to us for support. Recipharm has considerable experience in delivering OSD projects — from development all the way through to the manufacture of large commercial batch sizes — including everything from tablets and capsules to powders.”
“We have the technology to produce both immediate and modified release (MR) products, and to handle highly potent APIs, including sex hormones, corticosteroids, beta-lactam antibiotics and controlled substances.2 Regardless of the unique nature of their project, many companies that come to us already know that we have the technologies required to help them to turn their API into a successful OSD product that can be manufactured at large scale.”
KSR: Although excipients and their functionalities are generally well understood, what about working with poorly soluble and highly potent drug substances? For example, what’s the best excipient and API compound choice strategy for complex small-molecule drug development?
“The trend we are seeing at the moment,” continues Torkel, “is that there are more and more APIs being used in drug development that have low solubility, high potency or both. These APIs present an interesting challenge for drug formulators as they work to develop a commercially viable and therapeutically effective formulation.”
“Poorly soluble APIs pose a particular challenge; they often require specialist technologies and excipients to overcome solubility and associated bioavailability challenges. Further complicating the issue is that no two APIs are alike; each one has its own unique features that mean there is no one-size-fits-all technology or formulation approach to successful solubility enhancement.”
“Nevertheless, in most cases, holding to the principles of Quality by Design (QbD) and Design of Experiments (DoE) is still the most important measure that should be taken either by a drug formulator or its development partners. These can help to lay a systematic foundation to identify a solubilisation approach that is not only effective, but also scalable to ensure the commercial viability of the finished formulation.”
“Sustained- or modified-release formulations enable drug release during a defined period at a specific rate and at targeted locations,” advises Brad, “which makes it possible for the active substance to stay in the body longer as it travels to where it needs to go."
"This is particularly relevant for targeted oncology therapies. Controlled-release formulations are typically achieved by utilising high-molecular-weight, water-soluble polymers to form hydrophilic matrix tablets or by film coating using predominately water-insoluble polymers.”
“The most important property when designing a controlled-release formulation is to ensure robust and accurate API release, particularly for those with a narrow window of absorption and/or therapeutic range. For their part, excipient suppliers need to thoroughly understand manufacturing processes and provide QbD samples that represent the ranges observed for critical material attributes, such as polymer molecular weight, relative substitution levels and particle size.”
“Lower molecular weight polymers are typically used to generate a more erosion-based drug-release profile for low-solubility drugs, whereas higher molecular weight polymers that swell more and afford a diffusion-based drug-release profile are paired with high-solubility drugs. The rate of API release from a sustained-release coating is modified by changing the ratio of the water-insoluble and water-soluble polymers in the formulation and the film coating thickness.”
Bringing Part I to a close, Vincent comments that amorphous formulations tend to be unstable and prone to revert to more stable crystalline forms. “This is not desirable in most cases; but, the correct use of excipients can help. Hypromellose (HPMC) and similar polymers such as hypromellose acetate succinate can be applied using proven processes to render and maintain drugs in an amorphous state.”
“Proving to be a robust excipient strategy in small molecule formulation, HPMC’s ability to promote solubility and dose regulation in formulation are well understood. Weak base solids naturally and quickly transition from soluble to crystalline states when shifting from gastric to intestinal pH."
"These basic moieties are the main class of molecules at work here because active chemistries based on them are highly solubility and have a low pH in the gastric environment. These compounds crystallise quickly in the higher pH of the intestine when drug absorption is desired in the GI tract.”
“As referenced studies reveal, HPMC excipients can reliably inhibit these interactions when used in formulations. When HPMC dissolves with the active formulation, the excipient generally promotes (desired) supersaturation and reduces the number of actives crystallising at the higher pH.”