What is solubilization, and what are some challenges the industry is facing when trying to ensure current or new products meet their solubilization requirements?
Solubilization is a process to solvate the molecule so it dissolves and remains in solution for an extended period without nucleation or precipitation, and becomes available for absorption in the gastrointestinal (GI) tract to improve its therapeutic efficacy. If it is not dissolved, it will not be absorbed and thus will not be bioavailable. The key challenges not only stem from higher melting points and higher logPs, but often arise from the lack of maintenance of the drug in solution or supersaturation in the GI tract. With the history of many drug molecules kinetically unstable in the GI track, insolubility poses challenges for designing more stable formulations to overcome precipitation or nucleation. Equally challenging is the lack of understanding of drug molecules and their interaction with functional excipients in formulation. Some excipients may have attributes appropriate for solubilizing one molecule and not another, suggesting one size does not fit all. Thus, there is continued interest for new innovative excipients within the pharma industry and excipient manufacturers are collaborating to overcome the challenges often regarded as the “brick dust” of new molecular entities (NMEs).
What are some technologies/products/solutions that are available to pharmaceutical companies in order to meet solubilization demands? Do specific technologies address specific issues? Can they be used in combination?
Several commercially viable formulation technologies are available, but the selection of those technologies depends upon many factors including a molecule’s structure, dose strength, compatibility and thermal stability of the API and excipient when exposed to high temperatures. Some formulation technologies are often referred to as the conventional ones; for example, wet and dry granulation, micronization, pH modification or salt formation or complexation, while others considered non-conventional including spray drying, hot melt extrusion, co-precipitation, Kinetisol® among others for solid dispersions, and lipid based emulsifying drug delivery technology for liquid dispersions.
The requirements for formulating an individual API may be different depending upon the dose strengths and mode of delivery or route of administration. Furthermore, if the API is seemingly compatible with some excipients it may be incompatible with others due to a lack of solubility, loading and long-term stability. This raises concerns and introduces complexity in design and development of a stable formulation to achieve desired bioavailability. For example, insoluble compounds with higher melting points, may not be well suited for a formulation technology requiring lipid based emulsifying systems (SEDDS) but could be good candidates for development of amorphous solid dispersions (ASD) to improve bioavailability. In contrast, those with relatively lower melting points, such as lipophilic compounds with 2 < logP > 4, could be the better candidates for lipid based emulsifying/micro-emulsifying drug delivery systems (SEDDS/SMEDDS). With few exceptions, these technologies can be switched for the same molecules but the choice of excipients might be different in each. For example, Norvir® (ritonavir) is available in both tablets and soft gel capsules, but the excipient’s requirements are different for melt extruded and SEDDS formulations. Another example is the development of oral tadalafil in solid dispersion by hot melt extrusion with Soluplus® while using a different solubilizer in wet granulation. For molecules with smaller dose strengths, pharma companies will find ways to use conventional formulation technologies such as granulation or micronization or pH modification and/or salt formation to improve bioavailability. But, those requiring medium to higher doses, the amorphous dispersions technologies (solids and liquids) will prevail. In fixed dose combination, for instance, these technologies can be combined to address the controlled and efficient release of drug molecules. Examples of combo products in the future may include the use of continuous manufacturing by twin screw extrusion for solid dispersions as well wet/dry granulations for fixed dose delivery, and for manufacturing of tablets or pellets encapsulated in lipid based soft gels. In such technologies the choice of excipients, polymers and lipid based solvents and surfactants will play an important role in achieving the supersaturation and the stability of molecules in the drug products in general.
What can a company like BASF offer in terms of solubilization solutions and expertise? How does your company approach a solubilization issue that is different from how other companies assess a problem?
BASF offers a range of inactive ingredients- polymers, lipid based surfactants and solubilizers to overcome the challenges the industry faces today. With in-house technical expertise in polymer chemistry, solid dispersions as well as lipid based technologies, BASF provides technical support to address the complex formulation challenges that not only arise from poor solubility but other factors as well. In most cases, we find that conventional approaches might be the best avenue for the development of most drugs molecules. This is evidenced by the fact that over 70% of marketed drugs are poorly soluble small molecules, and are still developed using standard enabling formulation technologies such as wet granulation, dry granulation and fluid bed granulation technologies. For formulations requiring more advanced processing technologies, BASF is the pioneer in the application of hot-melt extrusion which helps combine effectiveness with cost efficiency when processing poorly soluble drugs. Our experience in a broad range of dosage forms due to our portfolio of over 80 products, combined with our solubilization expertise enables us to address most challenges faced by formulators.
Specifically, how important is excipient selection to achieving optimum solubilization? Can you tell us how functional excipients are changing the way pharma companies are addressing solubilization problems? Are functional excipients one of the best tools for this formulation challenge?
Excipient selection is critical for formulation development, and equally important for optimization of solubility and bioavailability. It sounds simple but requires a basic understanding of the functionality of excipients, drug molecule and formulation technologies. It is complex because each component has its own contribution in the formulation of drug molecules. Most notable are excipients with high or multifunctional attributes that lead to their variable usage levels either as a matrix, solubility enhancer, crystalline inhibitor, or solvent/co-solvent, or dispersing agent. The usages of many of the individual pharmaceutical excipients and their dosage level have been reported in FDA’s inactive ingredient database, suggesting that the amount and application of high functional ingredients can be varied and interchangeable. For example, copovidone (Kollidon® VA 64), a copolymer with 60% povidone K30 and 40% polyvinyl acetate, is a good dry binder in direct compression and roller compaction, and as a solubilizer in hot melt extrusion of ritonavir and lopinavir formulation (Kaletra®). In other cases, PVPVA 64 has been used in transdermal patches as a stabilizer and crystalline inhibitor. Monographed excipients like Polyoxyl 35 castor oil (Kolliphor® EL) and Polyoxyl 40 hydrogenated castor oil (Kolliphor® RH40), for instance, are used in soft gels as solubilizers but they are also used in topical and ophthalmic formulations. These highly functional excipient attributes facilitate their use in solid oral tablet, liquid, parenteral and topical applications and are changing the landscape in the industry. They allow formulators flexibility to help identify the appropriate excipients/ solubilizers and design better and smarter dosages by tackling the challenges stemming from solubility, stability, supersaturation, and bioavailability. Thus, their roles in design of solid or liquid oral and/ or parenteral formulations are simply guided by the functionalities rather by merely structure and physico-chemical properties of these ingredients. As more challenging molecules are discovered, the industry will continue to exploit the excipients to find better solutions for niche formulation challenges because of their unique and extraordinary properties that had never been explored before.
Looking ahead, how will BASF continue to help its customers meet the demands of better products, with better solubility profiles?
BASF is an excipient innovator. In the last 14 years, BASF has introduced over a dozen new excipients and will continue to pioneer the development of new polymers for formulation challenges that surface moving forward. As the number of poorly soluble NMEs with higher melting points (>200oC) continues to rise, BASF is developing new polymers for solid dispersions for increased solubility and crystalline inhibitory properties. Moreover, as the NMEs continue to challenge conventional technologies, the pharma industry will have to adapt innovative approaches to develop new molecules. Examples of this are hard-to-formulate hydrophobic NMEs, biologics and parenteral formulations that will require appropriate polymers and solubilizers for controlled and prolonged delivery of these molecules. BASF is committed to help the industry overcome these challenges for the benefit of their patients worldwide.