Close to 40% of currently marketed drugs are classified as having low solubility under Class III/IV according to the Biopharmaceutical Classification System (BCS), and that number doubles to 80% for pipeline candidates, according to market research firm Kline & Company.1 Solubility is important because it is a key factor in determining the efficacy of any medicine. The drug substance must be soluble in physiological fluids for it to be delivered to places in the body. Typically, a minimum concentration of the drug must be achieved to provide the desired pharmacological response.
Oral delivery is the preferred route of administration because it is the easiest method for patients and has the highest compliance rates
This issue is particularly important for oral dosage drugs, but is increasingly a challenge for parenteral formulation of biologic APIs. Oral delivery, when possible, is the preferred route of administration because it is the easiest method for patients and has the highest compliance rates. Oral formulations also tend to be the least costly, and there are many different dosage form options (tablets, capsules, gels, liquids, etc.). The bioavailability of medications taken orally, however, depends significantly on their solubility in aqueous systems, their dissolution rate, and permeability. The lower the solubility, the higher the dose required to achieve the desired response, which can lead to increased side effects.
The BCS is a system developed by the US FDA to predict intestinal drug absorption for a therapeutic agent. Drugs are considered highly soluble and highly permeable (Class I) if their highest dose strength is soluble in 250mL or less of aqueous media over the pH range 1 to 7.5. The other classes include low solubility and high permeability (Class II), high solubility and low permeability (Class III) and low solubility and low permeability (Class IV). Strategies used to overcome poor solubility depend largely on the characteristics of the drug substance (thermal stability, pH, etc.) and intended administration route (oral dosage, parenteral, inhalation, etc.).
Aiding formulation development
Access to solubilisation technologies and the capabilities of the formulator are important factors. Solutions must also be cost-effective. Many service providers have recognised the need for advanced solutions to this growing problem and have actively invested in the development of innovative approaches to increasing solubility and bioavailability. As a result, significant progress has been made in expanding the applicability of various techniques, such as particle manipulation (micronisation, surface morphology modification, etc.), the preparation of amorphous dispersions such as hot-melt extrusion (HME) and spray drying, the formation of salts/co-crystals and the use of lipidic vehicles.
Particle manipulation: Various properties of a powder particle influence its solubility, including the shape and size, hardness, and surface roughness and chemistry, among others. In some cases, conventional particle-size reduction via micronisation (jet or ball milling) or high-pressure homogenisation can overcome poor solubility. In others, newer technologies that provide greater control and allow for engineered particle design are needed. Examples include cryogenic spraying (spray freezing onto cryogenic fluids, spray freezing into cryogenic liquids, spray freezing into vapour over liquid and ultra-rapid freezing), in which highly porous, amorphous, nanoscale drug particles are produced at very low temperatures, and the formation of nanocrystals with significantly enhanced surface areas. UPM Pharmaceuticals is a CDMO that specialises in providing low-solubility solutions for R&D and cGMP production of solid dose forms using various particle manipulation technologies.
HME: This technology results in the formation of an API-polymer dispersion that is a solid glassy solution with the API molecularly dispersed in the polymer matrix. The API, polymer and any other functional ingredients are mixed and heated without the use of a solvent and then allowed to cool. The polymer and the processing conditions are carefully selected to form a melt with the desired properties, and then the glassy matrix is milled to obtain particles with properties suitable for different final dose forms (tablets, capsules, stick packs, etc.).
Excipients are typically used to enhance solubility and processability, but can also create different API release profiles and increase the stability of the melt
Excipients such as surfactants are typically used to enhance solubility and processability, but can also create different API release profiles and increase the stability of the melt. HME can be performed continuously, and the use of process analytical tools allows real-time monitoring of process parameters. Catalent is a recognised leader in this technology and offers HME process support from initial formulation optimisation to commercialisation of final dosage forms. Its OptiMelt technology has been used not only to enhance the solubility and bioavailability of poorly soluble drug candidates, but also to enable reformulation of existing products for competitive differentiation.2
Spray drying: Spray-dried dispersions (SDD) are amorphous dispersions, or solid solutions, of APIs in polymer matrices. An API is first dissolved in a suitable polymer and solvent and then spray-dried under carefully determined conditions that allow solvent evaporation without phase separation of the API and polymer. Capsugel, which acquired Bend Research in late 2013, is a leader in this enhanced solubilisation technology. The company uses predictive models to assess performance and stability and define process parameters to minimise risk and development times.
Several hundred drugs have been formulated using its SDD technology, and over 50 formulated drugs manufactured by Bend Research/ Capsugel have advanced to Phase I–III clinical trials.3 In fact, the company claims that as many as 60% of compounds identified as poorly soluble can be effectively formulated using its SDD technology.
Co-crystal formation: For crystalline materials, different crystalline forms have different dissolution rates and intrinsic solubilities. In some cases, the solubility of lipophilic materials can be enhanced via the formation of new crystal lattices with pharmaceutically acceptable co-formers, (i.e. the formation of co-crystals). Co-formers are non-ionisable and thus cannot form salts; they alter the physical properties of APIs without chemical modification while maintaining the benefits of a crystalline solid form. In addition, processes for the formation of co-crystals often require little or no solvent for improved sustainability and economics.
Co-crystals have not yet been fully embraced or adopted by the industry
The FDA has, however, classified them as ‘drug product intermediates’ (DPIs) like polymorphs rather than drug substances, such as salts. This regulatory decision has raised numerous questions about the practical application of co-crystals for drug synthesis and formulation. As a result, co-crystals have not yet been fully embraced or adopted by the industry. There are expectations, however, that issues related to intellectual property protections and other regulatory concerns will eventually be addressed, and that eventually co-crystal formation will, for certain poorly soluble APIs, be a competitive solution.4
Use of lipidic vehicles: Lipid-based drug delivery (LBDD) is another approach for increasing API solubility. Lipid systems for this purpose include oil solutions, suspensions and emulsions and self-micro or self-nano emulsifying drug delivery system (SMEDDS/SNEDDS).5 They often act not only as solubilisers, but also as adsorption enhancers and drug-delivery vehicles. The lipids surround the therapeutic agent and prevent it from precipitating out of solution before it is delivered to the appropriate site of action. Absorption of the API is then determined by its particle size, the level of dispersion, emulsification, and other factors.
The challenge with lipid-based solutions is formulating them into solid, or at least, semi-solid, dosage forms. In January 2015, Capsugel strengthened its position in LBDD with the acquisition of an ionic liquids platform technology developed by the Monash Institute of Pharmaceutical Sciences (MIPS). With this technology, lipid-like counterion salts are used to improve the solubility of drugs in lipid-based liquid, semi-solid and multiparticulate formulations.
Pharma and biopharma companies are most often seeking CDMOs that can find the optimum, tailored solution for each project through evaluation of a broad range of technologies
Many of the formulation technologies described above require specialised skills and expertise, if not specialised equipment. As a result, pharmaceutical and biopharmaceutical companies are more frequently relying on outsourcing partners for assistance in addressing drug solubility and bioavailability issues. Most often they are seeking CDMOs that can find the optimum, tailored solution for each project through evaluation of a broad range of technologies.
The CDMOs mentioned above are examples of service providers that have invested in the development of such capabilities to establish leadership positions in the preformulation/ formulation services arena. These companies have also expanded their capabilities beyond formulation to support all aspects of drug development and commercialisation, eliminating concerns about transfer and scale-up for their customers.
In particular, sponsor companies are looking for CDMOs with extensive knowledge and experience with many different API chemistries so that they can rapidly determine the specific tests required for a given compound. The goal is to quickly identify and then rapidly evaluate the most likely formulation technologies for a given drug candidate to achieve maximum performance, but at a minimum cost and in the shortest possible development time.
Respondents to the 2015 Nice Insight Pharmaceutical and Biotechnology Outsourcing Survey6 indicated that for preformulation projects, quality is the top attribute when selecting a new CDMO and also when evaluating the performance of existing partners. These results are not surprising given the central role that preformulation studies play in determining whether a drug candidate becomes a commercially viable, safe and effective drug product.
It is also interesting to note that, according to survey participants, the introduction of innovative technologies is helping service providers attract projects from sponsors looking to be first to market with differentiated products. In addition, the level of technological innovation at a potential outsourcing partner influences the selection process for survey respondents. Sponsor companies also look for strategic partners that have the capability and willingness to collaboratively develop operating procedures, use dedicated project managers, demonstrate a clear willingness to make long-term commitments and the ability to customise protocols for different projects.
References
1. Kline & Co, ‘Low Solubility Concern in the Pharma Industry Drives the Solubility Enhancement Excipients Market, Finds Kline’, Press Release, April 15, 2015.
2. http://www.drug-dev.com/Main/Back-Issues/HOT-MELT-EXTRUSION-OptiMelt-Hot-Melt-Extrusion-Tec-983.aspx
3. http://www.bendresearch.com/drug-delivery-technologies/spray-dried-dispersion.
4. C.A. Challener, Pharm. Tech., 38 (5), 2014.
5. S. Kalepu et al., Acta Pharm. Sinica B, 3 (6), 361-372 (2013).
6. Nice Insight, 2015 Pharmaceutical and Biotechnology Outsourcing Survey, January 2015.
To learn more about Nice Insight, the report or about how to participate, please contact Guy Tiene by sending an email to guy@thatsnice.com.