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Editor of Pharmaceutical Technology Europe
Several trends are driving change in oral solid‑dosage forms and giving rise to the requirement of ‘fit-for-purpose’ excipients.
According to market forecasts, the global oral solidâdosage (OSD) pharmaceutical formulation market is anticipated to grow by a compound annual rate of 6.5%, reaching a little less than US$930 billion by the end of 2027 (1). This growth rate stands to reason, as solid dosage forms remain the most popular and commonly used drug form within the industry.
“OSD forms, such as tablets and powder-filled capsules, are the most popular in the industry,” says Ronak Savla, global scientific affairs manager at Catalent. “These drug forms are cost-effective, scalable, and acceptable to patients. However, the manufacture of OSD forms is becoming less straightforward than API-excipient blends compressed into tablets or filled in capsules.”
Over the past decade, Savla notes that there has been a steady increase in the number of drugs formulated as solid dispersions, driven by technology advances and the increasing number of poorly soluble drug candidates.
Concurring with Savla, Krizia Karry, global technical marketing manager at BASF Pharma Solutions, specifies that technological advances enabling the ability to manufacture OSD forms of poorly water-soluble drugs is one of three major trends impacting the industry. “Technologies such as hot-melt extrusion and spray drying, which allow for the drug to be solubilized in a polymeric carrier and subsequently formulated into a tablet, have seen growth,” she says.
In Karry’s opinion, approaches to improve patient compliance and continuous manufacturing have been two further trends in the field of OSD formulation. “It is no secret that a large percent of the population has difficulty swallowing tablets and capsules. As a consequence, formulations such as oral dispersible tablets and mini-tablets have expanded the ability of patients to take lifesaving medications,” she notes.
“Finally, the adoption of continuous manufacturing platforms for solid oral dosage forms offers a cost-competitive advantage by reducing overall manufacturing footprint, accelerating drug product development, allowing for flexible batch sizes, being amenable for real-time release testing, and by enabling higher assurance of product quality through automated control strategies that react to process disturbances,” Karry continues.
Harald Stahl, head of application development at GEA, raises the point that the industry is moving away from the blockbuster and toward the development of specialized drugs that target rare and orphan diseases. “Consequentially, batch sizes decrease while at the same time prices per dose go up,” he adds. “As a result, companies are looking into technologies that allow for the necessary development and scale-up activities while using minimal amounts of API-one of the main drivers into continuous processing.”
“More than ever before, pharmaceutical companies are taking a holistic approach when formulating new drug products so that patients are at the center of everything they do,” says Jessica Mueller-Albers, strategic marketing director for oral drug delivery solutions at Evonik. “This has strengthened demand for solutions that can improve rates of patient compliance and brand preference, such as the development of pediatric or geriatric dosage forms, as well as coatings that enhance swallowability.”
Furthermore, Bruhalkumar Shah, senior formulation scientist at Cambrex highlights that outsourcing of pharmaceutical development and/or manufacturing to various contract organizations has also been rising. This is a result of an increase in merger and acquisition activity, pharmaceutical company downsizing, and the emergence of virtual companies, he explains.
“Each of the sector trends, however, require excipients that are ‘fit-for-purpose’ to overcome the various challenging tasks that face formulators of OSD drugs,” stresses Karry.
“Careful consideration must be taken in the selection of any functional or non-functional excipient as it greatly impacts the quality and efficacy of the finished product,” says Shah. “Special attention should be given to functional excipients, which can directly impact the stability of the product or can change pharmacokinetic performance, such as with controlled or modifiedârelease products.”
Excipients are rarely now just bulking agents, asserts Savla. “Rather, such agents are increasingly used to serve an additional function, such as improving solubility. It is highly likely that multiple excipients, each serving a different function, are required,” he notes. “Polymers used in amorphous solid dispersions retard recrystallization of amorphous drug molecules. Understanding the functionality, stability, and API interactions of the excipients is paramount.”
Karry adds that of primary importance is an understanding of API properties and solubility in common solvents. “From there, formulation screening methods vary depending on whether the excipient helps solubilize the drug (e.g., by complexation or solid solution systems where the API is solubilized in a polymeric carrier) and pharmacokinetic considerations such as the rate of administration (instant or modified release), and preferred site of drug absorption (pH dependent solubility),” she says. Further considerations are then made on a case-by-case basis but may include processing aids (glidants and lubricants), drug abuse deterrents, taste-masking or moisture protection coatings, and antioxidants to protect the API from oxidation reactions, among others, Karry states.
The first step is certainly screening of API compatibility, specifically, chemical and physical stability in a panel of common excipients used in regulatory-approved products, agrees Savla. “The goal of compatibility screening is to minimize risks, costs, and formulation development time,” he explains. “Some key areas of focus are keeping the drug in an amorphous state (for amorphous solid dispersions), change in polymorphism, and chemical degradation. Based on these results, formulation prototype development with other ingredients (binders, fillers, disintegrants etc.) is undertaken. For hot-melt extrusion, the miscibility of API and polymer is important, as is the melting temperature of the polymer.”
Then, it is vital to consider the amount of excipient in the formulation, as this should be kept under the maximum allowable potency per dose. “For pediatric patients, the number of allowable excipients is rather limited,” Savla continues. “An adult formulation may not be acceptable for pediatric use by regulatory authorities based on the components. Therefore, the formulator is challenged with designing a different formulation while maintaining safety and efficacy.”
If using large amounts of excipients in a dosage form, there may be a requirement to have a larger dosage unit or for the patient to take multiple doses to achieve the correct dosage of API, which can lead to swallowability and adherence issues. “The formulator must study the drug loading when choosing polymers for amorphous dispersions. Simply choosing the formulation with the highest drug load is not recommended, as high drug loading may lead to a higher propensity for recrystallization in an amorphous solid dispersion,” Savla stresses.
“The growing complexity of drug products has increased demand for specialized excipients and other delivery technologies that can facilitate the targeted release of the API at the right place over the right duration,” emphasizes Mueller-Albers. The crucial role these agents play in the properties and performance of the final drug product has meant that regulatory authorities have scrutinized the functionality and quality of excipients closely over the past decade.
“As a result of this scrutiny, pharmaceutical companies have been prompted to take a science- and risk-based approach towards the selection of excipients that are widely accepted across all key worldwide markets,” Mueller-Albers adds. Without the appropriate attention to excipient quality, companies may be taking significant risks to drug development and could end up with production downtime and supply shortages, she warns.
“As mentioned earlier, industry has been witnessing a shift away from the blockbuster style drug product and, as such, is seeing volumes of manufacturing decrease,” says Stahl. “Therefore, several companies have been focusing on a direct compression method, which negates the need for the wet granulation step, while also increasing the requirements on the physical characteristics of APIs as well as the excipients.”
Successful application of the direct compression method requires a critical selection of excipients, to ensure good flowability and compressibility. “Powder flow is an extremely important property for processes such as tableting and capsule filling, and therefore, excipients that can improve powder flow for ‘difficult’ powder blends are of interest to formulators,” emphasizes Savla. “These can be excipient grades with a particular particle-size and shape to provide good flow properties, or co-processed materials (e.g., silicified microcrystalline cellulose), which offer similar advantages.”
Co-processed materials are now more widely available and offer formulators a single, multi-functional excipient option, which helps to reduce development time and cost, particularly in early development phases, Savla explains. “Further, easy-to-prepare products, such as preformulated coating preparations for tablets are now freely available and can also cut down on processing time.”
As the drug development process itself becomes more complex, excipient suppliers are required to follow the various industry trends and innovate, confirms Shah. “Important advances have been seen specifically when developing novel drug delivery systems,” he says.
Giving some examples, Shah highlights that excipient advances have been seen as a result of industry trends towards immediate and controlled dosage forms, specialized delivery systems for poorly soluble molecules, and nanotechnology. “So, co-processed excipients and the development of new grades of existing excipients have helped with immediate and controlledârelease dosage forms,” he adds. “Then for specialized delivery systems, cyclodextrins, mesoporous silica, new polymers to inhibit crystallization, and copolymer dispersions for taste-masking have been introduced. In terms of nanotechnology, the sector has seen the use of PEGylated derivatives and drug targeting moieties for stabilization and specificity, respectively.”
However, Karry states that innovation has remained relatively slow. “Naturally, it is a significant gamble for pharmaceutical companies to utilize novel or innovative excipients in formulations, largely due to the increased risk on the drug filing,” she says. “Nevertheless, innovation for excipients continues.”
“Even though there are a number of excipient options available today with a strong history of safety and performance, there are still unmet market needs when it comes to functionality,” notes Mueller-Albers. “As one example, despite several companies seeking to develop new permeation-enhancing solutions, there is still a clear need for additional excipient offerings or drug delivery technologies that can better address poor permeability. Likewise, despite the use of solid dispersions to help address poor solubility, we are still seeking specialized solutions that can tackle the bioavailability constraints of certain new drug entities.”
In Savla’s opinion, despite growth in the number of acceptable excipients available to help with solubility enhancement, it remains one of the main issues for formulators. “There continues to be a need for new excipients that can help overcome the challenges offered by chemically diverse compounds,” he explains. “The limited number of polymers used in amorphous solid dispersions is not adequate to cover the wide chemical diversity of drug molecules.”
Additionally, Savla believes that there is a great unmet need in the number of pediatric-appropriate excipients that are considered to be acceptable by regulatory authorities. “The development of pediatric medicines has become of key importance within the pharmaceutical industry as developers are increasingly required to conduct clinical studies in pediatric populations with appropriate formulations first, before going on to get regulatory approval for adult formulations,” he states.
It is generally known that oral administration of biopharmaceutical products has been limited and progress within the field slow. “Most macromolecules are still formulated into parenterals and applied subcutaneously or intravenously,” notes Karry. “While clearly, oral delivery of these would improve patient compliance and avoid injection-related injuries and illnesses, the stability of large therapeutic molecules in the gastrointestinal (GI) tract remains a significant challenge, mainly due to the inability to protect therapeutic proteins from the body.”
Although many attempts have been made to develop oral versions of biopharmaceuticals, such as insulin, the enzymatic and chemical degradation pathways in the GI tract are too problematic, confirms Shah. “However, delivering biopharmaceutical products orally remains the holy grail for this molecule class, and there are advances being made in nanoparticle drug delivery systems and advanced manufacturing technologies coming to the fore. So, more progress is expected in this area,” he says.
Mueller-Albers concurs there has been a strong demand within the industry for excipients that can reliably control transit of biologic drug products through the GI tract. “There are many promising examples in the literature and in the start-up community to keep an eye on,” adds Karry.
“Oral solids are likely to remain the dominant dosage form within the pharmaceutical market for the foreseeable future,” confirms Mueller-Albers. “Above all, we expect tablets and capsules will continue to remain popular for use across the entire spectrum of drug candidates due to cost-effectiveness, stability, and strong rates of patient compliance. However, OSD forms will continue to become more complex and personalized.”
For Shah, the drug pipeline will continue to be healthy, with increasing numbers of smallâmolecule drugs being launched in the OSD sector, which is still considered to be the backbone of all medicines. “While OSD forms continue to remain an important part of the pharmaceutical industry, there is a continual drive to develop new drug delivery technologies, such as the use of nanotechnology for example,” he says. “On a manufacturing front, there seems to be a trend toward the application of continuous manufacturing technologies, improving processes for complex drug products, and introducing manufacturing technology for individualized and on-demand drug products.”
Spray-dried dispersions have been ‘on point’ for many drug developers in recent times, according to Savla, who believes this trend will likely continue. “There is a significant percentage of poorly soluble molecules whose sub-optimal solubility is not adequately addressed by current technologies or excipients,” he asserts. “This unmet need will require advancements in novel excipients or polymers, and novel technologies.”
Karry adds that cost-competitive manufacturing, increased use of functional coatings, dosage forms amenable for pediatric applications, and drug products with more than one API are all trends that have been identified and are anticipated in the future of global OSD forms. Adding to this list, Mueller-Albers and Shah raise the point that stronger collaboration between pharma and non-profit organizations or academia is benefiting drug development advancement and so should continue to be a promising trend.
1. Future Market Insights, “Oral Solid Dosage Pharmaceutical Formulation Market: Emerging Markets of Latin America, APEJ and MEA to Collectively Hold over 45% Market Value Share: Global Industry Analysis 2012–2016 and Opportunity Assessment 2017–2027,” Report, July 18, 2017.
Vol. 43, No. 7
When referring to this article, please cite it as F. Thomas, “Selecting a Solid Approach,” Pharmaceutical Technology 43 (7) 2019.