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An early formulation strategy for tablets that is simple and scalable is recommended to ensure fewer downstream problems.
The oral solid dosage formulation market is anticipated to experience growth in the coming years, reaching an estimated worth of $926.3 billion by the end of 2027 (1). Growth factors for the market are predicted to be the cost-effectiveness and convenience of manufacture, better chemical and physical stability of the finished product, and the potential for improved patient compliance.
Tablets remain one of the most popular types of OSD forms and are available in a range of shapes and sizes. Additionally, tablets can be coated to mask unpleasant tastes and odors, making them more acceptable and convenient to administer. To find out more about the ins and outs of tablet formulation, Pharmaceutical Technology spoke with Ali Rajabi-Siahboomi, vice president and chief innovation officer, Colorcon.
PharmTech: Could you run through some of the primary considerations that developers have to address when approaching tablet formulation to ensure success?
Rajabi-Siahboomi (Colorcon): Developing a detailed understanding of the molecule is the first step. Designing the formulation then involves many decisions: What is the desired drug release profile? Which excipients should be used and do they interact with the API? Which film coating should be used? What is the target population? And how should the tablet look? Key considerations are the properties of the API and dosage objectives, in-house manufacturing capabilities, and the value of planning from the outset.
The properties of the API and dosage objectives. Understanding the therapeutic area, dose, and any challenges related to the API are the first areas to consider. If the properties of the API, such as flow and compressibility, are poor, then this needs to be addressed at the outset to ensure tableting success. Other challenges the API may present, which need to be considered while developing the formulation, are solubility, along with sensitivity to moisture and other environmental factors, such as light or oxygen. Decisions on the formulation components will be influenced by the dosage objectives and the extent to which ingredients may be added.
The therapeutic profile of a drug is a key determinant in the frequency of dosing and release profile to be established during the formulation development. Is the target for immediate, enteric, or delayed-release? A once-daily dose is a good target as the aim is to design for patient convenience. The industry is increasingly moving towards patient centricity and ensuring that tablets are coated to help patients recognize their medications and reduce errors.
Available technology and manufacturing capabilities. Understanding where the product is likely to be manufactured and what production capabilities they have is imperative when considering the tableting process. Consider whether granulation is required or if it is possible to use direct compression (DC) to produce the tablet. DC is generally preferred as there are fewer steps for a simpler process—this reduces risks during manufacturing and means that the product is faster to make and get to market. DC allows a more robust manufacturing stream, so less troubleshooting is needed.
Production efficiency is influenced by tableting speed, whether single or double compression is required and what tools are available for in-process control. It’s also important to consider the tablet coating early on, as the coating can positively contribute to the robustness and stability of the tablet, as well as enhance patient acceptance/adherence.
Solubility is a separate issue that is often encountered with new molecules in development. Many technologies are available to help solubilize an API; however, not all companies have the capability to scale this to production. Even with the right technology, if a robust formulation and process are not developed then it can impact the subsequent manufacturing of a consistent product. With the right technology and choice of excipients, it’s possible to develop a stable formulation with reduced complexity.
The value of planning from the outset. The R&D team’s experience and understanding of formulation and manufacturing are important to ensure products are scalable. Generally, formulators should aim to keep their strategy simple. Reducing ingredients and process steps is the most cost-effective option and is likely to result in fewer downstream problems. From a regulatory standpoint, complex processes are likely to lead to more questions from regulators and may extend the approval process. Assessing the formulation strategy early can deliver key benefits, and having the end goal in mind leads to greater efficiency, as everyone will understand what they are working towards.
The process parameters for equipment used during development should be transferable to a commercial scale. Formulators should partner with suppliers before putting in place any special specifications for ingredients, thus avoiding future supply issues.
PharmTech: What are the most significant challenges to overcome when formulating tablets?
Rajabi-Siahboomi (Colorcon): Many companies understand the benefits of investing in early formulation and have resources dedicated to this role; however, particularly in the case of small and medium-sized companies, resources may be limited, and their priority is to establish the efficacy and safety of the API.
Rather than developing an optimized formulation strategy, a company will often resort to the same approach that it has used for previous products, even though it might not be well-matched with the newest molecule. At other times, a company may want to take a new approach to optimize the formulation but struggle to find a starting point, because there are many options.
Typical challenges faced by the formulator include API flow, compressibility, and managing extremes of dose. Low dose content uniformity is often an issue, and conversely, high dose presents the challenge of tablet size and inclusion of release modulating excipients.
Stability is key, especially when the API is moisture sensitive, and companies are now considering in-use conditions. Many patients and carers dispense their medications into pillboxes, especially if they are taking multiple tablets/capsules each day, but this means the dose is then exposed to the environment as pills are removed from the original packaging and dispensed into personal tablet holders. Choosing the right film coating can overcome the moisture stability challenges presented when tablets are removed from their protective packaging and are in use. Film coatings not only have an important role to play in terms of aesthetics by giving the tablet a perfect finish and defining a brand, but they also fulfill more practical roles. A good coating protects the tablet during storage from moisture, light, and oxygen, and ensures API stability. Specialist film coatings provide a barrier that reduces the ingress of moisture to the tablet core, helping to support stability for sensitive actives. The right coating choice also enables ease of transition of drug production between manufacturing sites; in early-stage development, the final site(s) for manufacture is not usually a consideration.
Failing to consider both the core and coating formulation early on can lead to delays, added costs, and in the worst-case scenario, project termination.
PharmTech: What solutions, approaches, or techniques are available for formulators to use that will help improve tablet formulation?
Rajabi-Siahboomi (Colorcon): Recent trends show that multifunctional excipients have a major role to play in tablet formulation, providing lubricity, disintegration, and moisture management. In-process technology (process analytical technology [PAT]) is available for measuring and managing content uniformity and robustness of the formulation.
Ingredients to improve flow and compressibility are valuable for manufacturing efficiency and robustness of the product for coating and packaging. It is also feasible to make equipment modifications to help with the flow and lubrication of the formulation and limit tablet damage.
DC is considered by many in the industry to be one of the simplest methods for manufacturing tablets and works well at large manufacturing scales. In comparison, wet granulation involves multiple steps and the use of moisture, which can introduce the risk that the API may degrade.
Many formulations require ingredients to improve processing and functionality—such as an excipient to improve flow and compressibility, as well as superdisintegrants. This can complicate the formulation and process, given that you need to examine how all of the excipients interact with one another, as well as with the API. For example, lactose is one common formulation ingredient that can interact with certain types of API.
With industry preference leaning towards direct compression, several excipients have been developed that excel in this area. One example is Colorcon’s StarTab, which is a single excipient that, due to its particle shape and size, is designed for direct compression and improves flow during manufacture. The excipient can also avoid the use of superdisintegrants—and be used at both small scale and large scale, as well as with the latest technology such as continuous processing. Excipients like this offer the manufacturer significant flexibility in terms of how they manufacture their product.
PharmTech: Are there any potential gaps where further improvements could be made?
Rajabi-Siahboomi (Colorcon): Pharmaceutical developers are now focusing on excipients that provide more targeted functionality for a specific manufacturing process. Co-processed excipients offer the possibility of simplifying drug product formulations while meeting functional and technical requirements, but there may be regulatory hurdles. Another opportunity to simplify tablet formulation would be to use ready-prepared blends of tried and trusted excipients.
Whenever possible, a reduced amount of ingredients to get the required functionality is preferable, as this means not only simpler processing but results in smaller tablets that are generally more patient-friendly. The exception being when very small tablets could be a concern in patients with handling issues, for whom a slightly larger tablet is beneficial.
Unique tablet designs are important. They can help to make medicines memorable to patients, caregivers, and pharmacists and may make a tablet easier to take. There are also production benefits; a unique design gives you differentiation on the packaging line, making it easier to spot a mix-up and prevent product recalls. Coatings play a key role in differentiation and branding and improve the patient experience through ease of swallowing.
For some companies, exploring different shapes can be daunting because it can affect the dissolution profile. Most companies do their R&D work on a standard round or oval tablet and only in Phase III will they start to think about the appearance of the final product. The earlier a developer thinks about their tablet design the better, but it’s certainly not too late at this point to change the shape.
Fake medicines continue to be a major problem around the world and recent developments to protect at the dosage level are now available. On-dose authentication technology, applied directly in the tablet coating can help deter counterfeits and product diversion.
Pharmaceutical companies are accountable for ensuring that their medicines are safe when they are delivered to patients. Track and trace are no longer sufficient to secure the supply chain, and the only reliable way to verify that medicines are authentic is the use of on-dose microtaggants, which can easily be incorporated into individual tablets or capsules.
The inclusion of taggants is simple and cost-effective, providing a digital security layer to safeguard patients and uphold brand integrity. A unique advantage is a positive impact on the speed of decision-making and action by enabling suspected counterfeit tablets to be verified in real-time, rather than waiting days or weeks for test results. With smartphone detection, this technology also provides the opportunity to help patients better engage with their medicines.
Taggants are directly applied in the tablet coating for on-dose authentication. With no change to the coating process, this innovative solution is easy to implement, resulting in a secure yet practical and cost-effective solution. Manufacturers increasingly recognize that they can no longer rely solely on secondary packaging security features to ensure the authenticity of the product and are turning to on-dose authentication solutions that offer more security.
PharmTech: How might the advent of new excipients (particularly given the fact that the Center for Drug Evaluation and Research [CDER] has launched a pilot review program) aid with tablet formulation?
Rajabi-Siahboomi (Colorcon): With tablet formulations, if the challenge of the API is related to solubility or bioavailability, then novel excipients would be a big opportunity.
The new CDER pilot program for novel excipients is a welcome initiative from FDA. It offers a new pathway for drug manufacturers to get an FDA review of novel excipients before the excipients are used in a formulation. Before this initiative, the selection of a novel excipient by a drug manufacturer carried a potential risk, for example, the new drug application could get held up by questions being asked about the safety and quality of a new excipient. The new program allows upfront testing and review of new excipient, reducing the risk to timelines and making it easier to select a novel excipient for dosage forms.
Taste masking is one of the areas where different approaches and new materials are constantly being explored, and it should be possible for new materials that have no history of use in pharmaceuticals or foods to be assessed more quickly.
PharmTech: What, in your opinion, do you foresee as being important trends that will impact tablet formulation in the near future?
Rajabi-Siahboomi (Colorcon): Tablet and solid dosage forms continue to be the gold standard for patients and manufacturers. New manufacturing methods such as 3D printing are emerging and are gaining interest. The nature of the materials needed for this type of technology is quite different from standard tableting and needs specialist equipment and knowledge to be practical from a manufacturing perspective. New methods such as hot melt extrusion and deposition of materials versus powder layering mean using different materials with different properties, such as the importance of thermoplasticity of the material being used.
The use of artificial intelligence to predict formulation behavior will reduce development time and lead to more robust formulations. Disruptive technologies such as ionic liquid technology that enables oral delivery of biologics and other injection-based drugs are now being developed. The ability to deliver injectable therapies orally has the potential to significantly improve patient experience, adherence and outcomes.
1. Future Market Insights, Oral Solid Dosage Pharmaceutical Formulation Market by Dosage Form (Tablets, Capsules, Powders), Drug Release Mechanism (Immediate Release, Extended Release), Distribution Channel (Hospital Pharmacy, Retail Pharmacy, Drug Stores), and Region—Forecast 2017–2027, Market Report (July 2017).
Felicity Thomas is the European editor for Pharmaceutical Technology Group.
Vol. 46, No. 4
When referring to this article, please cite it as F. Thomas, “Formulating the Best Approach for Tablets,” Pharmaceutical Technology 46 (4) 2022.