September 14, 2021 PAO-09-21-CL-06
Formulators face many challenges when developing tableted products for oral administration related to both tablet processing and tablet performance for the customer. While in rare cases, tableted formulations are produced without a film coating, most have at least a basic coating that facilitates passage of the tablets through post-processing steps, such as through feeders into a blister packaging machine or bottles. For these applications, there is no real alternative to film coatings; they have become the state of the art for tablet finishing.
Coatings have evolved from basic sugar-based systems to more advanced polymer-based solutions that create thin film layers and can — in addition to ensuring efficient processing — help improve the functionality of pharmaceutical tablets. They can be used to increase swallowability; for taste-, odor- and color-masking; as a protective barrier against moisture and oxygen to increase tablet stability; to control the release of the API; and to increase the value perception of the customer through color and design.
In summary, coatings help to improve the appearance, stability, and therapeutic effect of a formulation while also contributing to increased patient compliance.
Drug manufacturers have two options when producing coated tablets. They can purchase pre-mixed coating solutions or prepare their own coating systems. There are advantages and disadvantages to each approach.
Pre-mixed coating solutions are easy to use, require much less formulation know-how, and are often perceived to present a more cost-effective approach, although that is not always the case when considering total manufacturing costs. Users of pre-mixed coating solutions, however, rely on the supplier who created them and as such have limited flexibility. They also lose contact with the formulation process and thus limit their opportunities for innovation. For instance, if an ingredient in the pre-mixed solution is incompatible with the API, modifying the coating can be difficult. Responses to regulatory requests may be prolonged. In addition, pre-mixed coating solutions are often single-sourced, which can lead to supply issues.
While formulating coatings may seem to be more complex, if the drug manufacturer has a good toolbox of coating ingredients and access to detailed information about the properties of each, it is often not difficult to develop a fit-for-purpose, optimum, cost-effective coating solution. With this approach, it is possible to choose among different ingredients and match them together to create the perfect coating that is adapted to the specific manufacturing needs and the requirements of the particular drug substance.
Coating formulations designed for application to pharmaceutical tablets must be sprayable liquids that, once applied, will form a thin film layer with desired properties. They typically contain five main ingredients: polymers, plasticizers, anti-tacking agents, colorants/pigments, and a solvent, which is typically water.
The main ingredients are polymers that when sprayed onto a tablet form a homogenous film that completely surrounds the tablet and encapsulates it. They also must exhibit the targeted functionality and form solutions with an appropriate viscosity for spraying.
Plasticizers are typically required to support film forming of tablet coatings. Many polymers established as pharmaceutical excipients can be slightly brittle, and, with time in storage, the films they generate may undergo cracking if their glass transition temperature (the temperature at which a polymer begins to soften) is not lowered. Plasticizers ensure that the polymers used in pharmaceutical coatings maintain flexibility even at the target storage temperature.
Choosing the right plasticizer is therefore important for fine-tuning the flexibility of tablet coatings. Similarly, selecting the right polymer and plasticizer concentrations can impact the performance of tablet coatings and help to prevent cracking.
The addition of anti-tacking agents is necessary to prevent tablets sprayed with the coating solution from sticking to one another during the coating process. Deagglomeration of stuck tablets can lead to defects and even cracking of their coatings. Use of anti-tacking agents is thus quite important to ensure a robust process.
Finally, the addition of colorants or pigments can support product branding and/or provide a mechanism for identifying the tablets.
While it may seem complicated to formulate effective tablet coatings, we have established clear and direct guidelines that simplify and accelerate the preparation of coating solutions. In general, production of pharmaceutical coatings involves a series of simple mixing steps that allow for the combination of ingredients in a rapid manner. Our guidelines include recommendations on how best to introduce each type of ingredient to ensure dissolution and the maintenance of homogenous coating solutions during spraying.
Within our SAFC® portfolio, we are constantly seeking new solutions that will improve the drug manufacturing process. With immediate-release tablets, we observed that, for many of the polymers used to prepare coating solutions, dissolution in water was challenging and very time-consuming. Our attention was then focused on developing a new functional excipient that would rapidly dissolve in water while providing attractive functionalities.
The result of this effort was Parteck® COAT excipient, a functional excipient based on 100% PVA 5-88 milled to a specified medium particle size and specifically designed for use in coating formulations for immediate-release products. Parteck® COAT excipient is based on pharmaceutical-grade PVA that surpasses the requirements of all major pharmacopeias (USP, Ph Eur, ChP, JPE).
With 88% hydrolysis grade, this new excipient has a certain amphiphilic character that enables rapid dissolution of the polymer particles in water, even without heating. The carefully selected particle size and particle size distribution (Figure 1) also contributes to the free-flowing nature of Parteck® COAT particles and their rapid dissolution. The films generated with Parteck® COAT excipient protect sensitive APIs by forming a stable moisture and oxygen barrier.
We have developed a robust process for the consistent and reliable batch-to-batch production of this dedicated particle design that yields a very-high-quality, high-performance polymer product. In addition, Parteck® COAT excipient is supported by our strong knowledge of plasticizer interactions and a deep understanding of coating formulation. Formulation development assistance using our toolbox of Parteck® excipients is available for any customers that would like help creating their own coating solutions.
To demonstrate the advantages of Parteck® COAT excipient over traditional polymers used in immediate-release tablet coatings, a number of direct comparison experiments were performed.
First, time-to-dissolution was evaluated. Parteck® COAT PVA, a standard PVA and hydroxypropyl methyl cellulose (HPMC) grades were each added to water to ultimately generate 5% solutions (Figure 2). The mixtures were heated at 20 °C, 40 °C, and 60 °C and the time required for each polymer to dissolve was assessed. The standard 5-88 PVA grade did not dissolve at room temperature and was only partially dissolved at 40 °C. A temperature of 60 °C and 30 minutes of stirring was required to get this polymer fully dissolved. The cellulose-based hydroxypropyl methylcellulose (HPMC) polymers did not enter solution over the entire temperature range. For some immediate-release polymers (not shown), heating to 90 °C can be required.
Parteck® COAT polymer dissolved readily at temperature of 40–60°C, which is highly advantageous at large scale. Heating 200–300 liters of coating solution to a high temperature in order to achieve polymer dissolution (and then cooling) is time-consuming and costly. With Parteck® COAT excipient, this problem is avoided.
Next, we examined the impact of polymer concentration on viscosity for Parteck® COAT excipient and two low-viscosity HPMC-based polymers (Figure 3). For the cellulose-based polymers, the apparent viscosity increased nearly exponentially as the polymer concentration increased, limiting the maximum concentration to 10–15%. The apparent viscosity increased more slowly with Parteck®COAT excipient. As a result, coating solutions with up to 20% polymer load are possible, allowing the application of much more polymer in shorter timeframes, dramatically increasing the efficiency of the coating process.
The thermal behavior of Parteck® COAT excipient was also investigated using differential scanning calorimetry (DSC). The glass transition temperature (circled area in Figure 4) was confirmed to occur around between 60 °C and 75 °C. At this temperature range, the polymer is changing from the brittle to a more flexible, rubber-like state, which makes it the optimum temperature range for processing to ensure good film formation on the tablet surface. Thus, the recommended mixing temperature is 60 °C, with fine-tuning of performance achieved through the addition of appropriate plasticizers.
The dissolution kinetics of applied coatings based on Parteck® COAT excipient and an HPMC-based coating were evaluated on a model core tablet containing ascorbic acid as the model API (10%), Parteck® M 200 mannitol (87%), silicon dioxide (1%), and sodium stearyl fumarate (2%). The solid content of the sprayed liquid coating formulations comprised 70% polymer, 20% triethyl citrate, and 10% talcum. The goal was to achieve a 3% weight gain on each core tablet. Notably, the cellulose-based polymer coating affected the release kinetics much more than the polymer film based on Parteck® COAT excipient, which only slightly delayed the release of the ascorbic acid.
Finally, the permeability of coatings formulated using Parteck® COAT excipient, two HPMC-based polymers, and a polyethylene-glycol (PEG)-PVA graft copolymer and prepared via film casting for water and oxygen was evaluated. In both cases, the permeability of the Parteck® COAT excipient–based film was significantly lower than that for the other three coatings (Figure 5). These results confirm that Parteck® COAT excipient acts as an excellent barrier to moisture and oxygen and can provide reliable protection for sensitive APIs.
Given that plasticizers play a crucial role in the fine-tuning of tablet coating performance, an extensive investigation of plasticizer interactions with Parteck® COAT excipient was undertaken. Plasticizers were chosen in consideration of the fact that Parteck® COAT excipient is based on PVA, which has a semi-crystalline nature, with some portions having higher packing densities and greater potential for hydrogen bonding within the layers than others. The goal was to identify plasticizers that can enter into these areas of higher packing density and disrupt them, increasing the distance between the individual polymer chains and thus increasing the flexibility.
Screened plasticizers included various polyethylene glycols PEGs, polyols triethyl citrate, triacetin, glycerol, Parteck® SI 150 sorbitol, and Parteck® M 200 mannitol. Screening was conducted by forming coating solutions from stock Parteck® COAT excipient and plasticizer solutions. For each test, 50 µl of a coating solution was placed in a DSC aluminum pan and dried overnight. The dried material was then weighed, the pan closed, and the DSC analysis performed. Triethyl citrate, triacetin, PEG 1000, and several polyols were found to exhibit strong plasticizing effects
Next, the effect of different types of plasticizers at different concentrations on the tablet surface was explored by determining the surface roughness using a laser scanning microscope. Triethyl citrate and triacetin were found to dramatically reduce the surface roughness when incorporated into formulations at 30% of the solids content. Sorbitol and mannitol were also found to have a positive effect. Of the PEGs evaluated, PEG 1000 provided the greatest decrease in roughness.
Continuous manufacturing is recognized to provide significant benefits in improved product quality and consistency while reducing the manufacturing footprint and also potentially the cost. To be successful, however, inline, real-time monitoring is essential to ensure ongoing performance.
For tablet coating processes, we are evaluating the use of optical coherence tomography (OCT) in collaboration with RCPE and Phyllon, a company commercializing this technology. OCT provides valuable insights into the coating process, including the coating thickness and its homogeneity (structure) and surface roughness as the film is forming. With this system, it is possible to target a specific coating thickness rather than relying solely on assumptions of appropriate weight gain and back-calculations to determine spraying time.
With our team of SAFC® formulation experts and extensive portfolio of excipients, including Parteck® COAT excipient, we are well positioned to develop coatings suited for continuous coating operations. Indeed, we are currently automating the tablet coating process using OCT to determine the layer thickness and are achieving robust results even at large scale.
Parteck® COAT PVA is our latest addition to our extensive SAFC® excipient portfolio. Parteck® M mannitol and Parteck® SI sorbitol excipients are ideal for the formulation of tablet cores that can then be coated with Parteck® COAT films formulated with MilliporeSigma plasticizers, anti-tacking agents, and pigments and colorants.
With this wide range of products, our SAFC® portfolio is able to support customers through each step of the tablet formulation development process. Importantly, because these products are developed in-house, we have a deep understanding of their behaviors and how they can best be used in formulation development. Furthermore, all of these excipients are Emprove® qualified with high levels of documentation for reduced risk and smoother regulatory filings.
The development of Parteck® COAT excipient is indicative of our commitment to continuously develop solutions for challenges faced during coatings formulation development. Currently, we are exploring which existing pigments work just as well with Parteck® COAT excipient, as many in the pharmaceutical sector anticipate a potential regulatory change after the 2021 EFSA statement that titanium dioxide is not safe to use for food, and as such customers have started looking for potential alternatives. To date, we have identified some calcium carbonates with the potential to be suitable replacements for titanium dioxide, and work continues to fine-tune these developments.
Our excipient experts also continue to evaluate feedback from customers regarding pain points and areas where improvements are needed to overcome challenges presented by traditional excipients and formulating approaches.
Dr. Thomas Kipping holds a Ph.D. in pharmaceutical technology and is currently the Head of Drug Carriers for MilliporeSigma. With a broad expertise in the field of amorphous solid dispersions, Dr. Kipping provides a deep understanding of formulation development and process optimization in the expanding field of hot melt extrusion. He has a strong background in pharmaceutical industry, including industrial development, GMP manufacturing, clinical supply, and research and development