Detlev Haack, PhD, is head of Research & Development at Hermes Pharma.

Detlev Haack

Caffeine is frequently added to common painkillers, such as acetaminophen, to increase their pain-relieving effect. Used primarily for mild to moderate pain, the acetaminophen plus caffeine combination is mostly produced in tablet form. Because of the extremely bitter taste of these APIs, formulation into other dosage forms that are not to be swallowed whole can be challenging. This case study shows how hot melt coating (HMC) was used to develop orally disintegrating granules (ODGs) of acetaminophen and caffeine; this dosage form has been specifically designed to be easier to swallow.

	User-friendly dosage forms, such as ODGs, effervescent tablets, chewable tablets, instant drinks, and lozenges, offer a wide range of benefits to both the pharmaceutical industry and the end user. In a recent consumer survey, more than half of the respondents reported difficulties swallowing tablets and capsules, with approximately a third reporting the issue as serious (1). The most frequent reasons cited were that the tablets/capsules were too big, got stuck in the throat, or had an unpleasant taste or odor. These people did not report similar problems with foodstuffs or fluids.

	The same survey revealed that people who had experience with user-friendly dosage forms scored them more favorably than conventional tablets/capsules across almost all criteria (such as ease of intake, integration into daily routine, flavor, sensation in the mouth, and ease of swallowing). Such findings indicate that user-friendly dosage forms better meet consumer needs and can lead to improved compliance. In addition, pharmaceutical companies can expand their product lines and create new revenue opportunities with user-friendly dosage forms.

	To better meet the needs of patients and consumers, a demand was identified for an acetaminophen plus caffeine combination formulated as an ODG. Such granules are provided in stick packs that can be emptied directly into the mouth and swallowed without water. ODGs are a convenient dosage form and ideally suited to individuals who have difficulty swallowing conventional pills. A further benefit of ODGs is that, unlike tablets, they do not need to disintegrate in the stomach, which can lead to faster absorption, thereby achieving pain relief more quickly. While the benefits of an acetaminophen plus caffeine ODG were clear, a number of challenges were identified during the formulation development process.

	The bitterness of both acetaminophen and caffeine makes effective taste masking particularly challenging. Because ODGs tend to spend more time in the mouth and are tasted more thoroughly than conventional tablets and capsules, it is crucial that the final product is palatable.

	HMC was identified as a suitable coating technology for the development of taste-masked acetaminophen and caffeine ODGs. Originally developed for food manufacturing, HMC offers a faster, more economical coating method than many traditional solvent-based approaches. The process involves covering a solid core particle with a molten coating material, which immediately solidifies to form a homogenous coating. The coatings, which comprise a lipid and an emulsifier, enable the production of coated immediate-release products with a neutral taste. Those coated intermediates are then blended with further excipients and flavors and filled into stick-packs to create a pleasant-tasting, user-friendly oral dosage form. HMC parameters often need to be optimized for each API due to their individual properties and morphology. Although optimization creates an extra step in the development process, it also makes the formulation unique and therefore can be used to protect product lines from competition. Some formulations can even be patented, further strengthening intellectual property protection.

	The first step in formulating the acetaminophen plus caffeine ODG was to define the quality target production profile (QTPP), which is a crucial element of a quality-by-design (QbD) approach. In this case, the main requirements of the QTPP were an ODG with 500 mg acetaminophen plus 65 mg caffeine, immediate release, pleasant taste, and storage stability of more than three years (see 

	Immediate-release ODGs should ideally have a two-phase dissolution profile. The first phase lasts 30-60 seconds and encompasses the swallowing of the granules. During this period, drug release should be minimal. In the second gastric phase, API release should be as fast as possible to enable drug absorption. Drug release is a critical quality attribute (CQA) and has to be analyzed during development, stability testing, and product release. For this analysis, a compendial dissolution instrument (paddle apparatus) was used in combination with ultra-high performance liquid chromatography (UHPLC) as it is both fast and simple to use.

	HMC was selected as the technology of choice to mask the bitter taste of acetaminophen and caffeine, followed by a blending step in which further excipients were added before filling into stick packs. For both manufacturing steps, a risk analysis identified the critical process parameters (CPPs), which were the key variables affecting the coating and blending process.

	Much of the process development effort focused on coating acetaminophen and caffeine, which had to be performed separately. During the HMC process, the APIs were each suspended in the fluid bed coater and the molten coating mixture was sprayed onto the particles. The spray droplets first wet the API particle, before they solidified to form a homogenous layer. As no solvents were used, the process proved rapid and typically took less than 1.5 hours per batch. While developing the coating process, the intermediates were tested for successful taste masking, drug release, and content. Furthermore, the capability of the developed process was evaluated as to whether it could be scaled up for commercial production.

	After the two APIs were coated, they were blended together with further excipients to create the final formulation. The selection of suitable excipients and flavors involved a focus on palatability and mouthfeel, because these factors play a major role in the success of an ODG. A number of flavors were tested for their suitability including lemon, cassis, and cappuccino. Cappuccino was chosen for its association with caffeine and its pleasant taste. Then, the impact of these excipients on processing was assessed, including flowability and segregation (which were relevant when it comes to filling the granules into the small stick packs).

	Finally, the blend homogeneity was evaluated and the required blending time determined using an near infrared (NIR) probe and a scaled-down laboratory blender. Both APIs were blended with the excipients. It was important that blending was performed long enough to achieve homogeneity, but it was also crucial not to overblend, as overblending can destroy the coating and negatively affect the taste and release of the formulation.

	Ease of scale-up is essential for any formulation process to make the transition from development to bulk manufacture as fast, simple, and cost-effective as possible. An advantage of HMC is that it is relatively easy to scale up.

	It was recognized that there would still be a number of challenges in scaling up the acetaminophen plus caffeine ODG. In moving from laboratory to production scale, it was necessary to upsize the HMC equipment from the Ventilus V2.5 (Romaco Innojet) to the Ventilus V100 (see 

). The configurations of these instruments, particularly the spray geometry, are slightly different. To generate the desired HMC effect, it is essential that the spray rate and the temperature of the air, apparatus, and materials are all carefully controlled throughout the process. The equipment contains a number of sensors for temperature, air-flow, and spray-rate, ensuring this process is not arduous and is reproducible. For the scale-up, the process times had to be extended from 50 to 70 minutes.

	When carrying out HMC, it is important to monitor the size and shape of the particles, both before and after coating. If the seed particles are too small, they could clog the filter of the fluid bed (see 

), while the subsequent increase in overall surface area will lead to the coating on each particle being too thin. If the particles are too large, then the opposite occurs, with the coating ending up too thick. The frequency of filter changing becomes a more important factor for manufacturing campaigns. To optimize this parameter, a number of different filter materials and pore sizes were tested, and it was observed that the same filter can be used for a campaign of at least eight batches.

	Another challenge faced during scale-up concerned the storage of the bulk intermediate. Even within just a few days, compression from the weight of the material could cause agglomeration. It was necessary to consider early on which coating excipients would be least susceptible to such agglomeration. 

	Also during scale-up, the final blend was optimized by making minute adjustments of excipients, sweeteners, and flavors to create a palatable and processable finished product. After this, the final step was to optimize the filling of the final blend into stick packs to achieve tight packaging and uniform fill weights at the highest possible speed. A stability study is now being performed both on a pilot batch and on each of the intermediates. In these studies, parameters such as content, related substances, taste masking, and dissolution are tested at long-term (25 °C/60% relative humidity [r.h.]), intermediate (30 °C/75% r.h.), and accelerated conditions (40 °C/75% r.h.) (see 

	Having developed the acetaminophen plus caffeine ODG with proven processability, the next steps will be to manufacture three production scale batches to conduct process validation and to initiate stability studies for regulatory purposes. Depending on the regulatory strategy, it may be necessary to perform a bioequivalence study or to follow a biowaiver approach. Either way, the compilation of a dossier can begin because key elements have been successfully completed.

	The HMC process was optimized at laboratory scale to mask the bitter taste inherent of both APIs. It was then successfully upscaled from laboratory to production scale. Appropriate excipients were selected to ensure a pleasant taste and mouthfeel--both of which are particularly important for ODGs. The excipients were also deliberately chosen to reduce agglomeration in the final product. Tests have shown that the goals of maintaining low API release while the ODGs are swallowed, followed by rapid release afterwards, were both achieved. Once the final stability tests have been completed, the intention is to bring the product quickly to market, offering consumers a convenient, fast-acting, and effective painkiller that overcomes many of the disadvantages of conventional tablets.

	When referring to this article, please cite it as D. Haack and M. Köberle, " From Bitter to Sweet: Developing a User-Friendly Painkiller,” 

Articles

Hot-melt coating was used to develop taste-masked orally disintegrating granules of acetaminophen and caffeine.

From Bitter to Sweet: Developing a User-Friendly Painkiller

Tablets and capsules are often coated for various reasons such as to improve their appearance or to make them easier to swallow. Coatings also play an important role in maintaining drug stability, activity, and effectiveness. This article reviews the benefits of solvent-free processes and techniques specifically optimized for coating new dosage forms such as orally disintegrating granules (ODGs). 


  Coating is usually achieved with one of a variety of techniques but regardless of the equipment and coating process used, there are several common challenges and considerations that will influence coating success. Firstly, the coating should be immediately stable (e.g., without the need for a curing step), reproducible, and cost efficient. Secondly, the coating process used during formulation development must be easy to transfer to manufacturing conditions and ready for scale-up, using excipients that can be easily and safely stored in bulk amounts. 

  In terms of the coating itself, some approaches can lead to structural polymorphism within the coating, which can render it difficult to consistently predict drug-release profiles, bioavailability, and efficacy while also affecting intellectual property (IP) protection and infringement. Such variations can arise during the coating process or develop over prolonged storage; hence, it is important to select a method where these factors have been studied and are well understood. 


  Liquid coating is a reliable and well-established technology that is still the industry standard for coating many APIs but it has several disadvantages. Firstly, liquid coatings must be dried to form a solid final product, a time-consuming process that often requires an increase in temperature that incurs additional cost. The use of heat may also cause thermal stress, leading to API degradation. When using liquid coating, it may also be necessary to spray the tablet core or seed particle with several layers to create the final dosage form or intermediate with the  desired characteristics. This step adds time and complexity to the procedure and can have detrimental effects on the quality of the final product by causing variability in the crystalline form or an uneven, heterogeneous coating, thereby, leading to unwanted polymorphism or defects. Besides affecting stability, performance, and efficacy, such structural variations can also have important IP implications. For example, it may be that certain polymorphic forms of the API are protected by patents, and thus, must be avoided. For these reasons, solvent-free coating technologies are of interest.


Solvent-free coating offers several advantages over the use of solvents by reducing the time and costs associated with drying liquid coatings. It can also reduce the thermal stress imposed on the API and simplify the coating process by reducing the number of steps required to reach the final product. These methods include compression coating, electrostatic spray powder coating, supercritical fluid coating, photocuring, and hot-melt coating (HMC).


Generally, when coating tablets, the APIs are initially granulated before being blended with further excipients, compressed into tablets, and finally coated. It is also possible to use these uncoated tablet cores in a second compression step designed to surround them with an additional layer containing certain functional excipients, such as a second API or an additional dose of the same API. The method is well suited for producing multi-stage treatments that combine two or more APIs, particularly if they are incompatible and must be physically separated within the dosage form, or if their mode of action requires that they are administered to different parts of the digestive system.

Perhaps the biggest drawback of compression coating is that in the second compression step, it can be difficult to position the tablet core accurately in the center of the tablet, which is important for reproducible formulation and reliable pharmaceutical performance. Various efforts have been made to circumvent this problem, leading to the development of new approaches such as the one-step dry-coated (OSDrC) tablet manufacturing system, which can reduce the likelihood that the compaction process will negatively affect tablet performance (1). The excipients must also be carefully selected. Using appropriate fillers and/or binders is essential to successfully creating a solid dosage form by compression. Finally, because many APIs and excipients are simply not compressible in their crystalline or amorphous forms, an alternative solvent-free coating methodology must be selected. 


  An advantage of spraying liquid coatings onto tablet cores is that the final product is visually appealing, creating a clean, polished, and homogenous coating. To pseudo-replicate the process but without the need for solvents, researchers have developed ways to replace liquids with dry powders. One such approach, electrostatic spray powder coating, uses powdered raw materials that have been electrostatically charged through the application of high voltage. These materials are sprayed onto a neutrally charged seed pellet and will adhere to the surface by electrostatic forces. The coating is then fixed in place by temperature or exposure to infrared radiation for approximately 1 to 2 minutes (2, 3). The main advantage of the process is that the coating forms and hardens quickly while the final product can easily be customized in terms of properties and thickness by adjusting the composition and amount of mixture sprayed on the 
tablet core prior to fixation.

For the process to work, however, the coating and tablet core must possess certain conductive properties, or be modified using additional steps to introduce electric charge. To circumvent this issue, the conductivity of the core particle can by increased by wetting it with water to decrease resistance, although this method introduces moisture into the tablet and can lead to instability. Another way to improve conductivity is to modify the surface of the API substrate using polar groups. This method is usually achieved by dissolving the polar groups in a volatile solvent before spraying the solution onto the tablet core, thereby, reintroducing a solvent step into the process. Either way, the electrostatic attraction between the solid substances tends to be weak, hence, making it difficult to produce a thick coat without multiple rounds of spraying and fixing. The fixing step also requires moderate heating, hence, increasing the energy required to carry out the method, which potentially leads to API instability. Current research is focused on finding new ways to increase the conductivity of the tablet core and lower the glass transition temperature of the coating polymer (4).


A fundamental stage in the coating process is the fixation of the coating to form a solid, protective layer. In many cases, this step involves the use of heat. This increase in temperature requires costly energy and many APIs become more susceptible to degradation as temperature increases. Photocuring attempts to avoid these problems by employing a method of fixation dependent on light energy rather than heat. As such, it does not require any heating or drying steps and is ideal for temperature-sensitive APIs. The process hinges on the use of light energy to trigger a polymerization reaction to convert a liquid or granulate surface coating into a solid material. The technique has been successfully used in pharmaceutical coating to create immediate and sustained-release dosage forms (5). 

While coating can proceed rapidly, oxygen in the ambient atmosphere can slow or halt the reaction and in some cases, must be purged from the formulation or manufacturing system using nitrogen, which adds complexity and cost to the process. While this technique has clear applications for heat-sensitive compounds, it is unsuitable for excipients or APIs that are photosensitive. Moreover, the process is expensive and is still in early phase development.


One way to avoid the downsides of traditional liquid coating is to use supercritical liquids, which have properties between liquids and gases along a continuum that can be manipulated. Like liquids, they can be used to dissolve the excipients and API, thereby facilitating the mixing and formation of a homogeneous coating. Carbon dioxide is most widely used because of its low critical temperature (31 °C) and pressure (74 bar), making it easy to manipulate under manufacturing conditions. The major benefit compared with standard liquid coating is that supercritical liquids can be rapidly transitioned to the gaseous phase by a reduction in vessel pressure, causing the excipient mixture to precipitate and form a solid. Unlike solvent-based methods, the technique leaves no residue and does not require any heating or drying steps. 

Supercritical liquid coating has so far proven to be effective for coating of fine particles. The supercritical liquid solvating power can be controlled by small changes in temperature or pressure, thereby, enabling the fine-tuning of coating properties (6). However, for the process to work effectively, the core particle onto which the coating forms must be insoluble in the supercritical fluid. In addition, high-pressure equipment is required to carry out the process, which adds further cost to an already expensive approach. 


  Despite the various methods available for coating traditional dosage forms that improve taste, mouth-feel, and ease of swallowing, many patients still complain that swallowing tablets and capsules is painful and unpleasant. According to a large pan-European study, more than 25% of a particular general practitioner’s patients complained of swallowing difficulties (7). 

Orally disintegrating granules (ODGs) are user-friendly dosage forms designed to meet patients’ needs, improve adherence, and increase treatment effectiveness. ODGs provide value for patients as they rapidly dissolve in the mouth, thereby circumventing any issues with swallowing. They can also be quickly and easily administered without the need for water and are much simpler to administer to children and the elderly. As they are not constrained by physical size, ODGs can also be formulated to contain larger amounts of API and/or multiple APIs in a single dose, simplifying treatment regimens. 

The effective coating of APIs for ODGs is dependent on many factors. Solvent-based coating is applicable for ODGs, but suffers from heating, drying, and potential stability complications while most organic solvents inherently pose various health and environmental risks. Although several solvent-free approaches have been used with some success for coating ODGs, especially electrostatic spray powder coating, most of them are time-consuming and expensive, often leading to a final product that does not adequately mask the bitter taste of most APIs. In addition, many approaches are not practical for coating large numbers of small granules. For example, compression coating is better suited for coating larger tablets. While new approaches such as supercritical liquid coating and photocuring may offer an effective way to coat ODGs, both methods are still experimental, expensive, and impractical for scale-up. 

In an effort to avoid the use of solvents and identify coating methods that might be suitable for ODGs, there has recently been significant research and development into novel methods of pharmaceutical coating. One such technology, hot-melt coating (HMC), is gaining popularity as it offers short processing times (typically under 1 h) and significantly lowers costs compared to other solvent-free methods. HMC avoids the use of solvents by instead utilizing molten mixtures, which are sprayed onto solid particles usually using a fluid bed coating setup. This mixture then solidifies upon cooling to form a protective coating around the seed particle containing the API. The excipients most suitable for HMC include lipids, waxes, fatty bases, and hydrogenated vegetable oils, as they are easy and quick to process, cost-effective, and have relatively low melting points (below 100 °C). 

Compared to other solvent-free coating methods, HMC is particularly well suited for taste masking and careful manipulation of API release (8), making it ideal for formulating ODGs. By carefully selecting excipients based on molecular flexibility, hydrophobicity, melting point, molecular weight, and rigidity, as well as optimizing their relative concentrations, it is not only possible to fine-tune the release profile of the API to provide sustained or delayed release but also to provide immediate release products (see 

Although HMC can be carried out using a variety of methods and common manufacturing equipment including fluidized bed and spray coating, optimization of the protocol for each API/excipient mixture takes skill, knowledge, and experience. Air-flow, spray rate as well as spray and product temperature must be carefully controlled during the process to enable to successful melting and solidification of the excipient mixture to create a pleasant tasting, homogenous coating with the desired API release characteristics. These parameters are important and when the process is carried out correctly, dosage forms coated using HMC do not suffer from some of the polymorphic variations (and associated challenges) that other coating methods may exhibit. 

It is important to create formulation and manufacturing processes that embody quality-by-design (QbD) principles to enable a seamless transition during scale-up, and at the same time employ process analytical technology (PAT) that measure HMC parameters, such as coating thickness, to enable their accurate correlation with final product characteristics. Offline methods, such as scanning electron microscopy, can also be used to assess product quality, because they enable the surface and coating layer of ODGs to be visualized (see 


  While HMC is a suitable API-coating method for producing ODGs with delayed- or sustained-release profiles, optimizing the process for producing rapid-release medications such as analgesics has proven to be a challenge. A team at Hermes Pharma is collaborating with the Research Center Pharmaceutical Engineering GmbH (RCPE), INNOJET Herbert Hüttlin, CREMER Oleo GmbH & Co. KG, and the Karl Franzens University to identify and develop HMC parameters for producing such fast-acting medicines. The goal of the project is to develop new pharmaceutical formulations and manufacturing processes, and engineer new approaches and manufacturing controls for effective masking of the unpleasant tastes and smells associated with most APIs. 

Preliminary results from the ongoing project have highlighted that the production of fast-release medicines using HMC is feasible and amenable to scale-up. The transfer of the technology into production is underway. In several proof-of-principle studies, the parameters for formulating ODGs containing fast-acting APIs were successfully identified. The proof of concept studies included many different lipids, such as mono-, di- and triacylglycerides with varying carbon chain length (C14 to C22). In addition, more than 10 emulsifiers were tested. The resulting dosage forms provide rapid dissolution characteristics, similar to those of film-coated immediate-release tablets. Importantly, the granules are pleasant tasting and easy for patients to ingest. The HMC approach at Hermes is being extended to formulate other fast acting medicines such as ODGs, with the method expected to be fully validated and available for use by pharmaceutical developers in the near future.


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Detlev Haack, PhD, is director of R&D, and Martin Koeberle, PhD, is senior manager, analytical development, both at Hermes Pharma, Georg-Kalb-Strasse 5-8, 82049 Pullach, Germany.

The benefits of solvent-free processes and techniques specifically optimized for coating new dosage forms such as orally disintegrating granules are reviewed.