Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

Many petri dishes with calcium carbonate powder on white table | Image Credit: ©New Africa - stock.adobe.com

Coprocessed excipients are increasingly being used as an innovative and effective solution to overcome API challenges and reduce formulation complexity in direct compression (DC) applications. That is because coprocessing often enhances the properties of those excipients in ways that cannot be achieved if they are processed individually and then mixed together. In addition to improving processabiilty and product performance, coprocessing simplifies many aspects of tablet and capsule formulation and manufacturing and affords numerous business-related benefits.

It is important to highlight that coprocessed excipients are engineered materials designed to address specific pharmaceutical formulation and drug-delivery challenges, according to Joao Marcos Assis, global technical marketing manager at BASF Pharma Solutions. Their manufacturing involves processing of the individual ingredients using different pharmaceutical processes, leading to improved material properties. Their production does not, however, involve the formation of new covalent bonds between the components. Each ingredient maintains its individual chemical fingerprint and toxicological profile. As a result, coprocessed excipients should not be considered as novel ingredients but new ingredients. In addition, coprocessed excipients undergo rigorous testing and regulatory evaluation to ensure patient safety and effectiveness.

For all of these reasons, there is growing focus on the development and use of coprocessed excipients engineered to address top formulating problems including poor API processability, solubility, bioavailbility, and stability in many dosage forms.

The area in which coprocessed excipients have found the widest use is the formulation of coating premixes. “Preparation of coating solutions with consistent quality is often challenging due to their complexity. The use of ready-to-use preparations helps address this issue,” explains Philip Schäfer, head of process and formulation materials at MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany.

Coprocessed excipients are commonly found in oral solid dosage formulations. In this application, these ingredients are intended to be blended with the API to ensure appropriate processing behavior and the desired final product performance. There are, according to Assis, coprocessed excipients for use in immediate-release, sustained-release, and orally dispersible disintegrating tablets (ODTs), as well as for basic tablet and capsule applications.

Coprocessed excipients have enhanced functionality and performance compared to their individual components. “The combination of excipients in coprocessed excipients often results in synergistic effects that can address specific formulation challenges because of the improved characteristics, such as good blending properties, enhanced flowability, compactability, tabletability, superior lubrication, disintegration, and dissolution for faster and robust manufacturing processes of oral dosage forms,” Assis observes.

Typical functionalities used to generate combined excipient systems include fillers, binders, disintegrants, and lubricants. In ODT formulations, for instance, excipient systems generally combine fillers with disintegrants and/or lubricants, according to Schäfer. “A coprocessed excipient, which already includes a (super)disintegrant but at the same time yields robust and hard tablets by including a binder, can help to streamline formulation development while ensuring a consistent manufacturing process and output,” he notes.

Fillers generally comprise the major component of coprocessed excipients and work as bulking agents. The tableting and compression characteristics of lactose, microcrystalline cellulose, mannitol, dicalcium phosphate, and other fillers are improved by processing them with other ingredients, Assis comments.He adds that binders present plastic deformation characteristics and are responsible for particle binding, improving tablet strength. Povidone, copovidone, hydroxypropyl cellulose (HPC), (hydroxypropyl)methyl cellulose (HPMC), and polyvinyl alcohol-polyethylene glycol (PVA-PEG) copolymer are examples.

Disintegrants such as sodium croscarmellose, sodium starch glycolate, and crospovidone, Assis continues, promote tablet breakup, reducing disintegration time and increasing drug dissolution. Lubricants, meanwhile, reduce ejection force during tablet compression, with sodium stearyl fumarate preferred for coprocessed excipients due to its greater hydrophilicity, compatibility with APIs, and robustness to over-lubrication, according to Assis.

Coprocessed excipients come in many variations, as do their manufacturing techniques. In general, however, Assis stresses that standard pharmaceutical unit operations are leveraged under mild processing conditions to minimize chemical and physical instabilities. “In formulating a coprocessed material, potential chemical reactions between the ingredients must be considered, since neither new covalent bonds nor potential incompatibilities are desired or acceptable,” he says.

Common processing methods noted by Schäfer include spray drying, cogranulation, mixing, coextrusion, comilling, and cocrystallization. Assis adds that cogranulation can be achieved via fluid-bed granulation, high-shear granulation, dry granulation (roller compaction), or melt granulation. He also points to coprecipitation as another method for the generation of coprocessed excipients with improved functionalities.

“When selecting a manufacturing approach,” emphasizes Schäfer, “it is essential to identify a production strategy that creates a stable, homogeneous blend of the components and affords reliable, multi-functional performance without changing the chemical structure of the excipients employed.”

Indeed, when developing a coprocessed excipient, the main objective is to enhance its material properties, combining the most relevant functionalities, such as filler, binder, disintegrant, and lubricant, in a single material to improve drug processability while ensuring excellent product performance, according to Assis. “These enhanced excipient assets result in manufacturing cost savings, faster drug development, and reduced time-to-market,” he contends. Properties that are often enhanced include flowability, particle size distribution, blending behavior, storage stability, compressibility, and batch-to-batch consistency.

Another key benefit of coprocessed excipients is their ability to simplify formulation development and final product manufacturing. “Using coprocessed excipients reduces the number of ingredients in the formulation, simplifying development and consolidating quality-by-design (QbD) efforts. It also minimizes testing expenses by reducing quality control analysis, material handling, and documentation requirements,“ Assis explains.

Further drivers for use of excipient combinations highlighted by Schäfer include their ability to solve unmet formulation and delivery challenges, improve process efficiency, and enable new manufacturing approaches such as continuous processing, all while providing improved process economics. “In addition to combining different functionalities in one product and supporting a highly efficient and effective approach to drug development, coprocessed excipients provide flexibility to adapt formulations to specific needs,” he says.

Schäfer goes on to note that because the performance of coprocessed excipient systems is typically tailored to be robust and consistent, they are particularly well suited for processes that are highly dependent on performance parameters, such as continuous manufacturing.

In many cases, in fact, Schäfer observes that excipient systems are developed to solve a specific challenge, which may be as simple as reducing the number of process steps (e.g., the number of feeders, which is limited by the process set-up) or improving process parameters such as flow or sticking of formulations to equipment. The fact that the use of coprocessed excipients typically require less formulation and process know-how and reduces the risk of errors throughout is yet another benefit.

There are also business advantages to using coprocessed excipients, according to Assis. Beyond R&D and production benefits, these include purchasing and warehousing benefits due to a reduction of the number of excipients and excipient vendors, which reduces sourcing complexities and frees up expensive storage space, and quality and regulatory benefits from minimization of testing efforts and expenses, which reduces paperwork.

Given all of these advantages, it is not surprising that formulators are increasingly open to using coprocessed excipients. “We have observed that formulators today are more willing to explore combined excipients during product development. In part, this interest is likely due to the fact that APIs are becoming more and more challenging, particularly with respect to poor solubility, at a time when the pressure for realizing successful drug development in much less time is rising. Traditional excipients alone may not be able to overcome these hurdles,” Schäfer says.

For oral solid dosage forms, DC is the preferred manufacturing method as it is the simplest and contributes to reduced time and cost for production. For many novel APIs under development today, however, DC is not easily implemented due to their unfavorable characteristics such as high cohesiveness and poor flow and compressibility, according to Assis. In these cases, DC processes require the use of multiple excipients to obtain suitable material flow, compressibility, and efficient lubrication.

“Determining the proper excipient combinations and concentrations is often time-consuming and expensive, however. Even after optimizing the mixture of excipients, the formulation requires several processing steps to create the final blend. Formulations based on coprocessed excipients are a solution to these challenges,” Assis explains.

“All-in-one” excipient systems that combine multiple excipients into a single material have thus become a recent focus in the market, Schäfer observes. In these products, all of the basic tableting excipients are combined such that only one additive and the API are included in the final formulation.

“This approach reduces significantly the number of excipients necessary to achieve excellent processability and performance and requires a single dry blending with the API using standard process equipment. Consequently, all-in-one coprocessed excipients reduce drug product development time and manufacturing complexity and may significantly expedite time-to-market,” Assis adds.

The use of coprocessed excipients can vary depending on the properties of the API, the therapeutic requirements, and the desired formulation characteristics. In addition, formulators carefully evaluate and select coprocessed excipients to ensure they meet safety, efficacy, and regulatory standards before integrating them into pharmaceutical products, according to Assis.

One of the most important trends being enabled by coprocessed excipients is direct compression continuous manufacturing (DCCM). “Coprocessed excipients can facilitate more effective DCCM processes due to their excellent blending properties, flowability, and tabletability and minimization of the required number of gravimetric feeders and complexity of the process,” Assis notes.

Specifically, Assis highlights several benefits of coprocessed excipients for DCCM processes. The reduced number of ingredients in the formulation implies a faster material characterization and simplified design-of-experiment approach, reducing time and costs. Due to the high flowability, feeding performance in a gravimetric loss-in-weight feeder is enhanced with fewer perturbations. Development of an online process analytical technology (PAT) method is streamlined because of the reduced number of spectra and the analysis is less variable and more predictive. Besides, a dynamic residence time distribution (RTD) model of the API in a mixture with a single all-in-one coprocessed excipient can be more precise.

A second notable trend is the coprocessing of APIs with excipients, in other words coprocessed formulated drug products. This approach is being explored as a means for overcoming manufacturing challenges associated with DC formulations, Assis says.

Drugs can be pre-blended with excipients such as fumed silica, dry-granulated, or processed with low-melting point materials including poloxamers (P 188 or P 407), high-molecular PEGs (3350, 6000, 8000), and low-molecular-weight povidones (PVP K-12 or K-17) via melt granulation or melt coating using an extruder, according to Assis. Stearic acid, polyvinyl acetate, and other waxes, meanwhile, can be used for sustained-released products. “Coprocessing the API and the excipients can result in better particle shape, flowability, compressibility, stability, and dissolution, as well as taste improvement,” he contends.

Aside from these two trends, Assis highlights efforts by both pharmaceutical companies and excipient manufactures to create new coprocessed excipients with enhanced functionalities, particularly coprocessed excipients that can improve solubility, bioavailability, stability, and overall drug performance.

These improved properties have enabled coprocessed excipients to play a growing role in the development of advanced drug delivery systems, including controlled-release formulations, multi-particulate systems, and amorphous solid dispersions. “Coprocessed excipients have also been explored in topical and transdermal drug delivery systems, facilitating drug penetration through the skin and improving localized drug delivery while providing easy and fast processing,” Assis comments.

In addition, coprocessed excipients have been used to improve patient compliance by enabling the development of easier-to-swallow tablets, taste-masking formulations, and other patient-friendly dosage forms, according to Assis. He also notes that collaborations between drug manufacturers and excipient companies focused on the development of innovative coprocessed excipients for specific drugs and therapeutic areas have increased in number in recent years.

Although formulators are now more open to coprocessed excipients than they were in the past, the regulatory landscape can still prove to be an obstacle. In contrast to traditional excipients, coprocessed excipients have no dedicated pharmacopoeia monographs and are treated almost as novel by regulatory authorities if not yet used in already approved drug products, Schäfer observes. As a result, there is some regulatory uncertainty for new coprocessed excipients because they can only be introduced as part of a new drug application. “Today, many pharmaceutical companies are hesitant to take on this increased effort and risk,” Schäfer comments.

Regulatory authorities are, however, aware that there are limitations to the ability of traditional excipients to solve current formulating challenges and that new excipient combinations can provide significant benefits in bringing a much-needed therapy to the market, according to Schäfer. He adds that activities are ongoing to improve the situation for coprocessed excipients, such as the joint IPEC, European Fine Chemicals Group, Active Pharmaceutical Ingredients Committee (a sector group of the European Chemical Industry Council) initiative regarding European Union Excipient Master Files. “We expect that the regulatory situation for excipient combination will be eased in the future, opening up many new opportunities in the pharmaceutical sector,” Schäfer concludes.

Cynthia A. Challener, PhD, is a contributing editor to 


Vol. 47, No. 9
September 2023
Pages: 18-21

When referring to this article, please cite it as Challener, C.A. Formulating with Coprocessed Excipients: Current Trends. 

Articles

Coprocessed excipients save time and cost while improving performance in a widening array of dosage forms.

Formulating with Coprocessed Excipients: Current Trends

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Creating pediatric formulations with appealing taste and appearance has been a challenge since drugs were developed specifically for children. With regulations in the United States and Europe now requiring that palatability be addressed by pharma companies during clinical development of pediatric formulations, this issue has grown in importance. Patient adherence must be top of mind when formulating pediatric dosage forms, which cannot be achieved simply by reducing the size of an adult dose. Variables such as the age and weight range of the patient population, speed of symptom onset, liver enzyme function, swallowing capabilities, and ease of administration must be considered.

The most desirable attributes of pediatric formulations, says Joao Marcos Assis, global technical marketing manager at BASF Pharma Solutions, include acceptable taste and dosage form (typically oral), dosing flexibility, convenient and reliable administration, minimal manipulation needed by healthcare givers, minimal dosing frequency, minimum use of nontoxic excipients, and simple manufacturing processes that generate affordable and stable products (1).

Ultimately, an understanding of how to formulate for appropriate dose flexibility and patient compliance, along with an awareness of global regulatory changes regarding excipients, is needed to ensure a successful pediatric product, states Adam Hopper, president of the drug product business unit at Cambrex.

Pediatric drug formulations pose several unique challenges compared to adult drug formulations. These challenges arise due to the physiological and developmental differences between children and adults, according to Assis. In addition, age-appropriate pediatric-specific formulations and dosage forms that fit children’s needs at different ages are of the uttermost importance, adds Philip Schäfer, head of process and formulation materials at the Life Science business of Merck KGaA, Darmstadt, Germany. Furthermore, acceptance and preferences highly vary between children and are strongly influenced by several individual factors such as their socialization (2).

Dosage form selection can be particularly difficult, as children often have trouble swallowing tablets and capsules, Assis observes. The task is made more difficult for liquid dosage forms or formulations that disintegrate within the mouth due to the bitter taste of many APIs. “Drug size, texture, mouthfeel, smell, taste, and for liquids, viscosity and color, play an essential role in the child’s acceptability and adherence to treatment,” he notes.

Furthermore, precise dosing must be achieved based on age, weight, and body surface to reduce the risk of medication errors, which can be challenging due to the significant variability in drug absorption, distribution, metabolism, and excretion children exhibit compared to adults. Small volumes may be needed, such as for parenteral formulations administered to neonates, and potential modification of dosage forms in the home setting (crushing tablets, mixing with food, etc.) must also be factored into formulation designs, Schäfer comments.

Excipient selection must also be carefully considered, as there are excipients tolerated and widely used in adult formulations that can cause adverse effects in the pediatric population, according to Schäfer. He adds that impurities in excipientsmust also be controlled, as some have been known to cause severe consequences for children. To ensure safety and efficacy, Assis points out that pediatric formulations may therefore require additional studies to establish safety profiles and optimal dosing regimens.

Regulatory agencies require pharma companies to develop age-appropriate formulations. For oral dosage forms—solutions, suspensions, orally disintegrating tablets, and multipartculates (powders, granules, minitablets)—palatability remains the primary challenge, states Jeff Worthington, president and founder of Senopsys.

Taste is particularly important to children. Assis points to a survey conducted by the American Association of Pediatrics in 2023 that found unpleasant taste to be the most significant barrier to completing treatment for pediatric patients (3). “Acceptability, palatability, and ease for the caregiver to administer the medicine contribute to whether or not a child will ultimately take a medicine,” he says. Palatability includes not only taste, but the size of a tablet, the pH, texture, and volume of a liquid formulation, Hopper adds.

Many drugs are known to be bitter, some extremely so, or have other aversive sensory attributes including malodor and irritation, Worthington remarks. Each have fundamentally different perception pathways and importantly, require different amelioration approaches or technologies. “There are more technology approaches for managing a low or moderate taste masking challenge than a difficult one. For an extremely bitter drug active, it may be necessary to ‘sequester’ the API from taste receptors via particle coating, complexation, encapsulation, or other means,” he explains.

While product appearance is generally of minor concern for drug products unless required for placebo color matching or masking an aversive API color, it can be important in pediatric applications, according to Schäfer. “It is important that the appearance of medications is clearly distinguishable from candy in order to avoid mix-ups which could expose children to a high safety risk,” he explains. In the case of bitter-tasting APIs, Schäfer contends that formulators should ensure that the taste does not attract children too much; the final taste of pediatric formulations should thus be more neutral than sweet.

Bitterness is not only a challenge with respect to overcoming this undesirable taste experience. There are also significant challenges to predicting if new compounds are bitter, according to Assis. He does note, however, that the process for identifying bitter APIs has rapidly progressed in the past few years.

Assis points to BitterDB, a free database with more than 1000 naturally bitter and synthetic compounds available to formulators, as one example (4). Machine learning algorithms trained with these known bitter API molecules are leveraged to predict the bitterness of new compounds. Based on such predictions and additional physiochemical API properties, pharmaceutical formulators can proactively select taste-masking technologies. In addition to advanced digital technologies, trained human panels are still employed to test and optimize taste-masked formulations.

Another important issue in formulation of pediatric medicines is the need to maintain bioavailability while formulating to mitigate bitter taste or undesirable appearance, notes Hopper. “Successfully achieving this goal requires balancing solubility, molecular size, lipophilicity, and overall acidic strength—all of which impact the overall bioavailability,” he comments. Another consideration is how different patients may respond to medications, as liquid and tablet formulations can be held in the mouth for varied times.

In fact, palatability is comprised of four elements—basic tastes (sweet, sour, salty, bitter, and umami); aroma (fishy, oxidized oil, orange, grape, mint), trigeminal irritation (chemesthesis or mouthfeel); and texture (hardness, fracturability, grittiness), according to Worthington. “Each have different biological perception pathways that require tailored approaches to overcome,” he explains.

Bitterness is, as a result, not the only challenge in creating palatable, patient-accepted drug products. Senopsys compiled data from 150 API taste-assessment studies the company completed (excluding over-the-counter drugs). The primary taste masking challenge was bitterness for nearly 70% of the APIs (mostly new chemical entities) (5). Of the other basic tastes, sour and salty were problematic for 3% and 4% of APIs, respectively.

Aversive odors (“aromatics”) were the primary sensory challenge for approximately 7% of APIs, according to Worthington. Some descriptors of these malodors included “phenolic” (like Band-Aids), “sulfidy” (overcooked cruciferous vegetables), “oxidized oil” (like old paint), and “solventy” (e.g., acetone, or ether-like).

The primary challenge for another 4% of the APIs was a strong intensity trigeminal irritancy such as oral or throat burning, numbing, and tongue sting. Finally, 16% of APIs were fundamentally tasteless, but their challenge was driven by the negative sensory attributes of the excipient system (e.g., surfactants, co-solvents, and solubilizers).

Worthington also notes there is a general misconception that most APIs have a single aversive attribute, but that is not the case. Secondary taste masking challenges for those same 150 APIs are heavily represented by aromatics (malodor), followed by trigeminal irritancy, sour and salty basic tastes, “other” (e.g., aversive mouthfeels and textures), and bitter basic taste (5).

High-dosage drugs, meanwhile, are more challenging than low-dose formulations and typically require a combination of more advanced and efficient taste-masking strategies, such as particle film coating, Assis contends.

It is also worth noting, according to Assis, that previous approaches relying on the use of sweeteners or viscosity-modifying agents to suppress API bitterness generally have not been preferred by patients, as they generally require high concentrations of sweeteners, leading to a metallic taste. “Patients are even more opposed to both sweet-bitter sensations on the tongue, and many viscosity-modifying agents are not entirely tasteless or can provide an unpleasant texture,” he adds.

Addressing the palatability challenge for pediatric formulations, says Worthington, depends on the physical and chemical properties of the API, the dosage form, and the specific taste masking needs. He outlines five broad taste-masking approaches that are employed to improve palatability, including signal interruption, using flavor systems, altering the form of the drug substance, complexing the API, and physically encapsulating the API.

Still in the research stage, signal interruption uses an antagonist to inhibit taste via ligand binding, according to Worthington. Taste masking via the use of flavor systems is a common approach, but can be insufficient for particularly challenging actives. Modifying the active molecules as a prodrug, freebase or salt can be effective, but extends development timelines, may cause pharmacokinetic changes, and may still require the use of masking technologies. Complexation traps the API in a chemical matrix to hide it from the taste buds, but generally results in decreased drug loadings, may also cause pharmacokinetic changes and is generally limited to solid forms. Application of a physical barriervia encapsulation has similar limitations.

Assis reiterates that the taste of an API is pronounced if the drug is solubilized in saliva and able to interact with the taste buds, and thus less soluble APIs have a lower aversive taste than highly soluble ones. In addition, he notes that micronized drugs have more chance to interact with the taste receptors within the mouth. For such APIs, “using a more palatable prodrug or salt and a less soluble polymorph or unionized form to reduce drug-taste bud interactions can be alternative,” he says. He also points out that pharmacokinetic and bioavailability properties might be negatively impacted, and thus changes must be made with careful consideration to the effects they may have on other drug-substance attributes.

While formulation challenges with respect to taste, palatability, and appearance differ depending on the API and dosage form, all approaches have the same aim, according to Schäfer, and many rely on same or similar excipients.

High-intensity sweeteners such as neotame and sucralose, for example, offer benefits for any formulation type as they are safe, sugar-free, non-cariogenic, and effective in cost and use due to their high sweetness potency in both liquid and solid formulations, Schäfer comments. Mannitol, meanwhile, is also popular in pediatric formulations because it provides superior mouthfeel, which is particularly important for orally disintegrating tablets (ODTs).

There are some disadvantages to using excipients. Often a trial-and-error approach might be needed to identify the best mix of flavors and other additives to hide the bitterness of a particular API in a particular dosage form. In addition, all excipients, Assis says, should be evaluated for potential allergic and other side effects, particularly those that do not provide efficient masking effects and need to be used in large quantities. As a result, formulation development timelines can be extended.

Functional film coatings are used to prevent direct contact of the drug substance with the tongue, thereby avoiding an unpleasant taste sensation, according to Assis. Reverse-enteric polymers, such as methyl-methacrylate and diethylaminoethyl methacrylate copolymer (from BASF) are used for this purpose. “These film coatings are not soluble in saliva pH (pH 6.2 - 7.0), so they maintain the drug covered by the polymer. After swallowing, the film is immediately solubilized in the stomach for fast API release, allowing drug dissolution out of the coated core and its absorption in the stomach and intestine,” he explains.

These types of polymers can be applied to cover API particles, granules, pellets, tablets, and minitablets. The coating process can be performed using organic solutions or polymeric dispersions or suspensions in standard equipment like fluid beds and drum-coater machines, according to Assis. It is also possible to obtain coated particles through microencapsulation, high-shear granulation, melt coating, and spray drying.

Because the polymers have a high molecular weight, absorption is not expected, ensuring safety. Film-coating technology can be used for very strong APIs at low or high doses. One potential disadvantage is that solid drug formulations with large surface areas may involve lengthy coating processes. Optimization is possible, however, using a well-designed formulation and process parameters, according to Assis.

Lipophilic polymers such as ethyl cellulose and hydrophobic components such as carnauba wax are other alternatives, but they can impact drug absorption due to excipient insolubility and possible delayed release, Assis comments. “In addition to the need to confirm effective drug masking, formulators should guarantee complete drug solubilization and absorption to ensure bioavailability using suitable excipients,” he adds.

There are some potential disadvantages of API sequestration that Worthington notes. “Particle coating results in an increase in particle size that can result in a gritty texture. The presence of particulates can also encourage chewing as part of normal oral processing, which can lead to coating rupture and release of the API into the oral cavity. Multiparticulate formulations, if added to foods with physicochemical properties (e.g., pH, water, sugar, fat, and flavor content) that can interact with pH-sensitive polymers, may also have a negative effect on palatability,” he explains.

New dosage forms are improving the viability of oral solid dosage forms for pediatric use. Hopper points to advances in mini-tablets, multi-layer beads, and ODTs, all of which allow for dose flexibility and improved compliance due to improved palatability and ease of administration. “These new innovation areas make flexible dosing based on age and weight possible, leading to increased dosage form acceptability and safety,” he observes.

Schäfer highlights oral thin films, which he says have become more popular due to their ability to overcome swallowing difficulties associated with traditional oral solid dosage forms while also enabling taste masking. Mini-tablets, he adds, have been shown in some studies to be superior to liquid formulations (6).

Titanium dioxide is widely used in tablet formulation as a white colorant and opacifier to ensure a uniform appearance. Toxicological concerns about nanoparticulate titanium dioxide and its ban from use in foods and nutritional supplements in the European Union have led to increased interest in suitable alternatives to titanium dioxide for use in drug products, Schäfer observes. MilliporeSigma has for this purpose developed a particle-engineered calcium carbonate with a unique morphology and designed particle size distribution that provides uniform tablet finishing and good opacity.

Using novel excipients can be challenging given the lack of a separate approval pathway. Currently, new excipients can only be approved within a drug formulation, and drug developers are generally hesitant to risk approval by using a novel excipient.

FDA’s Center for Drug Evaluation and Research (CDER) has launched a new pilot program for the review of novel excipients. BASF and Senopsys support CDER’s pilot program. “Many pharmaceutical technologies and excipients trace their roots to the food industry. Co-processes, sustained-release flavor and sweetener systems like those used in confectionary and chewing gum products could potentially be used with great effect in drug products, particularly with APIs with long aftertastes, such as clarithromycin and many others. Such excipient developments have been to date hindered by the current lengthy approval pathway,” says Worthington.

Signal interruption, one of the five main approaches to improving palatability noted by Worthington remains, he says, a “Holy Grail” of taste masking. Bitterness is detected by a family of several dozen receptors (TAS2Rs), and APIs generally activate multiple TAS2Rs simultaneously, making development of signal interruption solutions challenging.Bitter blockers work by biochemically interfering with the taste transduction from the mouth to the brain via an antagonist that inhibits a specific bitter receptor site, blocking the taste cascade (interrupting the G-protein coupled receptor, or GPCR, signal cascade) (3), notes Assis.

This approach is challenged by the large number of different bitter taste receptors and their high genetic diversity. Trial and error is often required to identify compounds that follow the same receptor pathway as the API, leading to longer development times, Assis notes. There are novel compounds under development that act as antagonists to these receptors, Worthington notes, but the technology is still in its infancy, and the regulatory risk is high and commercialization timelines are unknown.

Schäfer is interested in the potential of three-dimensional (3D) printing for the production of pediatric medications, as it offers the opportunity for tailored dosage forms and can be implemented for the manufacture of age-appropriate solutions. Assis adds that 3D-printing technologies enable the manufacture of pharmaceutical dosage forms according to patient requirements, such as dose, release profile, color, texture, and size, which are all highly relevant to pediatric drugs. “With production via direct powder or filament-based extrusion combined with a functional taste-masking polymer or a lipidic, this approach can provide the right taste-masking,” he states.

For parenteral pediatric products administered in a clinical setting, there is a need for technologies that enable the administration of higher doses in smaller volumes to children, according to Schäfer. One new development in this field is MilliporeSigma’s Viscosity Reduction Platform, which allows for highly concentrated, small-volume protein formulations to be administered to patients.

The most challenging topic when formulating a pediatric drug is developing suitable options to overcome swallowing issues with an appropriate taste for better convenience and compliance. Worthington agrees that palatability and swallowability will continue to be a challenge for not only pediatric populations, but increasingly for geriatric and special needs populations as well.

Easier-to-swallow dosage forms, however, increase the opportunity for contact with oral cavity receptors—gustatory (taste buds), smell (olfactory receptors), and irritation (chemoreceptors). “Accordingly,” observes Worthington, “many of these alternative, age-appropriate dosage forms have increased palatability challenge compared to traditional tablets and capsules.”

“Defining the most efficient taste-masking approach to hide or minimize the unpleasant taste of a drug, aiming to improve patient adherence to treatment when taste is the main reason for non-compliance, still needs further understanding and research,” Assis contends. Improvements in taste masking and bioavailability enhancement, Hopper believes, will continue to be critical. “As our understanding of how the pharmacokinetics can change within different age populations, it will make flexible dosing and potentially different release profiles even more important,” he states.

Litalien, C.; Bérubé, S.; Tuleu, C.; Gilpin, A.; Landry, ÉK; Valentin, M.; Strickley, R,; Turner, MA. From Paediatric Formulations Development to Access: Advances Made and Remaining Challenges. 

Mennella, J. A. and N. K. Bobowski. The Sweetness and Bitterness of Childhood: Insights from Basic Research on Taste Preferences. 

Walsh, J.; Cram, A.; Woertz, K.; Breitkreutz, J.; Winzenburg, G.; Turner, R.; Tuleu, C.. European Formulation Initiative. Playing Hide and Seek with Poorly Tasting Paediatric Medicines: Do Not Forget the Excipients. 

Wiener, A.; Shudler, M.; Levit, A.; Niv, MY. BitterDB: A Database of Bitter Compounds. Nucleic Acids Research. January 2012.

Klingmann, V., H. Linderskamp, et al. Acceptability of Multiple Uncoated Minitablets in Infants and Toddlers: A Randomized Controlled Trial. 

Cynthia Challener, PhD is a contributing editor for Pharmaceutical Technology Group.


Vol. 47, No. 8
August 2023
Pages: 20–25

When referring to this article, please cite it as Challener, C. Overcoming Challenges to Formulation Development for Pediatric Medicines. 

The biggest hurdle is developing palatable formulations that are efficacious and patient friendly. 


Overcoming Challenges to Formulation Development for Pediatric Medicines

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Highly potent drugs exhibit a combination of high toxicity and therapeutic efficacy at low doses. They also often suffer from poor aqueous bioavailability, have specific release requirements to minimize potential toxicological effects, and bitter taste. As such, they present formulation challenges, including selection of necessary and appropriate excipients such as solubility and permeation enhancers to improve bioavailability, polymeric excipients to modify release profiles and flavor compounds to mask taste, according to Marcus Jenkins, Technical Consultant with SGS.

Analysis of high-potency formulations can also be difficult. The main analytical in-vitro release tests required for pharmaceutical drug products are confirmation of identity and quantification of the drug substance and impurities, as well as performance tests, such as determination of dissolution behavior for solid-dose products. In addition to the use of numerous and varying excipients, dose-form design and solubility pose specific challenges for analytical method development and implementation for highly potent drug formulations.

SGS has worked with many different highly potent drug formulations, and each has presented its own set of challenges. Two examples include a thyroid hormone product and a highly potent drug candidate dosed in the microgram range.

For the thyroid hormone product, solid-phase extraction (SPE) technology was used to reduce excipient interference. Initially, reproducible recovery of the drug was challenging when using low rinse volumes to maintain the required concentrations for analysis, according to Marcus Jenkins, Technical Consultant with SGS, as the loss of even small amounts of drug substance during sample preparation resulted in a large percentage decrease in its assay result. “Fortunately,” he says, “SPE technology has advanced and today more reliably prepared cartridges with a wide range of stationary phases are now available that allow analysis of drug substances with different physicochemical properties.”

The drug candidate dosed in the microgram range severely limited sample dilution. In fact, a higher concentration was required for impurity analysis to maintain the necessary level of sensitivity and ensure that low-level impurities could be effectively quantified. In addition, the use of dedicated glassware was necessary to avoid contamination and ensure no additional compounds (drugs or excipients) from other ongoing projects could interfere with the analysis. Dilution was then performed prior to analysis of the drug substance assay.

There are a few main analytical challenges that developers of highly potent drug formulations face. First, the high potency and low concentration of the drug substances in these formulations make it necessary to limit sample dilution in order to achieve suitable nominal concentrations for testing. “While the limitations will depend on the physicochemical properties of each drug substance, low sample dilution typically results in high excipient contributions to samples when they are tested,” Jenkins comments.

Low sample dilution may also enable greater external interference of samples via contamination from glassware, processes, or equipment. Such an issue is generally not observed for higher-dose products because the low levels of contaminants present are often diluted out of testing concentration ranges, according to Jenkins.

A second issue is the level of sensitivity needed for effective impurity analysis. “Due to the low doses for highly potent drugs, analytical testing concentrations will often be low and thus provide a challenge to the sensitivity of any method or equipment used,” Jenkins states. The use of higher sample loading to improve the response and sensitivity for low-dose products creates the third challenge, which is that larger injection volumes increase the quantities of injected excipients.

This approach can not only result in reduced equipment lifetimes, but also require the addition of extra cleaning steps, contributing to increased equipment downtime and reduced throughput and capacity in testing laboratories, Jenkins adds. Furthermore, to minimize or eliminate excipient interference requires additional preparation steps, which lengthen the process and increase complexity, potentially leading to greater variability.

Last but not least, to ensure the safety of operators and the environment, handing of highly potent drug samples must be pursued with the proper controls in place, which can include containment such as hoods or isolators. Jenkins notes that this additional complexity can also introduce variability to testing processes.

Excipients cause concern during uniformity determination

For highly potent, low-dose drugs, ensuring the uniform distribution of the drug substance throughout the matrix is essential and often challenging. “Accurate and reliable analytical data [are] needed to enable effective and efficient product-development decisions. Should there be any doubt about the the accuracy of the analytical data regarding drug substance uniformity, development time, effort, and associated cost may be wasted trying to resolve potential formulation issues that are not real,” Jenkins observes.

The biggest issue often relates to detection difficulties due to the presence of excipients that absorb in UV wavelength regions similar to those for drug substances. One way to avoid this issue is to consider the analytical impacts of excipients during early screening and selection efforts before too much time and effort have been invested in prototype generation, according to Jenkins. Another approach is to choose alternative detection wavelengths that minimize excipient contribution, but the ability to do so depends on the absorption properties of the drug substance.

Polymeric excipients used to modify the in-vivo release of drugs can impact accurate extraction during sample preparation. “For some high-potency drug formulations it may be necessary to complete additional preparation steps to ensure full recovery of the drug substance as required to meet industry in-process checks or finished-product specifications,” Jenkins says.

Polymeric excipients may also present challenges to lab equipment such as chromatographic columns, as they can be difficult to remove and may create the need for additional cleaning/regeneration steps to return columns to optimal performance or irreversibly reduce column lifetimes, according to Jenkins. “Column deterioration during analysis can, in fact, increase the risk of an analysis failing to meet typical system suitability criteria, leading to the need to repeat analyses, thus reducing testing efficiency and cost-effectiveness,” he states.

To achieve effective analysis, all ingredients of interest in a drug formulation must be soluble in a solvent suitable for the intended method of analysis. That can be an issue for highly potent drug substances with poor water solubility, as organic solvents are typically required. “For a particular formulation, the solvent should effectively dissolve the drug substance or other ingredient of interest (e.g., preservative or anti-oxidant) but not the other formulation excipients in order to minimize excipient contributions; however, drug substances and excipients often exhibit similar properties and tend to be soluble in the same solvents,” Jenkins explains.

Careful column stationary- and mobile-phase selection can be used to separate unwanted excipient interference from peaks of interest ensuring acceptable specificity. These choices can be guided somewhat by consideration of the chemical structures of the compounds involved, according to Jenkins. “Polar functionalities in the drug substance will interact with imbedded polar groups on columns, while delocalized electron systems will interact with similar systems in certain stationary phases such as pentafluorophenyl, and alkyl chains will interact with C8 or C18 stationary phases, etc. Modern analytical columns now have combinations of these groups to allow for a wider range of stationary phases for evaluation during analytical development,” he observes.

Another approach is to use secondary or tertiary wavelength maxima to minimize interference from excipients in a highly potent drug formulation. “It is necessary, however, to consider the analysis of degradation products, as they can have different UV absorbances compared to their parent moieties,” Jenkins states. He adds that while longer wavelengths will reduce excipient contribution to the analysis, they do not prevent physical interactions of excipients with the stationary phase and the need for additional cleaning steps.

Sustained-release formulations require increased sensitivity and non-routine analyses

Highly potent drug formulations that are engineered to enable sustained release of the drug substance with targeted delivery to minimize potential toxicological effects often rely on alternative or novel excipients. These systems, according to Jenkins, reduce the initial onset and prolong the therapeutic effect window.

In-vitro release testing for such formulations requires detection of low levels of drug substances (particularly at early time points) released at slow rates. For instance, a sustained-release formulation may release 5–0% of the drug substance after 5–10 minutes, while an immediate-release formulation will typically release >45%, observes Jenkins. “Increased sensitivity achieved through use of higher-sensitivity detectors or modifications such as higher path-length flow cells or application of non-routine/non-pharmacopeial equipment, such as micro-dissolution and/or sample concentrators, is therefore often necessary. Justification of the suitability, control, and use of such equipment is, however, usually required during regulatory review,” he says.

It is not just sustained-release formulations that can cause challenges to effective dissolution analysis. For oral-dosage-form drugs formulated as capsules, during dissolution analysis certain combinations of excipients, dissolution media, and the polymers used to form the capsule shells can react to form pellicles that retard drug-substance release, according to Jenkins. “This issue is addressed either through the development of specific dissolution media to prevent crosslinking or the inclusion of the enzyme pepsin to degrade any formed pellicles,” he says. He does note, however, that these approaches are not generally applied from the outset, as often this problem does not appear until several months into
stability testing of a product.

Need for instrument innovation combined with analytical expertise

As more knowledge is gained about disease mechanisms and new drug targets are identified, the nature of highly potent drug substances continues to evolve. They are becoming steadily more potent while their solubility/permeability continues to decline. At the same time, demands for safer, easier-to-use drugs that are not only developed with patients in mind but also cost-effective are growing.

Formulation of highly potent drugs that meet those demands can be challenging, particularly given the complexity of drug formulation and analysis for these products. “The largest contribution to the cost of new, novel medicines is the time taken for development (circa 8–12 years). Improving the efficiency of development should therefore result in a reduction in the cost-per-unit and earlier availability of drugs to patients. One way to reduce development times is through introduction of more advanced analytical instruments and methods with greater sensitivity that support quick resolution of analytical challenges,” Jenkins contends.

Combining innovative systems with experienced analytical and formulation scientists using a collaborative approach would, Jenkins adds, further ensure sound scientific rationale resulting in effective development decisions. He points to, for example, consideration of the downstream impacts of formulation development decisions on required analytical methodologies. The overall result, Jenkins believes, would ultimately be expedited development timeframes for novel medicines that address unmet patient needs.

When referring to this article, please cite it as Challener, C.A. Overcoming Analytical Challenges in High Potency Formulation. 

Sample dilution, sensitivity, excipient interference, and containment are key issues that must be addressed.

Overcoming Analytical Challenges in High Potency Formulation

Numerous pharmaceutical companies from startups to well-established firms are exploring the potential of cannabinoid-based drug substances as therapeutic agents for the treatment of a wide range of disease indications. Developmental cannabinoid medications must follow the same approval pathway established for all other small-molecule drug candidates. Early in 2023, the agency also determined that a new regulatory pathway for cannabidiol (CBD) products is needed that “balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks” (1). “Smart companies,” says Jordan Tishler, president and CEO of inhaleMD, President of the Association of Cannabinoid Specialists, and an Instructor of Medicine at Harvard Medical School, “will see the value of following the pharmaceutical pathway and pursuing clinical trials and FDA approval, while the rest will simply make recreational products.”

Regardless of whether companies are seeking to develop therapeutics or dietary supplements based on cannabinoids, they face the challenge of realizing effective delivery of these highly hydrophobic compounds. “Cannabinoids present many of the same difficulties that other poorly soluble and/or absorbable APIs present,” states Gavin Chandler, CEO of Trokie, a company working on novel delivery systems for cannabinoids for use as dietary supplements in strict compliance with FDA and Federal Trade
Commission (FTC) rules.

In addition to being highly lipophilic molecules, cannabinoids can also undergo extensive first-pass metabolism, which creates difficulties for dosing and titration and impacts the speed of therapeutic onset, according to Chandler. He points to testosterone and triptans as being examples of other APIs that share these difficulties.

Furthermore, Tishler notes that bioavailability of cannabinoids is poor regardless of route of administration, and it is also quite variable, particularly for oral delivery. The challenge, agrees John A. MacKay, founder and CEO of Synergistic Technologies Associates, is to get nonpolar cannabinoids into some type of media or delivery vehicle that will enable sufficient quantities of them to be transported across membranes to targeted areas.

Growing numbers of patent filings and publications regarding the pharmacodynamics of cannabinoid delivery using novel technologies indicate high interest in addressing the shortcomings of cannabinoid products delivered via the standard oral routes of administration, according to Chandler. Technologies of interest include buccal, intra-nasal, and transdermal delivery systems, as well as the use of various nanoscale approaches to enable improved oral delivery.

Of the more than 120 different phytocannabinoids that have been identified, Δ9-tetrahydrocannabinol (Δ9-THC, or THC) and CBD are the most abundant and most investigated (2). Many synthetic cannabinoids have also been produced and evaluated. Most cannabinoids that have been shown to be pharmacologically active are Class II compounds under the Biopharmaceutics Classification System, which are considered to have low water solubility and high lipophilicity.

Inhalation gives best bioavailability, but presents many problems

Although inhalation of cannabis-derived products is the most common method of administration and does generally provide the best bioavailability and fast onset of action (5–10 minutes) as well bypasses first-pass metabolism (2), smoking and vaping oil extracts supply the cannabinoids in conjunction with toxic byproducts. In addition, the bioavailability still only reaches 20–30%. “The best solution to date,” says Tishler, “is a flower vaporizer, but this device is costly and the results are typically very user-dependent.”

Inhalation must be done appropriately, too, adds Mackay. “If patients don’t inhale correctly, the cannabinoids can be delivered into the mouth instead of the lungs. In addition, some people experience a gag-reflex when using an inhaler.” Due to the “stickiness” of these hydrophobic compounds, Tishler adds that it is difficult to put them in metered-dose inhalers because the devices fail after just a few uses.

Buccal and intranasal delivery could be alternatives

Buccal and intranasal delivery are other approaches to avoiding first-pass metabolism. These delivery methods also may offer reduced variability compared to oral administration of cannabinoids, according to Chandler. “We see increasing clinical evidence coming out in various publications both domestically and internationally that these types of formulations provide higher and more reliable absorption of cannabinoids that will benefit clinicians and their patients,” he observes. He does, stress, however, that there is still much work to do.

Whether one form of administration is better than another remains to be seen. In addition, Chandler remarks that cannabinoids are a diverse set of molecules, so what would be an advantage for one might be a disadvantage for another depending on the specific attributes of the cannabinoids. “On the purely theoretical side, buccal formulations are potentially easier to use because they are solids rather than liquids,” he comments.

On the other hand, intranasal delivery, based on the results with other similar APIs, could have slightly faster speed of onset at the expense of total absorption because of the washout down the throat, according to Chandler. There are concerns, however, about irritation of the nasal mucosa and mucociliary clearance, and it has been suggested that this route of administration may be most appropriate for highly potent APIs that require small dosage amounts (3).

Separately, depending on the cannabinoid, buccal or intranasal might provide for better patient tolerability, as some cannabinoids can be either very bitter or spicy, and where one technology or the other might provide a better patient experience. “We need more clinical data, but I expect there will be a place for both technologies depending on the clinical context and specific cannabinoids,” Chandler says.

For buccal formulations specifically, Chandler notes that analogous cases such as buccal delivery of testosterone show that buccal improves total absorption and reliability. Similarly, improvement of efficacy has been reported when going from oral gastric tablets of triptans to sublingual or intranasal delivery. The published literature on buccal delivery of cannabinoids, he continues, suggests that there is evidence that buccal delivery improves total absorption with pharmacokinetic (PK) profiles swinging from predominantly first-pass metabolites towards more non-metabolized actives in patients. “These papers, however,” says Chandler, “describe small trials with only a handful of patients and not powered or controlled at a level to really address the question of variability.”

Developing buccal formulations (orally disintegrating tablets, buccal mucoadhesive tablets, films and patches, sublingual disintegrating thin films, sprays, chewing gum, and lozenges) can be challenging for cannabinoids because buccal delivery comprises a group of technologies, all of which might not be suitable for all cannabinoids, according to Chandler. In addition, he notes that cannabinoids have diverse flavor profiles, which can be an issue.

“Buccal delivery tends to involve greater residence times in the mouth, and depending on the unit dose they can be highly concentrated,” Chandler explains. Furthermore, the small size of the oral cavity limits the volumes that can be comfortably delivered compared to traditional tablets/capsules. Some cannabis and hemp extract products are in development.

It is worth noting that buccal and intranasal delivery are just two forms of transmucosal drug administration, which is intended to deliver drug substances through the mucosal epithelium into systemic circulation. Others include rectal and vaginal delivery. Several different cannabinoid candidates are being developed as transmucosal products, with many of them based on THC or CBD and most as oromucosal formulations (2).

Nano products claim to tackle GI tract absorption issues

Given that oral delivery via tablets and capsules is generally the preferred route of administration due to simplicity, many developers of cannabinoid medicines are focused on overcoming the poor absorption of these molecules in the gastrointestinal (GI) tract, which is typically 15–20%. Nanoscale solutions are receiving the greatest attention, according to Tishler, but solid data has yet to be supplied, he says.

Nano-based technologies are attractive because they have the potential to not only improve solubility and bioavailability, but increase stability and provide mechanisms for controlled- and other types of modified-release profiles and taste masking (2,4).

Various solutions are being developed, including those based on lipid and polymeric nanoparticles (2,4). Other lipid-based formulations such as nanomicelles, nanoemulsions, lipid nano capsules, and nanostructured lipid carriers, self-micro emulsifying drug-delivery systems, and self-nano emulsifying drug-delivery systems are being explored, as are ethosomal systems containing phospholipids, ethanol, and water; complexation by cyclodextrins; extracellular vesicles or exosomes; mesoporous silica; and electrospun fibers (2,4).

Nanoemulsions are particularly popular, according to MacKay, with different companies using a number of different approaches to generate them. “The challenge is selecting the right emulsifiers and emulsification technology (for example, controlled cavitation) for a given cannabinoid to achieve nanoemulsions of the correct particle size that maintain their emulsified state for throughout shipment, storage, and use,” he contends.

Stability is essential, as formulations in which the emulsion has degraded will not have a consistent concentration of the cannabinoid active throughout the entire solution. The particle size is important because it not only determines how efficiently the nanoparticles will cross membranes, but which cells are targeted and how the nanoparticles interact with them, Mackay observes.

Another way to improve the solubility and bioavailability of cannabinoids is to chemically modify them in such a way as to reduce their lipophilicity without affecting the parts of the molecule involved in receptor binding and thus their pharmacological activity. Examples of modifications include adding long-chain alkyl substituents to the main ring structure to increase hydrophilicity and preparing conjugates with polar molecules.

MacKay points to the work of Alexander Makriyannis, George Behrakis Chair of Pharmaceutical Biotechnology at Northeastern University, and John W. Huffman, now deceased, previously a professor of organic chemistry at Clemson University, as being the most well known in the field. These two and many others have produced hundreds of synthetic cannabinoids with wide-ranging properties, some of which are now in preclinical or early-stage clinical development.

Cannabinoid receptors exist in the skin, and some companies are seeking to develop topical or transdermal cannabinoid formulations to skin conditions, such as psoriasis, atopic dermatitis, and acne. A common approach in this case is to generate synthetic prodrugs that can cross both the lipophilic stratum corneum and the aqueous dermis (2). Many of these formulations are also nanoscale solutions.

The key takeaway about cannabinoid drug delivery is that no one delivery approach will be effective for all natural and synthetic cannabinoids. “There is too much variability in the physicochemical characteristics of the many different pharmacologically active cannabinoids being investigated today,” MacKay states. As with other drugs, different indications and different
patient populations will require different routes of administration to meet
therapeutic, patient, and physician needs. A formulation intended to treat acute pain, which requires fast onset, will be different from one to treat chronic conditions, for which extended release will be preferable.

Woodcock, J. FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will Work with Congress on a New Way Forward. FDA Statement, Jan. 26, 2023.

Stella, B. et al. Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain. 

 81(13): 1513–1557. doi: 10.1007/s40265-021-01579-x/

Tijani, A. O., et al., Delivering Therapeutic Cannabinoids via Skin: Current State and Future Perspectives. 

 Vol. 334, June 10, 2021, pp 427-451. https://doi.org/10.1016/j.jconrel.2021.05.005

Palrasu, M. et al., Perspectives on Challenges in Cannabis Drug Delivery Systems: Where Are We? 

 5:102–119. https://doi.org/10.1159/000525629.


Vol. 47, No. 6
June 2023
Pages: 19-20, 23

When referring to this article, please cite it as Challener, C. Overcoming the Poor Solubility of Cannabinoids. 

Nanotech-based delivery technologies are receiving significant attention.

Overcoming the Poor Solubility of Cannabinoids

Continuous manufacturing has the potential to offer benefits in terms of reduced costs, footprint, raw material consumption, and byproduct and emission generation combined with increased process consistency and product quality. Regulatory submission timelines can also be advanced by more than 12 months and approval times by three months compared to products generated via batch manufacturing (1). Not surprisingly, the US Food and Drug Administration (FDA) encourages the development of continuous processes, and these processes are slowly becoming more prevalent in both small-molecule and biologics manufacturing. It is expected, in fact, that in the near future continuous operations will be the norm rather than the exception, according to Hibreniguss Terefe, director of research and development at Catalent. As such, outsourcing providers that develop continuous manufacturing expertise and leverage this technology can establish a differentiating competitive advantage.

Editor's Note: This article was published in 

Hot-melt extrusion (HME) by its nature is a continuous process, and its integration with other continuous manufacturing operations has the potential as an amorphous solid dispersion (ASD) solution to offer more benefits than just enhanced solubility and bioavailability for poorly soluble APIs. “Given that HME is one of the best tools for enhancing solubility, linking HME processes effectively with other unit operations such as tableting/capsule filling will reduce the number of unit operations, ease scale-up to commercial production, and ultimately help patients realize earlier access to products with positive economic impacts for sponsors as well,” states Purushottam Singnurkar, vice-president and head of formulation development at Syngene International Limited.

Formulating drug substances into ASDs is a widely accepted approach to enhancing the solubility and bioavailability of poorly soluble molecules, according to Terefe. “The conversion of a crystalline API into an amorphous form by dispersing and immobilizing it in a polymeric carrier can be achieved through solvent- or fusion-based technologies. Spray drying is a solvent-based process, while HME is fusion-based technology,” he observes.

In addition to improved solubility, other benefits of using HME are good process control, scalability, and avoidance of solvents, notes Hannes Fuderer, technical operations manager with AbbVie Contract Manufacturing. “Good process control enables balancing of incoming variability into the extrusion process and reduces the variability of the extrudate itself to improve the performance of downstream processing. Good scalability provides the opportunity for faster development and transfer from
lab through pilot to commercial scale and affords flexibility to accommodate volume and extruder-scale changes during life-cycle management,” he explains.

“The ability to practically transfer material inputs continuously and have them transformed into output materials that are continuously removed leads to increased product quality assurance and enhanced product capability and control,” adds Singnurkar. He also comments that the fact that HME is a “green technology” that involves fewer processing steps than spray drying and freeze drying provides further advantages.

HME takes place in a twin-screw extruder, which is, according to Terefe, a continuous, versatile, and highly efficient self-wiping small mass mixer amenable to process analytical technology (PAT). That is why process parameters can be well controlled and HME processes can be readily scaled from R&D to commercial-scale equipment. “Once process parameters are established at a given equipment scale, the batch size is then a function of time and can be easily changed by running the process for a longer or shorter period without needing to change other process parameters,” he notes.

In addition, HME offers a high degree in flexibility and many use cases. “Based on the HME process design, there are many options to integrate an HME process into a fully continuous process or combine it with discontinuous up- and/or downstream processes if required, such as batch blending to feed the extruder or storage of extrudate intermediate prior to further (batch-wise) processing into final drug product,” Fuderer says. HME can also be used for potent compounds and due to the equipment design it typically results in high yields.

An HME unit operation is usually performed as a continuous process through a sequentially assembled equipment system consisting of powder feeder(s), optional liquid pump(s), a twin-screw extruder, a conveyor, and a pelletizer (or a chill roll flaker) working in a harmonized and continuous manner, Terefe notes. The extrudate, however, is typically handled as an intermediate and further processed as a batch, limiting HME to a semi-continuous process.

On the upstream side, the material feed can be a mixed powder blend or individual streams of different ingredients (API and excipients) fed directly. Either approach can be performed continuously, according
to Fuderer.He also notes that, based on material properties or to increase the throughput, the blend can be densified prior to extrusion by a continuous roller compactor or side-stuffer.

The extrudate, meanwhile, can be shaped into nearly any form by the design of the extruder die in combination with several cutting and shaping technologies that are also all continuous processes, Fuderer says. Common shapes are flakes, pellets, and beads depending on the downstream unit operation. “It is possible rather than collecting and buffering the shaped and cooled extrudate in containers prior to further processing, it can be dosed immediately to the next unit operation as the mass flow is still controlled,” he adds.

Integrating the extrusion process with other upstream and downstream semi-continuous unit operations such as continuous blending, milling, tablet pressing (direct compression), and tablet coating would, Terefe says, create a fully end-to-end continuous solid-oral-dosage-form manufacturing process. “Combining a continuous HME process with continuous downstream operations could be envisioned as a viable means for taking full advantage of a continuous process to manufacture solubility- and bioavailability-enhanced products,” he concludes.

One example provided by Singnurkar involves transfer of the hot extrudate directly to dies of suitable sizes for the manufacture of 3D tablets. “Integration eliminates many process steps such as cooling and milling of the extrudate and mixing with excipients, among others,” he says. Any integration of continuous operations without a centralized computer system for control and the implementation of PAT tools for constant process monitoring will, however, reduce the likelihood of success, Singnurkar stresses.

Understanding the critical material attributes (CMAs) of the API and polymer, such as the melting and glass-transition temperatures is also important for developing high-performing HME processes. “The machine settings, including the screw configuration, screw diameter-to-length-ratio, barrel-free volume, distribution of heating and cooling zones, die-orifice size and shape, and the cooling system are equality important. Critical process parameters include the barrel temperature, screw speed, residence time, and throughput,” Singnurkar from Syngene observes.

Controlling material inputs often presents the greatest challenge for HME process optimization, according to both Fuderer and Terefe. “Blend homogeneity, dosing accuracy, and risk of blend segregation during powder conveying are important issues that must be managed,” Fuderer stresses.

Inconsistent and inaccurate feeding of input material into the twin-screw extruder may be caused by poor flow properties of certain raw materials, or very low amounts of certain excipients such as plasticizers and surfactants, Terefe notes. “Feeding all of the components separately at an appropriate ratio of feed rates, as reflected in the formulation composition, would be ideal for a well-harmonized continuous
process, but this assumes that no additional pre-extrusion unit operations are necessary,” he says. Poorly flowing APIs may need to be preblended with a carrier polymer, and often, with additional flow-enhancing excipients, Terefe adds.

Fuderer does point out, though, that one advantage of the HME process is that variances in blend homogeneity and dosing are smoothened to a certain extent, and therefore, variances will not immediately impact extrudate quality.

Blend segregation, however, must be avoided during powder conveying into the extruder, according to Fuderer. This issue is particularly associated with discontinuous batch blending, as it poses higher risk for segregation at bin changes or if the upstream equipment runs empty.

In cases where the poor flow properties of the API or any excipient cannot be overcome by simple blending, Terefe observes that a pre-extrusion granulation step may be required. “Appropriate selection of the powder feeders with suitable feeder screw designs and the choice of liquid pumps for accurate liquid feeding without pulsation can help alleviate many of the input material feeding challenges,” he comments. Introducing a continuous blending process upstream of the extrusion step can also be beneficial for formulations for which simple blending cannot overcome these challenges, Terefe says.

Optimum HME processes generate extrudate with acceptable critical quality attributes (CQAs), such as amorphicity, content uniformity, and purity. Many CQAs impact downstream unit operations, according to Terefe, and thus it is crucial to have online monitoring capabilities (such as near-infrared spectroscopy for evaluating an extrudate’s crystallinity and content uniformity) to track these properties. Fortunately, says Fuderer, if HME processes are properly developed, they are robust and have good process control, and thus typically exhibit only minor variances in physical properties of extrudate intermediate that could impact downstream processing due to HME process performance.

Improper identification of critical material attributes and CQAs for HME processes can, believes Singnurkar, impact the uniformity, degradation profile, and dissolution behaviour of the final drug products. Misidentification of CPPs, meanwhile, can impact the milling of extrudates which can affect compressibility and thus make tabletting difficult. In addition, the API loading and miscibility of the API with the polymeric carrier can also, he says, significantly impact downstream processing.

It is the physical properties of the extrudate that are most important for downstream processing, Fuderer agrees. He adds, however, that they are mainly dependent on the product composition and less dependent on the HME process parameters such as the temperature profile. “As long as the product composition is controlled (e.g., blend homogeneity or ratio of solid and liquid feeds), no impact is expected on downstream processing,” he states.

In addition to product composition, Terefe emphasizes the importance of achieving consistent and controlled material throughput that is harmonized with downstream processes. For example, he points out that the material feed rate into a mill impacts particle size distribution, which may lead to inconsistency in the dissolution of the final product. Inconsistent material input into the continuous direct blending process downstream may also lead to poor blend uniformity, resulting in poor content uniformity of the final tablets.

Here again, the HME process benefits from good monitoring and control technologies. “Twin screw extruders typically have features for controlling and monitoring material throughput consistency, allowing the feed rate, extrusion load, and melt pressure to be continuously measured and monitored in real time,” Terefe explains. Any fluctuation in one of these parameters is a direct indication of material throughput inconsistency and the need to adjust the process.

Ultimately, the successful use of HME to enhance solubility and bioavailability of poorly soluble APIs manufactured in a fully continuous process, as is the case of any continuous manufacturing process, requires a well-engineered process design that can be controlled, Terefe contends. “When developing an HME process, there is a broad choice in polymers, equipment design, and development and scale-up approaches. It is important to involve appropriate subject matter experts at each stage to ensure the highest quality and most robust process for commercial manufacturing,” adds Fuderer.

The polymer and composition as well as the equipment and screw design are typically defined in early development at small extruder scale, according to Fuderer. At this stage, it is very important to understand how the material behaves in the extruder to prevent any issues to product quality or processability during scale-up because the opportunities to make changes to the composition later on are limited, he observes.

The processibility of the input material must be considered, says Terefe. For example, he highlights the need to understand the flow properties of the excipients in order to select appropriate feeders and determine pre-extrusion blending requirements.

“Investigating all possible variables that can impact product quality at the early stage can be challenging, however,” Fuderer comments. “Defining a design space that ensures product quality and processability, but also gives enough flexibility for post-development changes performed during lifecycle management (process and cost improvements, yield increases, supplier notifications for raw materials, etc.) is essential,” he concludes.

A well-planned process design that considers all technical and commercial perspectives and the company’s long-term strategy is fundamental, Terefe agrees. “The type of product(s) to be manufactured, the process flow, and unit operations need to be well understood, and the core equipment, along with necessary accessories, process control for each unit operation, and the CQAs of intermediate output material must be identified,” he states.

An effective means for achieving these goals is to use a quality-by-design (QbD) approach, according to Terefe. “A thorough risk assessment of CMAs and CPPs that impact CQAs for each unit operation must be conducted, along with identifying mitigation and control strategies,” he explains.

In addition, because continuous manufacturing aims to facilitate real-time batch release, a good understanding of each unit operation, both independently, and in combination with all other unit operations working in tandem, is essential, according to Terefe. In addition to PAT and real-time process analytics, he notes that model-based process optimization using relevant output data from sensors and processes is important.

It is also highly recommended, notes Fuderer, to keep process requirements for continuous processing in mind when developing HME processes to ensure that not only the HME process is developed to its optimum, but also that the interfaces to the up- and downstream unit operations guarantee final drug product meeting the desired quality.

Furthermore, well-organized and planned process integration into a computerized system that complies with GMP and good automated manufacturing process requirements needs to be established, as do proper IT structures and supervisory and control systems, Tenefe says. Such a centralized computer system that is integrated with various unit operations and PAT tools and provides real-time quality and process control is, in fact, essential for achieving consistent and optimum continuous HME processes, contends Singnurkar.

1. Mahesh R. An FDA Self-Audit of Continuous Manufacturing for Drug Products. FDA Podcast, 

. 28 June 2022. (Accessed March 30, 2023).

Process control is essential for using continuous hot-melt extrusion to enhance solubility.