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

Cynthia A. Challener

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Hot-melt extrusion (HME) enables formation of amorphous solid dispersions (ASDs) of crystalline compounds, trapping the molecules in less-stable states that have higher solubility in water, and more importantly for drug formulations, physiological fluids. Excipients play a significant role in these products, as the amorphous API is stabilized in a polymeric matrix, and other excipients improve their processability and enhance their in vivo performance. Certain excipients, meanwhile, expand the applicability of HME to a wider range of APIs, including those with high melting points and those that are temperature-sensitive. The challenge for formulators is to select the optimum combination of excipients for any given API, dosage form, and disease target.

Polymers certainly represent the main excipient type used in HME formulations. Depending on the physicochemical properties of the API and its degradation pathway, HME products comprise mainly the amorphous API, the polymeric matrix carrier, which dissolves and entraps the API, and additives such as plasticizers, surfactants, antioxidants, acidifiers or alkalizers, and lipid solubilizers, among others, according to Hemlata Patil, senior manager of HME technology with Catalent.

Indeed, in addition to becoming highly crystalline and highly lipophilic in nature, new chemical entities (NCEs) are also increasing in molecular weight, Patil comments. “First-generation ASDs comprising the API and polymeric matrix alone are not sufficient to resolve the issue of poor API solubility,” she states.

Plasticizers such as mannitol, sorbitol, and meglumine are sometimes required to soften the polymeric material and facilitate the extrusion process, notes Philip Schäfer, head of Business Franchises, Process Solutions, MilliporeSigma, the US and Canada Life Science Business of Merck KGaA, Darmstadt, Germany. Easing extrusion, which can also be achieved with lipid-based plasticizers may also improve the physical and chemical stability of the product, according to Cécile Morin, scientific communication manager, pharmaceuticals with Gattefossé.

Antioxidants counteract the oxidation of APIs, while acidifiers and alkalizers act as stabilizing agents to prevent hydrolytic degradation of the API. Surfactants and stabilizers such as poloxamer and polyvinyl alcohol (PVA) improve both the overall process and amorphous stability of the API in the polymer matrix by reducing the glass temperature of the melt, says Schäfer.

Generally, observes Patil, the solubility/bioavailability of “brick dust” molecules (poorly soluble in aqueous and lipoidal vehicles) can be increased by using binary mixtures (API and polymeric carrier) with processing aids depending on the physicochemical properties of the API, while for “grease ball” molecules (highly lipophilic), additives such as lipids and solubilizers are required.

“Ultimately,” concludes Schäfer, “the selection and combination of excipients needs to be considered carefully and fine-tuned depending on the intrinsic characteristics of the API and the intended performance of the dosage form.”

Solubility enhancement is not the only reason for developing HME formulations. Many small molecules (and biologics, too) also suffer from limited permeability, says Morin.

Thermal stability of the API is another critical factor. Heat sensitivity of the active ingredient is a concern when using HME because process temperatures can reach 120–200 °C, according toElsa Gattefossé, project leader, pharmaceuticals at Gattefossé. Selecting an appropriate polymer through rigorous pre-formulation studies is, therefore, essential, according to Patil. “The molten polymer should have a high capacity for solubilizing the drug, which can be especially beneficial when the drug’s melting point or decomposition temperature is a concern. The objective is to find a polymer that allows the API to dissolve at elevated temperatures that are still below the decomposition temperature of the API, thus minimizing the risk of thermal degradation of the drug substance during the manufacturing process,” she explains.

With the emergence of PVA-based HME excipients, the typical processing range can even be extended to process temperatures of up to 250 °C. “This way, even high-melting-point APIs can be processed via HME due to the high thermal stability of the polymer excipient,” Schäfer comments.

Adding a plasticizer can also be helpful. Lipids in particular can dramatically reduce the glass-transition temperature (Tg) and thus enable processing at substantially lower temperatures, according to Gattefossé. “Solid lipid excipients can allow extrusion to occur at temperatures as low as 40–70 °C, depending on the excipient melting point, which makes it possible to process most heat-sensitive APIs,” she remarks.

Due to the trend to more hydrophobic APIs, Schäfer adds that there is also a rising need to prevent recrystallization and ensure both amorphous stability in solution and stable performance of the final formulation. “Selection of excipients for use in the HME process with good precipitation-inhibiting and amphiphilic properties, such as polymers like PVA 3-82, is crucial to address this challenge,” he comments.

The propensity for phase separation and recrystallization from the amorphous state can be predicted by calculating the ratio of the melting point (Tm) to the Tg of the molecule in degrees Kelvin, according to Patil. “A Tm/Tg value of greater than 1.4 indicates a high potential for recrystallization. In this case, a low drug loading in the ASD is important, as higher drug loadings generally result in higher API diffusion rates within the polymer matrix, which result in accelerated kinetics for phase separation and recrystallization during processing and storage,” she says.

The extrudate generated by the HME process can be used directly, but most often is ground to generate granules that are then used to fill hard capsules, sachets, and stickpacks or to form tablets and thin films.

The intended dosage form has a high impact on the selection of the processing technique and the excipient, according to Schäfer. For instance, the drug-loading capacity of the matrix polymer of an ASD directly impacts the size of the final tablet product. “A high drug-loading capacity is specifically important to reduce pill burden for the patient and can directly be linked to patient compliance,” he observes. In this case, selection of a suitable polymer with amphiphilic properties can improve both loading content and long-term stability.

For tablets, the choice of excipients is also dictated by the intended release profile for the drug product. For immediate-release products, typically a water-soluble filler (e.g., lactose, mannitol, etc.), water-insoluble diluent (microcrystalline cellulose), and super disintegrants are added in the extra-granular phase of tablet formulation, according to Patil. Enteric polymers, such as hydroxypropyl methyl cellulose acetate succinate (HPMCAS), are used for modified (delayed)-release formulations. HPMCAS delays drug release by enabling release of the API in the intestine rather than the stomach.

Developing sustainable processes should be considered from the outset of any development project, insists Morin. “Processes requiring less energy and/or water and [that] avoid the use of organic solvents should gain preference in the pharmaceutical industry worldwide,” she states.

The overall rethinking for higher sustainability standards as well as the importance of an ecological fingerprint brings processing techniques such as HME into focus, adds Schäfer. The other main method for generating ASDs—spray drying—requires the use of large amounts of solvents for processing and energy for their subsequent removal. HME, in contrast, is a solvent-free process and thus has the potential to be a more environmentally friendly approach to enhance solubility of APIs and to form ASDs. The continuous nature of the HME process also makes it attractive.

The availability of excipients that not only meet the needs for broad processability and flexible performance characteristics, but also satisfy the demand for sustainable options is equally important, Schäfer continues. Lipids are an example of excipients that can contribute to improved sustainability of HME processes, according to Gattefossé. “Lipid excipients that help reduce the Tg of matrix polymers and thus lower the HME processing temperature contribute to improved sustainability of the processes,” she states.

Given that polymers are used to form ASD matrices, their properties influence the shelf-life, stability, and dissolution performance of the APIs they contain. Polymers also impact the physicochemical and stabilization characteristics of the final formulation, as they are determined by the maximum drug loading capacity, precipitation inhibition aspects, and processing properties of the matrix material, according to Schäfer. Finding the right polymer is, therefore, essential.

Numerous criteria must be met before a polymer can be considered optimal for an HME formulation, observes Patil. First and foremost, the polymer must be miscible with the API and have sufficient solubilization and stabilization capacities. It also must exhibit the appropriate thermo-plasticity and thermal stability, and have a molecular weight that allows for sufficient melt viscosity.

The availability of polymers that are suitable for pharmaceutical applications, with consistency in supply and quality, is a big challenge, however, according to Schäfer. “While many different polymers can be used for general HME processes, only a limited number of polymers and other excipients have been approved for use in pharmaceutical applications based on worldwide pharmacopeias,” he comments.

“Within this limited selection, the right polymer must be found that features adequate processability and excellent performance characteristics to overcome potential challenges associated with the specific API and, ultimately, result in a pharmaceutical drug formulation with the desired properties. Every API has unique physicochemical characteristics; thorough and careful selection of an HME polymer and additional functional excipients is important, [because there] is no one-size-fits-all solution,” Schäfer emphasizes.

New types of excipients are gaining attention in HME formulations due to several limitations with existing commercial polymers. These limitations, Patil notes, include issues with drug-loading capacity, reduced shelf-life, and physical and chemical instability. Additionally, some polymers have shown complications in preclinical studies involving species known to have toxicity issues or that have extensive first-pass metabolism, making it difficult to differentiate between formulations. “Given these challenges, there is growing interest in identifying and using new HME-compatible polymers to improve formulation performance and stability,” she says.

A repurposing of already approved traditional excipients is increasingly important because it combines the benefits of fast-track approvals of a drug formulation with a background knowledge of the physicochemical nature of excipients, observes Schäfer. One example of this strategy is the development of PVA polymers, which have traditionally been employed in pharmaceutical coating applications, for use in HME, spray drying, thin films, and as binders during wet granulation.

“PVA is a perfect example of a flexible polymer that features excellent HME processing properties paired with outstanding performance criteria,” Schäfer contends. “It is suitable for use with APIs possessing a broad range of Tm values (up to 250 °C), can be used to achieve a wide range of release kinetics and various dosage forms, and depending on the specific PARTECK MXP PVA (MilliporeSigma) polymer type, shows best-in-class performance for precipitation inhibition by maintaining a supersaturated state of the API,” he continues.

The flexibility of PVA also makes it suitable for use in sustained-release final dosage forms, according to Schäfer. In particular, he points to PVA 40-88 as an effective polymer matrix for this application. As a result, Schäfer believes that with its ability to enhance bioavailability, solubility, and patient compliance, PVA can be used in HME formulations to ensure the level of therapeutic effects needed to alleviate or cure diseases.

In a slightly different scenario, hypromellose (hydroxypropyl methylcellulose), a hydrophilic amorphous polymer shown to be an effective recrystallization inhibitor for ASDs, has been modified to generate a polymer with a lower Tg and lower melt viscosity. With AFFINISOL HPMC HME (IFF), HME can be performed without the use of large quantities of plasticizers, simplifying both processes and final product formulations, according to Patil.

Lipids are attracting growing interest as excipients for HME as well because depending on their properties, they can be advantageous from both process and formulation perspectives, says Gattefossé. “Lipid excipients constitute a vast family of inert, biocompatible products with very different functionalities,” she notes.

When mixed with polymers, certain lipids can act as plasticizers and drastically reduce the Tg of the polymer, and consequently the extrusion temperature. “Their role in this case,” Gattefossé comments, “is to facilitate extrusion, lower energy consumption, and limit API degradation.” At higher use levels, lipid excipients also provide easy cleaning with water and time savings and enable higher drug-loading levels.

Formulation performance can be enhanced in several ways. Different options include oily vehicles and various types of surfactants (water-insoluble, water-soluble, and water-dispersible) for solubilization of poorly soluble drugs, even grease- ball and brick-dust molecules, according to Morin. Certain lipids also act as penetration enhancers to increase the oral bioavailability of low-solubility and/or low-permeability drugs, and some can be employed as sustained-release agents in hydrophobic matrices. “Sustained-release dosage forms can contribute to life-cycle management for drug companies by providing patients with more convenient products less frequent dosage regimens, which can in turn contribute to increased patient compliance,” she adds.

 salt formation as a new formulation approach

Processing heat-sensitive APIs using HME can be challenging, even with access to different lipid excipients. One new strategy for overcoming the difficulties associated with extruding thermally labile drug substances and those with high melting points is in-situ salt formation. Salt formation to produce crystalline salts is an extremely common approach for improving the developability of candidate APIs, according to Patil.

“It is generally accepted that salt formation occurs when the difference in the pKa values of the API and salt-forming material is > 3. Salt-forming materials are therefore selected based on the physicochemical properties of the drug substance (acidic or basic). A weakly acidic API would thus be extruded with a base, and vice-versa,” Patil explains. Schäfer, notes, meanwhile, that meglumine, which is a sorbitol derivative with a terminal amino group, is a very suitable in-situ salt former for APIs with pKa values of 6 or lower.

With each API requiring selection of the optimal combination of polymer matrix and excipients to support processing and product performance, formulation development can be quite challenging. Extensive screening of different formulation options is typically required.

To screen polymers for a given API, traditionally solvent film-casting has been used for preliminary performance assessment of the specific polymer-API combination. The downside of this screening process, says Schäfer, is that it does not take into consideration processability characteristics associated with the HME process. Vacuum compression molding, he notes, is a new approach for screening that is more representative of the HME process. “This process involves a prior mixing step and temperatures closer to those used in HME, making it more suitable as a screening method that overcomes potential drawbacks of other approaches,” Schäfer contends.

The benefits of HME are no longer only leveraged for solubility enhancement for large-scale pharmaceutical manufacturing. Fused deposition modeling (FDM) is a three-dimensional (3D) printing technique using a process similar to HME, but on a much smaller scale. Its development, according to Morin, has created new possibilities, such as implementing HME formulation at the point of care and on a highly personalized level.

There are additional challenges to FDM not faced by traditional HME processes. In particular, Patil points to the fact that not all polymers and excipients (and their various combinations) suitable for traditional HME will be appropriate for preparing FDM filaments for 3D printing. “The desired application and the thermal and mechanical properties of the generated filaments must allow their passage through the 3D printer head, during which tensile and compressive forces and heat are applied.”

Other extrusion-based 3D printing technologies attracting interest for drug-product manufacturing include melt-drop deposition and melt-extrusion deposition (MED), which according to Schäfer show potential to be scalable future manufacturing process options.

Hope for easier introduction of novel excipients

Considering recent advancements and challenges in HME technology, as well as the overall versatility of twin-screw extrusion technology, Patil believes there is a need for new polymers for HME technology that can overcome these issues and meet the global health challenges of today and the future.

The success of HME and increasing interest in other promising novel drug-delivery technologies such as 3D printing underline the importance of the availability of broadly applicable excipients, especially regarding the potential future demand for personalized medicine, adds Schäfer. “[Because] there is a constant need for improvement and HME is still a rather new technology in the pharma sector, there is a rising demand for a toolbox of excipients which can be used within this space,” he continues.

While most agree novel excipients are needed to close the gap of HME processing suitability, novel excipients lack compendial status, which makes their global usage complex and time-consuming, and introduces significant regulatory hurdles, Schäfer observes.

Fortunately, regulatory authorities have recognized the risk of limited excipient options. For instance, FDA’s Pilot Program for the Review of Innovation and Modernization of Excipients (PRIME) is very encouraging and supportive for excipient vendors, notes Patil, as this program evaluates novel excipients for safety and acceptability for use in clinical trials, independent from a specific new drug application.

In addition, the International Pharmaceutical Excipients Council (IPEC) has developed a DMF guideline and continues to have discussions on how to support the development and use of new, safe excipient options, according to Schäfer. There are also ongoing efforts to expand the pharmacopeias to include additional monographs and/or adapt specifications, such as to enable minor fine-tuning and repurposing of well-known excipients.

There are many excipients available for increasing the oral bioavailability of small-molecule APIs. Each has different functionalities and physicochemical properties. It cannot be emphasized enough, Gattefossé insists, that the optimal excipients must be selected by considering the properties and functionalities of the API.

To do so requires a thorough understanding of the physicochemical properties of the API. “There are myths that certain types of molecules, such as those with a high melting point above 220 °C, molecules that break down when heated, or molecules that tend to recrystallize again, may not work well with HME technology,” says Patil. With the right combination of polymeric and other excipients, it is possible to overcome some of these issues.

The key, Patil believes, is early identification of any such limitations of an API. With this knowledge in hand, formulators can identify the right combination of polymers and other excipients to enable successful generation of ASDs using HME. She adds that it is particularly important to understand the degradation pathways of the API to select the right type(s) of excipient(s) to prevent that degradation from occurring during processing and storage.

Schäfer reiterates the value afforded by a toolbox of suitable high-quality excipients for overcoming development hurdles and bringing successful drugs to the market within the relevant regulatory framework. “There is no one-size-fits-all approach available for all APIs, requiring the need for different formulation solutions generally and different excipient options for HME processing specifically,” he says.

The need for such broad knowledge and expertise in many areas of formulation development, along with a significant equipment footprint and qualification capabilities places a strain on drug developers. “Suppliers can help by supporting their customers with strong partnerships that go beyond providing excipients of high quality. True partners back those excipients up with reliable information, share their expertise on excipient application and manufacturing procedures, and have their own application labs for evaluation of the suitability of excipients and methods and the pursuit of innovative solutions,” Schäfer concludes.

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


Vol. 47, No. 12
December 2023
Pages: 16-20

When referring to this article, please cite it as Challener, C.A. Selecting Excipients for Enhancing Solubility of Hot-Melt Extrusion Formulations. 

Articles

Matching excipients to API properties is essential.

Selecting Excipients for Enhancing Solubility of Hot-Melt Extrusion Formulations

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Poor water solubility continues to present a major challenge to formulators. Poor solubility (and permeability) generally translates to low bioavailability, which in turn results in reduced efficacy. Many approaches have been developed to enhance bioavailability, including the formation of solid amorphous dispersions and salts. Less common solutions include the use of coformers and the generation of cocrystals or complexes. One of the reasons these last three methods are employed less often is the greater challenges associated with finding the right molecule for a given API. Extensive experimental screening is often required. For this reason, predictive modeling capabilities could potentially accelerate the development of coformers, cocrystals, and complexes.

Coformers, cocrystals, and complexes of APIs have the potential to enhance bioavailability when carefully developed, but there are several challenges when traditional approaches are used, according to Jo Varshney, founder and CEO of VeriSIM Life.

“Exploration of the chemical combination space, given its vastness, is impractical,” Varshney states. For example, she points out that bioavailability may change in a non-linear fashion with different ratios of the same two coformers, or two very similar molecules may lead to a substantial change in the bioavailability of the API.

Thermodynamics of combination stability can also be a non-linear and/or non-monotonic function of the ratio of the two compounds, Varshney observes. “Traditional approaches can only explicitly investigate discrete combinations, and optimizing formulation stability using such sparse knowledge is often inaccurate,” she says.

Key to expanded use of predictive modeling in the development of specialized formulations aimed at increasing solubility enhancement is the advances being made in the fields of artificial intelligence (AI), machine learning (ML), and various other computational methods. Numerous technologies are now being applied across all aspects of drug discovery and development, including the formulation of APIs with poor solubility and bioavailability.

For the design and selection of coformers, cocrystals, and complexing agents in particular, the use of advanced neural network algorithms, ensemble-based methods, and knowledge-based models is making predictive modeling more relevant, according to Varshney.

They allow for more accurate interpolation between available experimental data. “This interpolation can be to different ratios of combinations or even to different types of combinations,” Varshney notes.

In addition, the inclusion of knowledge-based models in the framework of predictive modeling is having an impact. “When AI-based models are used in combination with knowledge-based models, more robust predictions can be generated even in limited-data scenarios, of which formulation science is definitely one,” contends Varshney. She adds that these knowledge-based models can accelerate the development of coformers, cocrystals, and complexing agents through an accurate consideration of the physiological, physicochemical, and structural aspects of molecules in the combinatorial space. VeriSIM Life uses such hybrid AI and knowledge-based models extensively in drug and formulation development.

The main benefit offered by predictive modeling is the possibility to save time and resources. Information gleaned from effective models can narrow down to a reasonable number the potential molecules that can serve as effective coformers or form attractive cocrystals or complexes. That in turn reduces the number of physical experiments that must be performed to identify the optimum solution.

Predictive modeling, says Varshney, allows for a rapid exploration of the combinatorial chemical space. She also emphasizes that when deployed in a hybrid-AI framework—especially those that emphasize the physicochemical and physiological aspects of the chemical moieties involved, predictive models can provide robust solutions for different compound combinations to enhance bioavailability of poorly soluble APIs.

Furthermore, Varshney observes that by extracting explainable insights from predictive modeling, it is possible to make observations about both existing and novel drug formulations to identify which features of drug formulations are most closely associated with improving bioavailability. “This increased understanding then guides novel formulation exploration in the most promising directions, further expediting the development of effective formulations,” she comments.

There are several advantages to using predictive modeling for identifying potential solutions for enhancing the bioavailability of poorly soluble APIs, agrees Sanjay Konagurthu, senior director, science and innovation, pharma services at Thermo Fisher Scientific. In addition to shortening development timelines, he emphasizes the ability to reduce risk in product development and remove barriers in each phase of development. Predictive modeling can also help reduce costs, avoid rework, reduce the amount of API required, and support sustainability, Konagurthu observes.

The greatest challenge to deploying predictive modeling solutions for coformer, cocrystal, and complex development is the need for high-quality data, according to both Varshney and Konagurthu.

“Predictive technologies/algorithms such as ML and AI are dependent on the quality and quantity of available data. Large data sets spanning the druggable formulation space are required,” Konagurthu explains. Unfortunately, that data can be hard to come by when it comes to coformer, cocrystal, and complex formulation.

Most predictive modeling technologies require a lot of high-quality data to make accurate predictions, the amount of which is essentially very limited for coformer, cocrystal, and complex formulations taking the vast space of possible compound combinations into consideration, Varshney agrees. She further notes that even that limited data are often not readily available for broad use because of the heterogeneity of the sources.

Adding to the challenges of limited data with limited access is the lack of data curation and accuracy standards, according to Varshney. “This issue leads to the propagation of errors from inaccurate data to predictions,” she explains.

There is also, Varshney believes, a lack of explainability with current modeling technologies. For instance, she says that if a complex or a combination is predicted to display low bioavailability, the underlying reason for it typically remains obscure. “This lack of explainability in terms of the physicochemical characteristics of the compounds in the combination precludes the design of combinations that could result in a higher bioavailability of the API,” Varshney explains.

There are some technical challenges as well. Konagurthu highlights the fact that predictive models require robust experimental validation, and models can be computationally intensive.

The best way to maximize the potential benefits of predictive modeling for the development of coformer, cocrystal, and complex formulations is to use a combination of approaches. The first, according to Varshney, is to use robust data mining algorithms to gather data from heterogeneous sources. The second is to employ enhanced data curation and accurate evaluation methods to reduce inaccuracies in the data used for predictive models. The third is to leverage knowledge-based models within the framework of predictive modeling to enable more robust, physicochemically accurate predictions in limited-data scenarios. Lastly, Varshney emphasizes the use of model explainability to help design the next generation of complexes, coformers, and cocrystals with higher API bioavailability.

Physical experimentation can then be employed to augment the available “prediction space” through the generation of high-quality data, Varshney observes. In addition, she notes that physical experimentation can help validate predictive models and increase trust in them, particularly when physical experimentation outcomes align with insights from model explainability.

As a separate comment, Varshney notes that VeriSIM Life’s BIOiSIM platform incorporates data gathering, data validation, hybrid AI, and model explainability aspects to de-risk and accelerate drug and formulation development.

Increasing importance for bioavailability enhancement

Despite the data, cost, and computational challenges, both Konagurthu and Varshney expect predictive modeling to be increasingly used to solve specific formulation development problems, including enhancement of bioavailability.

In the near term, Varshney expects efforts in predictive modeling for bioavailability enhancement during the drug formulation stage to focus on curating available data and incorporating novel algorithms, including hybrid AI methods, in order to identify and select appropriate coformers, cocrystals, etc. for certain poorly soluble APIs.

“In the longer term,” Varshney suggests, “the use of predictive modeling in formulation development and to improve bioavailability is going to be widely adopted by the pharma industry to reduce the burden of exhaustive experiments required to create appropriate cocrystals, coformers, etc.” She also expects it will help bring difficult-to-formulate drug compounds to market faster, thereby improving the lives of patients suffering with complex and rare diseases.

In the near term, Thermo Fisher Scientific anticipates significant advances in predictive modeling for formulation development and bioavailability enhancement, according to Konagurthu. “Increased integration of AI and ML techniques will enable the development of more accurate and versatile models,” he remarks.

In the longer term, the evolution of predictive modeling for formulation development and bioavailability enhancement will evolve in sophistication, Konagurthu contends. “Advances in quantum computing will allow for large and complex calculations and simulations, enabling the modeling of larger and more intricate molecular systems. In addition, with the incorporation of real-world data, such as patient outcomes and clinical-trial results, the precision and accuracy of these models will evolve even further,” he concludes.


Vol. 47, No. 11
November 2023
Pages: 16-19

When referring to this article, please cite it as Challener, C.A. Predictive Modeling for Formulation Development: Coformers, Cocrystals, Complexes. 

Predictive modeling facilitates the identification of coformers, cocrystal components, and complexing agents.

Predictive Modeling for Formulation Development: Coformers, Cocrystals, Complexes

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When synthetic organic chemistry transformations were first developed, chemists did not take into consideration their impact on the environment; the goal was to transform one substance into another. Use of large quantities of organic solvents, toxic and hazardous reagents combined with the need to often heat or cool reactions, however, adds up to a significant carbon footprint. As a result, when producing small-molecule pharmaceuticals, which involves many reactions performed on larger scale, the impact to the environment can be significant. The pharmaceutical industry has been aware of the need to improve sustainability of its operations across the board and has been taking action to improve its performance. With respect to small-molecule API synthesis, one solution has been to take a green-by design (or
greener-by-design, according to some) approach to establish more sustainable synthetic processes from the outset.

The field of organic chemistry, the basic science through which small-molecule pharmaceutical agents are prepared, is constantly evolving, contends Martin Eastgate, executive director of chemical process development for Bristol Myers Squibb (BMS). “More efficient, effective, and safer reactions (key elements to sustainability) are being discovered every day. In essence,” he concludes, “our ability to prepare small-molecule pharmaceuticals is consistently ‘getting greener’.”

Indeed, sustainability is becoming a cornerstone of drug development, according to Mahesh Bhalgat, chief operating officer at Syngene International. As a result, he observes that small-molecule API synthesis is evolving to meet the twin goals of producing life-saving medications while minimizing its ecological footprint, ultimately benefiting both patients and the planet. “We strongly believe that in a world with a rising need for innovative healthcare solutions and urgent environmental actions, the pharmaceutical sector is at a crossroads where it can combine scientific development with sustainable practices.”

Applying the basics of ‘greener-by-design’ principles to small-molecule pharmaceutical synthesis is fairly common across the major pharmaceutical companies, with organizations highlighting their work to explore more sustainable approaches to drug manufacturing, Eastgate says.

Merck, for instance, along with many collaborators is active in advocating for green and sustainable science across industry and academia. “We work to develop new technologies, such as novel enzymes and catalytic reactions, that have sustainability impacts across the field,” notes Kevin Maloney, executive director of process chemistry at Merck. He points to the ACS Green Chemistry Institute Pharmaceutical Roundtable (GCI PR), with more than 30 members, including Merck, dedicated to promoting the adoption of green chemistry and engineering in the pharmaceutical industry, as an example of an industry group taking real action in this area.

Each company takes its own approach to designing synthetic routes to small-molecule APIs, but increasingly there has been a cultural shift toward sustainability practices, according to Bhalgat. “One of the most widely applied approaches leverages green chemistry principles during process development, which involves the engineering of chemical products and processes to reduce or eliminate the use and generation of hazardous substances,” he says.

The 12 principles of green chemistry (1) guide small-molecule API process developers to use sustainable and non-toxic reagents and have the shortest possible synthetic route, with the fewest operations and highest yields possible to afford the most efficient process with the least waste, summarizes Patrick Fier, process chemistry principal scientist with Merck. He highlights five key factors that are affected: personnel safety, efficiency, selectivity, waste minimization, and the use of renewable resources.

“The safety of the API synthesis process is paramount. The reactants, solvents, and process conditions should be chosen with safety in mind and steps should be taken to reduce the likelihood of accidents or unexpected reactions,” Fier states. In addition, the use of high-yielding reactions and minimization of by-products and the number of reaction steps should be prioritized. By definition, then, the selectivity of reactions is crucial in ensuring the desired product is obtained, which drives the use of catalysis and highly selective reagents. Furthermore, Fier notes that recycling and reuse of materials such as solvents, catalysts, and reactants should be considered, as should the use of biobased or biosourced feedstocks and green solvents.

Overall, the selection of a sustainable synthetic method stresses resource conservation, reduces environmental impact, and increases compliance with regulatory norms, according to Bhalgat. “These strategies promote responsible chemistry by encouraging a healthier ecology and safer working circumstances,” he says.

Balancing sustainability and practicality

Green-by-design API synthesis does not occur in a vacuum. “Optimization of the way drugs are prepared sits side-by-side with the robustness needed to manufacture a drug with the quality, consistency, and purity needed for commercialization,” Eastgate notes.

In addition, Eastgate observes that the development of a novel therapeutic is a high-failure-rate activity. “That context provides a lens through which we need to consider the timing of investment (and the level of investment) in optimizing a molecule’s synthesis,” he says. Drug-development timelines are also very long, meaning committing to a synthetic method must be made long before launch, and changing synthetic methods post-launch is very difficult. Different APIs may also have different volume demand (from a few kilograms a year to 100s of metric tons). “Focusing on the right projects at the right time with the right perspective is critical to managing a large portfolio of drug candidates,” he concludes.

The most challenging aspect of attaining green-by-design small molecule API synthesis is balancing sustainability and practicality, agrees Bhalgat. “The synthesis of many pharmacologically active compounds is fundamentally complicated, necessitating multiple steps utilizing a variety of chemicals, solvents, acids, and bases with harsh reaction conditions. Changing these synthetic routes to greener approaches can be time-consuming and costly, or sometimes not possible (for example, a sulfonation or a nitration reaction), or both,” he explains.

There are various ways to articulate the many factors important to consider when evaluating the sustainability of a manufacturing route to an API. BMS often refers to the ‘three Ps of sustainability’—people (safety), planet (environmental impact), and portfolio (robustness, quality, efficiency, etc.), according to Eastgate.

All of these elements are important, Eastgate suggests. “When we discuss ‘greener-by-design’, the mind often slips purely to environmental sustainability. However, safety is foundational. Robustness during manufacturing is critical. The ability to deliver high-quality drugs is vital to every patient. Acting with urgency to deliver life-saving molecules is an imperative. As we consider greener-by-design, we have to be very nuanced in our thinking and broad-minded when considering how to implement this concept; it is important to globally optimize and not locally optimize only one parameter,” he comments.

A company culture that is committed to increasing sustainability across the board is, in fact, another key ingredient to successfully pursuing a green-by-design approach to small-molecule API synthesis. “Maintaining a sustainability-focused culture is an important piece of the green-by-design puzzle and one we choose to embrace as an opportunity to build engagement in our organization,” Maloney states.

At Merck, periodic evaluations of process metrics are routine and requisite within the process development workflow, so the entire R&D organization is involved in this type of decision-making, Maloney outlines. Additionally, the company hosts a Green and Sustainable Science Symposium annually with external leaders in green chemistry and sustainability, as well as internal talks, posters, and awards that allow Merck’s teams to showcase their work and exchange ideas.

In addition to cultural and contextual challenges, there are also technical hurdles that must be overcome when attempting to successfully achieve green-by-design small-molecule API synthesis routes. “Over the past several years, the overall complexity of molecules in drug discovery and development has been increasing with new modalities, ultimately necessitating the invention of new types of synthetic chemistry reactions and even reactors to streamline their synthesis,” Fier observes.

In addition, while science is constantly improving, many current synthetic methods still require environmentally challenging conditions (solvents, reagents etc.) or the use of raw material that may be mined or produced in unsustainable ways, according to Eastgate. “Consequently,” he states, “methods that avoid organic solvents, rare elements, etc., continue to be needed.”

Green reagent availability can, in fact, be a significant problem. “Creating a diverse and dependable set of green reagents is a continuously challenging task,” comments Bhalgat. “Further development of a green chemistry ecosystem is needed so that not only smaller companies, but larger manufacturers with strong marketing channels are offering greener materials,” he adds.

Merck’s approach to solving this problem is to build molecular complexity rapidly from simple commodity chemicals using novel enzymes and multi-enzyme cascades, according to Fier. “Such approaches can enable access to stereochemically complex molecules that would require many steps and protecting-group manipulations using traditional chemistry approaches,” he says. Fier also stresses that as the molecule development field evolves, there is a critical need to advance new reaction discovery.

With most small-molecule APIs, there are countless potential synthetic routes that can be used to produce them. Not all of these hundreds of potential pathways can be physically evaluated in the lab, according to Eastgate. He believes the best approach is to combine predictive, real-time quantitative and retrospective assessments (predictive, developmental, and life-cycle analyses).

“Simulated assessments are used to down-select to only a few options to be explored in the lab using quantitative, real-time assessments to ensure the optimum choices are made during development. Highly detailed retrospective assessments serve as a feedback loop for continuous learning,” Eastman explains. He adds that once a compound is placed on the market internationally, it is extremely difficult to tweak/adjust the way it is made, so predictive and developmental assessments need to be robust to ensure a sustainable design is achieved right the first time.

During route scouting, Merck leverages synthetic chemistry innovation, high-throughput experimentation, and the application of enabling technologies (biocatalysis, chemocatalysis, photocatalysis, flow chemistry, etc.) to identify the most direct route (least number of chemical steps while maximizing convergency and yield) from commodity chemicals to API, with particular focus on the 12 principles of green chemistry.

“Our focus is on developing the most robust and sustainable process. To do so, we leverage data-rich experimentation and mechanistic understanding to optimize the process to maximize yield, minimize hazardous waste, and reduce energy consumption while trying to incorporate relatively environmentally benign reagents, solvents, and raw materials. Consistent use of reliable metrics is critical in evaluating the decisions made based on these experiments, along with comparing the types of reagents, solvents, and building blocks used,” Fier says.

In fact, having reliable metrics as a fundamental aspect of designing a green process is necessary to achieve process sustainability, Maloney notes. It is equally important, he says, to foster a culture of using those metrics to set objectives and evaluate routes throughout development. “Without these tools, it can be difficult to objectively compare process alternatives or to align on what it means to have a green synthetic route when communicating with partners,” Maloney contends.

Some of the best approaches to selecting the greenest/most sustainable synthetic routes rely on the use of a range of metrics, agrees Bhalgat. The E-factor is the mass ratio of waste to desired product (2) and considers waste byproducts, leftover reactants, solvent losses, spent catalysts, and catalyst supports (3). Green solvent selection guides can be used to assess environmental impact, and life cycle assessment (LCA) provides information on the overall sustainability of the process, he adds.

“Collaboration among cross-functional groups (chemists, engineers, and sustainability experts) ensures a thorough examination of the process, which when overlaid with green chemistry principles and followed by an economic viability assessment, leads to selection of the greenest/most sustainable option,” Bhalgat comments. “This approach guarantees that the chosen strategy not only minimizes environmental impact but also corresponds with practical industrial needs,” he contends.

Many pharmaceutical companies and contract development and manufacturing organizations (CDMOs) use not only tools developed by outside organizations, but proprietary solutions developed internally.

Merck, for instance, developed SMART-PMI, which leverages large data sets to provide predictive PMI values of target PMI values for any API based on the chemical structure, with the aim of setting aggressive targets to drive innovations in green chemistry. “The goal is to set the baseline for what a ‘good’ PMI is for a given molecule and provide ambitious targets. By utilizing this tool, chemists are challenged to invent new synthetic strategies that make the biggest impact to PMI,” Fier explains. In addition, Fier notes that as innovation in green chemistry leads to improved PMIs, these data can help drive more aggressive targets for the model.

The company also uses a Streamlined PMI-life cycle analysis tool to calculate these metrics for processes and evaluate them against alternate routes, digging deeper into the potential lifecycle impact of each synthetic step to highlight areas where additional development could yield substantial improvement.

BMS, meanwhile, has developed a number of tools internally that help assess the potential of various synthetic routes for APIs. Some have been published and released as apps in collaboration with the GCI PR, according to Eastgate, such as a tool for predicting the potential PMI of synthetic routes under consideration (the PMI Calculator) (4). “Our culture focuses on developing excellent internal tools, merging them with the best external tools, the expert opinions of our scientists, our prior internal knowledge as a team, and our industry’s institutional insight—all of which are vital. Sustainability of API manufacturing is not a single-point assessment; there is no one tool that we can use,” he emphasizes.

Continuous progress toward green-by-design small-molecule API synthesis provides ongoing potential for refinement. Greener synthesis processes, says Bhalgat, can be supplemented by more sustainable purification procedures, such as membrane separation or alternative crystallization methods. Techniques for minimizing the energy intensity of processes, such as microwave or ultrasonic-assisted reactions, could improve efficiency. The use of artificial intelligence and machine learning to identify alternative reagents and synthetic routes has significant potential as well. Wider use and review of metrics for green chemistry will also drive more clarity around management interest in green-by-design API synthesis.

Even though the field of organic synthesis is highly advanced, adds Maloney, researchers are always seeking new innovations and ways to develop sustainable methods for synthesizing APIs. Merck routinely seeks to identify major gaps in existing synthetic methodologies with respect to the need for more environmentally benign reaction conditions and streamlined routes.

Technology is constantly advancing, Eastgate agrees, and the industry should be seeking to bring innovations into pharmaceutical manufacturing as quickly as possible to improve sustainability. One area of particular opportunity for him is the combination of data science with organic chemistry, which he sees as creating significant opportunity for innovation. “We are on the cusp of a significant digital revolution within organic chemistry, with data analytics, modeling, and simulation based on large lakes of high-throughput reaction data from large screens significantly improving our ability to rapidly develop more efficient and sustainable synthetic routes,” he believes.

“The ultimate goal,” Maloney says, “is to have a ‘zero waste’ API manufacturing process. With this ambition in mind, the pharmaceutical industry must continue to invest in the development of new synthetic methodologies and enabling technologies that rapidly and efficiently build molecular complexity with simple and relatively environmentally benign reagents.”

The speed at which the pharmaceutical industry is moving toward sustainability must be increased, however, contends Bhalgat. “The ecosystem must evolve through a comprehensive exercise wherein scientific solutions are developed, evaluated, and implemented. Incentivization approaches must be brought in, such as priority review and rapid regulatory approvals for drugs developed using green chemistry technologies,” he observes.

CDMOs in particular, Bhalgat says, have the potential to make a significant difference in the pharmaceutical industry’s journey toward sustainability. “Outsourcing partners may expedite the adoption of greener processes, ethical practices, and environmentally friendly solutions through the integration of innovative technologies, collaborative alliances with multiple clients, and adherence to best industry practices,” he comments.

Pharmaceutical companies and CDMOs alike are investing in the development of sustainable methods for synthesizing APIs. Green-by-design approaches that focus on renewable raw materials, non-toxic and sustainable solvents, and efficient processes are gaining momentum, according to Maloney. Companies are also leveraging technologies like flow chemistry and biocatalysis to achieve sustainability by realizing greater process efficiencies and lowering environmental impacts.

In fact, Eastgate believes there is great opportunity in the next 5–10 years to make significant strides in improving the sustainability of small-molecule manufacturing. “The coupling of improved synthetic methods with data analytics and predictive modeling/simulation will be critical going forward, as decision making is really at the root of improving sustainability,” he states.

“Having greater tools to explore the options through modeling/simulation to bring the greater longer-term consequences and perspective (What would the environmental impact be? Would this be robust? What risks will we face in developing this approach?) are key questions that we are getting closer to being able to understand … at the very stage when we are generating the ideas we want to try,” Eastgate adds.

Given these developments, Bhalgat believes that the trajectory of small-molecule API synthesis is moving decisively toward a more sustainable future and some significant shifts should be expected. “As environmental concerns grow, the pharmaceutical industry is embracing greener practices; however, this trend needs to intensify further. Innovation in green chemistry principles, catalysis, and alternative reaction methods will drive the development of processes that reduce waste, minimize energy consumption, and employ safer reagents. Continuous flow technology, biocatalysts, and AI-driven approaches will become more vital, enabling precise control, selectivity, and resource efficiency. A deeper understanding of the process impact on the products and impurity profiles will also be crucial to understanding the level of control needed on process parameters. Collaboration among researchers, industry, and regulatory bodies will foster the exchange of knowledge and best practices.

To fully implement green chemistry principles across the world, however, Maloney cautions that cultural shifts and ongoing investments in innovative technologies, education, and training will need to be undertaken.

Anastas, P. T. and Warner, J.C. Green Chemistry: Theory and Practice, Oxford University Press, New York (1998).

Manahan, S.E. The E-Factor in Green Chemistry. LibreTexts™ Chemistry
(accessed Aug. 28, 2023).

ACS Green Chemistry Institute. Recap of the SELECT Criteria (accessed
Aug. 28, 2023).

ACS Green Chemistry Institute. PMI Calculator.


Vol. 47, No. 10
October 2023
Pages: 18-23

When referring to this article, please cite it as Challener, C.A. Green-by-Design Small-Molecule API Synthesis. 

Sustainability advances are being made, but more investment is needed.

Green-by-Design Small-Molecule API Synthesis

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.


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. 

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

Formulating with Coprocessed Excipients: Current Trends

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).

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