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Matching excipients to API properties is essential.
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.
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.
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 Pharmaceutical Technology®
Vol. 47, No. 12
When referring to this article, please cite it as Challener, C.A. Selecting Excipients for Enhancing Solubility of Hot-Melt Extrusion Formulations. Pharmaceutical Technology 2023 47 (12).