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PharmTech.com Trends in Formulation eBook September 2024 Pharmaceutical Technology ® 35 Industry trends Additional formulation trends include deliver y through lipid nanoparticles, ultra-high protein con- centration formulations, continuous manufacturing, automation, and the creation of orphan drugs. Enhancements in solid-dosage formulation Automation has had a significant impact on the develop- ment of medicines delivered in capsule and tablet forms, according to Vinay Patil, Product Development Manager at Sharp Services. "Modern machines offer high-speed, precision filling and can handle various fill materials such as powders, granules, pellets, and even liquids," says Patil. "Even more currently, micro-dosing technology allows us to accurately dose small quantities of API, which is critical when working with potent drugs. These advancements have increased the speed and precision of drug produc- tion and expanded the range of materials that can be used." Patil also points to advances in granulation, compression, and coating that have impacted formulation. "The introduction of high-shear granulators, fluid-bed processors, and roller compaction has enhanced the production of tablets with better mechanical proper- ties and dissolution profiles. Coating technologies have also advanced, with enteric coatings and controlled-re- lease formulations becoming more common," says Patil. "Recently, continuous manufacturing processes have improved tablet production efficiency, allowing for real-time monitoring and increased production speed. One very recent advancement is the use of 3D printing technology, which has allowed for the production of tablets with controlled release profiles personalized to individual patients." The solubility problem Poor solubility is a prevalent issue in the industry, with most new compounds currently in development exhib- iting poor solubility, according to Levet. "[I]nnovative formulation strategies supported by nanotechnologies or amorphous solid dispersions have become truly piv- otal in bringing these molecules to the clinics and in the end to patients." Technologies such as spray-drying dispersion, spray drying, hot-melt extrusion, and nanoparticle systems are being used to combat the challenges of solubility, specifies Biswas. "Micronization, another common technique, continues to be essential for low-solubil- ity compounds," says Biswas. "In some cases, where spray-drying is unsuitable due to physicochemical prop- erties, alternative approaches like liquid formulations or hot melt extrusion are employed. Liquid formulations, such as those using liquid-filled hard gelatin capsules, provide quick-to-clinic solutions for lipophilic drugs, enhancing exposure and enabling rapid Phase I clinical studies. Hot-melt extrusion, although less common than spray-drying, is another viable technology, especially for stable drugs that can withstand high temperatures." Missaghi points to use of prodrugs and salt formula- tion, particle size reduction and other physical methods, as well as lipidic formulation, as ways to address poor aqueous solubility. "The technologies are continually evolving to ref lect more innovative methods that en- hance solubility and bioavailability, and ultimately improve the patient outcome. There is a lot of special- ized innovation in the market," Missaghi says. "Each approach has advantages and drawbacks and should be carefully evaluated based on the specific properties of the drug molecule, the desired final dosage form, and the required formulation performance." Patel stresses that there is no one-size-fits all ap- proach, with each molecule being unique. "Our formu- lation development approach uses the Developability Classification System (DCS) to help aid the technology selection for how we address poorly soluble molecules," says Patel. "DCS assesses human jejunal permeability and the aqueous dose-to-solubility ratio to determine whether the molecule is Class I, IIa, IIb, III, or IV. For Class IIa molecules, employing particle size reduction or using wetting agents are two techniques we've used to increase the molecule's dissolution rate. However, Class IIb molecules may require advanced strategies such as developing amorphous systems using spray drying and hot-melt extrusion technology." Levet points to amorphous solid dispersions, which disperses the drug in an amorphous state in a polymeric carrier, as an approach to enhance solubility and bio- availability. Levet also states that nanosuspensions, which reduce particle size to nanometer scale, improve dissolution rates and solubility. "Cyclodextrins have also been employed to enhance the solubility of drugs," says Levet. "These cyclic oligosaccharides can form inclusion complexes with drug molecules, which can greatly improve their solubility and stability. Recently, the European Medicines Agency (EMA) has helped for- mulators, by providing clear guidance on the safety of cyclodextrins in formulations, particularly for oral and injectable products." High viscosity is a specific challenge in the develop- ment of ultra-high protein concentration formulations, according to Himanshu Gadgil, CEO of Enzene. "Scien- tists and excipient manufacturers are addressing this issue by choosing and combining different excipients to decrease the viscosity of the formulations, making them suitable for the subcutaneous route," says Gadgil. "To counter the challenge of higher viscosity, primary container closure manufacturers are also innovating drug delivery systems, such as changing the needle structure of pre-filled syringes or modifying the force required for auto-injectors. Additionally, to enable the distribution of high viscosity drugs from the site of injection, advances are being made to combine such high concentration drugs with other agents like Hy- aluronidase."