The Modern Medicinal Chemist’s Guide to Formulations
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Nanoform is a nanoparticle medicine enabling company that works with pharma and biotech partners globally to provide hope for patients. We are focused on reducing clinical attrition and on enhancing drug molecules’ performance through our nanoforming technologies and formulation services. Our capabilities include GMP manufacturing, and our services span the small to large molecule development space with a focus on solving solubility and bioavailability challenges and on enabling novel drug delivery applications.
This article briefly summarizes clinical formulation options for oral drugs available to drug discovery teams. This succinct guide also highlights which formulation strategy is most likely to succeed based on the class of your compound defined by the Biopharmaceutical Classification System (BCS). While we encourage you to engage your internal formulations group or an external formulations partner at an early stage of your drug discovery project, this resource can help prepare you for the conversation.
Ideal Formulations Are Often Key to Improving Bioavailability
To guarantee ideal absorption, modern medicinal chemists recognize the importance of optimizing physicochemical parameters and properties of their molecules. Industry teams increasingly need to have development and formulation discussions at earlier stages in the drug discovery process to maximize probability of clinical success. We recently had the privilege of hosting a webinar on formulation options to improve bioavailability from Nanoform’s Tamas Solymosi and Christian Jones, who invited drug hunters to consider the formulations of their final drug product earlier in the process. In times of increasingly tight timelines between bench and clinic and greater commercial competition, considering formulation strategies early on can give your program an edge. The advent of novel formulation technologies has unlocked unprecedented opportunities for medicinal chemists to develop orally active drugs with high molecular weights and other previously unimaginable properties.
Typical Drug Formulation Strategies
The most common lever to pull in drug formulation is the drug’s crystal form and related modifications, which include salt forms, polymorphs, amorphous forms, and co-crystal formulations. Typically, a polymorph screen will give discovery teams an idea which crystal form is the most stable. The solubility of this form must be considered and is oftentimes lower than that of the amorphous form profiled during the discovery process. When the API faces low solubility, decreasing the particle size increases the surface areas for dissolution, giving rise to size reduction formulation methods such as micronization, nanomilling, and nanoforming. Another formulation route to improve solubility is through generation of amorphous solid dispersions through techniques such as spray drying, hot melt extrusion, and co-precipitation. When the API has very low aqueous solubility, turning to solubilizing systems such as lipid-based formulations or cyclodextrin complexes can improve bioavailability.
Figure 1. Representative examples of clinically-used formulations with approved drugs. The nanoformed piroxicam tablets have not yet been approved, but proof-of-concept was demonstrated in a Ph. I study.
Where to Start When Finding a Formulation for Your Drug Candidate
When deciding which formulation approach for your new drug candidate is best, the Biopharmaceutical Classification System (BCS) is commonly considered. The BCS classifies drugs based on their solubility and permeability characteristics. It classifies compounds into four categories (Figure 1, bottom): Class I typically displays excellent oral bioavailability. In classes II and III, oral bioavailability can be modified with formulation strategies. Class IV is the most challenging, and compounds from that category are typically delivered via injection.
Class I – High Solubility and High Permeability
Class I compounds represent the simplest cases with high solubility, defined by the highest dose being soluble in 250 mL of aqueous solution in a pH range from 1.2 to 6.8 at 37 °C, and high permeability, defined by 85% absorption in humans by mass-balance or in comparison to intravenous dosing. Permeability can also be assessed using a standardized and validated in vitro method such as Caco-2. For class I drugs, conventional tablet/capsule formulations for APIs are often sufficient to ensure ideal oral bioavailability. While class I drugs made up 30-40% of the top 200 drugs in 2013, there has been a trend away from this class in modern drug discovery, with class I compounds comprising only 5-10% of drugs in 2019. Imatinib is an example of a class I drug, and has been formulated into a tablet as a mesylate salt to provide ideal oral bioavailability.
Class II – Low Solubility and High Permeability
Class II compounds are defined by low solubility with high biological permeability. Class II can be further subcategorized into class IIa (dissolution-limited absorption) and class IIb (solubility-limited absorption). The formulation selection in this category depends more on the API’s dose, solubility limitations, organic solvent solubility, thermal stability, solid-state properties, and compatibility with excipients. Salt formation and micronization are the default methods for class II compounds but can be insufficient for low-solubility compounds requiring amorphous solid dispersions or nanoparticles to solve PK issues. Other approaches to improve PK in class II include lipid solubilization and cyclodextrin complexation. Enzalutamide serves as a good example of a class II drug, where an amorphous solid dispersion (ASD) formulation resulted in a five-fold improvement in the extent of enzalutamide absorption in rats relative to crystalline control. As an alternative, Nanoform has recently addressed the same issue with enzalutamide in a clinical setting utilizing a nanocrystal formulation, offering a lower pill burden and a greener manufacturing process compared to ASDs.
Class III – High Solubility and Low Permeability
Class III APIs have high solubility and low permeability, commonly allowing for formulations with conventional tablets/capsules. A medicinal chemistry strategy to improve permeability for this class of molecules is use of a prodrug (see for example this recent article on the NLRP3 inhibitor prodrug NT-0796). In some cases, a permeation enhancer can be included in oral peptide formulations such as that used for MK-0616. Examples of permeation enhancers include salcaprozate sodium (SNAC), an N-acetylated amino acid derivative of salicylic acid, and sodium caprate. Water-soluble compounds in the class I and III categories can also be formulated with Nanoform’s Bio Lines process.
Class IV – Low Solubility and Low Permeability
Class IV compounds are characterized by low solubility and low permeability, making them the most challenging class to formulate. Identifying the reason for the compound’s poor permeability is usually the first step. Sometimes compounds may exhibit adequate permeability that remains unrecognized due to limitations in the assay (e.g., precipitation). For such compounds class II strategies designed for low-solubility compounds can prove effective to increase absorption. True class IV compounds pose significant challenges for oral formulation, often necessitating delivery via injection. These class IV compounds are frequently subject to extensive first-pass metabolism and may be susceptible to efflux by transporter proteins. An example from a true class IV compound is the antifungal, amphotericin B.
Get Your Formulations Team Involved Early
The nuanced understanding of absorption challenges specific to different BCS classes has ushered in an era of strategic formulation tactics to improve oral bioavailability. Since formulations are a critical part of the development process in modern drug discovery, it is important to consider your formulation needs early in the program. We hope this guide is helpful in making decisions specific to your programs. For more advice, we recommend contacting your internal formulations representative or external partners like Nanoform for an expert opinion on how to best advance your compound into development.
Nanoform Offers Cutting-Edge Formulation Technology to Improve Bioavailability
With extensive experience partnering with numerous commercial-stage pharma companies, Nanoform has the expertise and technologies to assist you with your drug formulation needs. With Nanoform’s AI tool Starmap®, the best methods most likely to achieve a more bioavailable formulation of your API can be predicted. If the API has low solubility, Nanoform’s CESS® system can manufacture nanoparticle formulations without using organic hydrocarbon solvents, excipients, or complex production processes. For instances of peptides and macromolecules, Nanoform’s proprietary bionanoparticle technology can co-process multiple APIs and excipients with tunable and consistent particle size at low processing temperatures. Finally, if your the program must turn to injectables, Nanoform offers long-acting injectable nanoparticle formulations for less frequent injections and more uniform implants, resulting in better patient compliance and therapeutic efficacy.
