FORMULATION DEVELOPMENT - Solving Tough Solubility Issues With Fewer Compromises & Better Outcomes

INTRODUCTION

Approximately 40% of drugs with market approval and nearly 90% of active pharmaceutical ingredients (APIs) in the dis­covery pipeline have bioavailability challenges due to low solu­bility that can impact drug delivery.¹ In fact, bioavailability challenges result in new drugs under development either being delayed or failing to reach the market. To address this issue, there is now an array of enabling technologies available that help over­come the pharmacokinetic challenges of poorly soluble APIs.

There are two main causes of low solubility: high crystalline lattice energy and high lipophilicity. Because drug discovery con­tinues to rely on high-throughput screening techniques to identify drug candidates based on receptor binding affinity, new chemical entity (NCE) pipelines are mostly composed of lipophilic com­pounds. Fortunately, enhanced solubility can be achieved using a variety of approaches. For oral solid dosage forms, well-estab­lished approaches include micronization, nanoparticles, amor­phous solid dispersions (ASDs), lipid-based formulations, salts, and co-crystals.

MICRONIZATION: PRACTICAL PARTICLE SIZE REDUCTION

Particle size reduction technologies are routinely used to in­crease the bioavailability of poorly soluble drugs. The principle is relatively straightforward in practice: reducing particle size in­creases the relative surface area and, consequently, its rate of sol­vation. Because the degree of crystallinity is reduced, particularly at the nanoscale, apparent solubility increases, resulting in faster, more complete dissolution.

Although traditional milling and homogenization techniques are widely available for particle size reduction, these tend to be high-energy processes that may not be ideal for heat-sensitive APIs. However, alternative, lower-energy techniques are becom­ing increasingly widely used, using both top-down (cryo-milling) and bottom-up (nanocrystals) approaches. While bottom-up tech­niques typically result in smaller, more uniform particle size dis­tributions compared with top-down methods, they require the API to have appreciable initial solubility, which limits their effective­ness with extremely insoluble compounds.

NANOCRYSTALS: SHAPING BETTER SOLUBILITY PROFILES

Nanocrystallization may help formulators deal with complex and poorly soluble APIs by offering better stability due to the crystalline characteristics of the particle. Nanocrystals improve solu­bility through an increase in the surface area beyond that provided by micronization alone and can be administered as a dispersion in the liq­uid medium or the solid state. Amorphous nanoparticles offer even greater solubility enhancement, but they require mecha­nisms to maintain their stability in amor­phous forms to prevent conversion to more stable crystalline forms.

Nanocrystals can be prepared by bead milling, high-pressure homogeniza­tion, and antisolvent precipitation. Another characteristic of nanocrystals that supports therapeutic performance is the fact that particles are 100% API and require no ex­cipients. This technology can enable higher API drug loads per dose. However, this process requires surfactants as stabi­lizers, which may lead to new formulation complexities.

ASDS: IDEAL FOR HIGH-ENERGY APIS

ASDs offer better dissolution profiles and enhanced bioavailability by eliminat­ing the crystal structure, making this tech­nique ideal for APIs where high lattice energy is the main reason for low solubil­ity. High lipophilicity can also be ad­dressed by choosing a more hydrophobic carrier.

Both spray drying and hot melt extru­sion (HME) can be used to produce ASDs. Several factors come into play including performance, projected dose, stability, and manufacturability. When determining which technology to employ for optimizing ASD’s performance, two key factors should be considered: the physicochemical prop­erties of the API and the phase of develop­ment, which influences the amount of API available for formulation development.

In the early stage of discovery, API availability is often limited, which makes spray drying the more efficient approach because the feasibility studies can be de­termined with much less API than with HME. For APIs that are amenable to HME, which is typically identified after proof-of-concept clinical studies, an initial spray-drying process can be converted to HME if necessary.

Important physicochemical properties for creating an ASD include the solubility of the API in a solvent suitable for spray drying, as it affects process efficiency, par­ticle formation, API recovery, and formula­tion stability. HME is sometimes preferable as it does not rely on solvents. Notably, the heat and shear forces exerted during HME can be critical for overcoming tough solu­bility challenges but pose significant bar­riers when processing heat-sensitive APIs.

ASDs present several challenges to downstream formulation. Poor flow is one undesirable characteristic of spray-dried dispersions. Dry granulation can be em­ployed to improve flow, but this technique can affect tablet compression. Due to the ratio of polymer to drug required to create stable ASDs, additional excipients are nec­essary to produce a reasonably sized fin­ished drug product. Ideally, an increase in dose size is balanced by an increase in bioavailability, which allows for less-fre­quent dosing. Given the increased focus on patient centricity and compliance in today’s drug delivery industry, size and swallowability are important considera­tions.

NOT TO BE OVERLOOKED: ASD PERFORMANCE IN VIVO

Residual crystallinity and re-crystal­lization of APIs during ASD processing also pose a challenge for drug development. Stability studies are required to ensure a viable product is developed. However, in vivo performance is often overlooked once the ASD has been optimized for its solid state.

ASDs are subject to what is often re­ferred to as the “spring and parachute” ef­fect. Compared with pure crystalline API, ASDs in the gastrointestinal (GI) tract ex­hibit more rapid and complete dissolution (the “spring”) resulting in a metastable su­persaturated solution of API. If this effect is not maintained or slowed by crystallization inhibitors, API precipitation can result, re­turning it to its most thermodynamically stable (ie, low-solubility) form. To prevent API precipitation and improve bioavailabil­ity, it is crucial to add polymers that act as a “parachute” effect, keeping the drug in solution after release into the GI tract and maintaining supersaturation. Although ASD polymers can provide additive effects, such as inhibiting crystallization or influ­encing the polymorph formed during re-crystallization, their volume and the need for additional crystallization inhibitors should all be carefully evaluated to opti­mize in vivo performance and stability while fully capturing the benefits of ASDs.

LIPID-BASED DRUG DELIVERY SYSTEMS: AN EFFECTIVE ROUTE FOR THE RIGHT FORMULATION

Lipid-based drug delivery systems (LBDDS) are formulations containing a dis­solved or suspended drug in a lipidic ex­cipient. They can be filled into hard or soft gelatin capsules and provide an adaptable platform to deliver APIs that possess im­pediments to suitable bioavailability.

These formulations range in complex­ity from simple drugs in oils to doses de­signed to spontaneously emulsify upon contact with aqueous media – known as self-emulsifying drug delivery systems or self-microemulsifying drug delivery sys­tems.

The versatility of this approach is a re­sult of the number of excipients available to create formulations with targeted prop­erties, including enhanced solubility and permeability, and sustained release. How­ever, this variety, combined with how changes in composition affect solubiliza­tion, permeation, and stability can make the development of a LBDDS seem com­plex. Fortunately, CDMOs with lipid-based formulation development experience can offer extensive expertise that enables ro­bust and expedited approaches for this de­velopment.

SALTS: OPEN WINDOWS TO SOLUBILITY BY CHANGING PH

One of the most frequently used ap­proaches to increase the bioavailability of poorly soluble ionizable APIs is salt forma­tion and salt selection. However, while par­ticular salts and their formation can enhance solubility and the drug release rate, certain salt formation gets precipated and converted to its respective free acid/base form when it is orally administered, causing variability in exposure due to dif­ferences in solubility in the stomach and upper intestine. The lo­cation and extent of absorption are affected in vivo as the changing pH along the GI tract creates “windows” where more of the drug molecule is in its neutral form and can be more easily absorbed. In addition, the in vivo dissolution of some salts, espe­cially hydrochloride salts, can be limited by the common ion effect of chloride in the GI tract. Overall, realizing the benefit of salt formation depends on the careful analysis of factors such as the API’s inherent solubility, its acidity or basicity (expressed through pKa values), and the available options for salt formation to in­crease the chances of successful salt preparation.

CO-CRYSTALS: LOWER LATTICE ENERGY & HIGHER APPARENT SOLUBILITY

Unlike salt formation, co-crystal technology is best applied to non-ionizable APIs. A more contemporary approach to improv­ing bioavailability, co-crystallization involves co-precipitation of an API with a soluble co-former, leveraging non-covalent inter­molecular forces between the two compounds (primarily hydro­gen bonds) to form a single-phase crystalline material with lower lattice energy and higher apparent solubility compared with pure crystalline API. The improvement in physicochemical properties, including solubility, dissolution rate, stability, and melting point, make co-crystallization a more attractive option for poorly soluble APIs. However, it is important to note that although co-crystals are more stable than ASDs, they suffer from the same “spring and parachute” effect, but without the additive effects of many ASD polymers on crystallization inhibition. Here, as well, addi­tional formulation development is needed to optimize in vivo per­formance.

RESOLVING SOLUBILITY PROBLEMS REQUIRES SOLID ANALYTICS & PARTNERS

With so many viable options for bioavailability enhancement, developers who invest in thorough API characterization are well positioned to swiftly overcome challenges by identifying the tech­nologies best suited to their drug.

However, the benefits of these innovations cannot be realized without a thorough characterization of solid-state chemistries. As new technologies and complex formulations enter the pipeline, careful development strategies and transparent partner collabo­rations will increasingly be seen as the best strategy to avoid de­lays in getting new therapies to markets and patients.

By working with specialist contract development and manu­facturing organizations, pharmaceutical companies can access the expertise and infrastructure to overcome these challenges and harness new technologies. As a result, they can be confident they have the tools at their disposal to optimize the solubility, safety, and effectiveness of their formulations.

REFERENCE

1. https://www.mdpi.com/2075-1729/13/5/1099.

Dr. Anshul Gupte joined Catalent in 2022 and currently serves as Senior Director, Scientific and Technical Affairs. He has over 15 years of experience in product and analytical drug product development. He has contributed to several branded and generic regulatory submissions for US and worldwide markets. He has experience in working on drug product concept to commercialization from both a CDMO and sponsor prospective for a variety of solid oral and topical dosage form delivery systems. He earned his BPharm in India, his MS in Pharmaceutical Sciences from Temple University, and his PhD from the University of Kentucky. He also holds Regulatory Affairs Certification (RAC Drugs) from Regulatory Affairs Professional Society (RAPS).