Impact of Surfactants as Formulation Additives and Media Components on the Performance of Amorphous Solid Dispersions

Abstract

Amorphous solid dispersions (ASDs) make a significant contribution to enhancing the solubility of poorly soluble drugs. The incorporation of surfactants in ASDs serves not only to facilitate the preparation process but also to further enhance solubility and bioavailability. However, the introduction of surfactants may also bring some risks, such as surface enrichment of surfactants during manufacturing, reducing the physical stability of ASDs during manufacturing or storage and accelerating the precipitation of drugs during dissolution. Drug in ASD typically exists in an amorphous form, which is inherently unstable and tends to revert to a more stable crystalline form. Surfactants often accelerate the diffusion of drug molecules or interfere with the ability of the polymer carrier in ASDs, thereby affecting the performance of amorphous drugs in vitro and in vivo. At present, the prediction of how surfactants influence the crystallization, dissolution, and bioavailability of ASDs, as well as the delicate balance between enhancing solubilization and maintaining the physical stability of ASDs, has attracted significant research interest and attention. This review is intended to provide a detailed summary of the structures and properties of surfactants commonly employed in ASDs, as well as their effects on the performance of ASDs as formulation additives and media components. It is intended to serve as a reference for selecting appropriate surfactants during the development of ASDs.

Introduction

With the advancement of drug development technologies, a growing number of new chemical entities (NCEs) are being developed as candidate drugs. (1−3) However, the majority of these NCEs exhibit poor water solubility. The low solubility of these candidates leads to slow dissolution, which in turn results in low bioavailability. This has become a significant barrier in the development of these candidates into marketable drugs. (1−3) Currently, converting crystalline drugs into amorphous forms is a widely adopted strategy to increase solubility and bioavailability. (1−5) According to a recent statistical analysis, the U.S. Food and Drug Administration has granted approval to 48 drug products containing amorphous solid dispersions (ASDs) over the 12 – year period from 2012 to 2023. (6) However, compared to the total number of water insoluble drugs and candidates, the proportion of marketed amorphous drugs still remains relatively limited. The factors that limit the development of amorphous drugs into ASD products are multifaceted. (3,6−9) First, there is the difficulty in preparing amorphous drug formulations. The various techniques employed to create ASDs can be divided into two main categories according to how the API dissolves within the polymer. These categories are solvent-based methods and solvent-free methods. (3) Transforming poorly soluble drugs from a crystalline state to an amorphous form requires overcoming lattice energy, while also maintaining the chemical stability of the drug and avoiding solvent residue. (10) Meanwhile, special attention should be given to the dosing requirements for preclinical and clinical studies. (3,6,9) ASDs with higher drug loading are preferred for delivering high doses and reducing the pill burden in clinical settings. (3,6,9) Moreover, after meeting the dosing requirements, it is also necessary to maintain the stability of the amorphous form. Amorphous drugs are in a higher energy state and therefore have poorer physical stability. They may transform into crystalline drugs during preparation, storage, and dissolution processes. (11) Ensuring the full conversion of crystalline drugs to the amorphous state during preparation, and maintaining this amorphous state during storage and dissolution, is crucial for achieving rapid drug dissolution and enhanced bioavailability. (1,2,12,13)

Table 1. Marketed Products of ASDs with Surfactants

The addition of surfactants is often primarily aimed at facilitating the preparation of ASDs, or further enhancing the dissolution and bioavailability of ASDs. (14−17) This strategy is widely applied in the development of ASDs, and there are already related ASD products on the market. For example, Orkambi, which is used to treat cystic fibrosis, contains the surfactant SLS in its formulation. (18) Surfactants can help wet water insoluble drugs or reduce the surface tension, thereby enhancing the dissolution and ultimately improving their bioavailability. (14−16)Table 1 provides a summary of several marketed ASDs, along with their respective surfactants and polymers. (18,19)

Meanwhile, existing research indicates that surfactants exhibit a plasticizing effect, which reduces the Tg and decreases the melt viscosity of the polymer. (20,21) Thus, the addition of surfactants is also beneficial for the preparation of ASDs, especially for methods involving heat treatment. (22) Among the current methods for preparing amorphous drugs, HME offers unique advantages, including no concerns regarding solvent residues, and ease of compliance with Good Manufacturing Practice (GMP) requirements.

However, during the HME process, the drug is subjected to heating, which may impact its thermal stability. (13) To enhance the chemical stability of drugs during the preparation process, surfactants can be incorporated to decrease the viscosity of the system, thereby lowering the processing temperature.

However, the plasticizing effect of surfactants on ASDs increases the molecular mobility within the ASDs, thereby potentially threatening their physical stability. (18,23−25) The polymers in ASDs often act as antiplasticizing agents, which can inhibit the crystallization of amorphous drugs. However, surfactants typically exhibit a plasticizing effect, as they increase molecular mobility within the system. This can accelerate phase separation and crystallization. (25,26) Moreover, as an external third component to the drug-polymer system, surfactants may disrupt the interactions between the drug and polymer, thereby adversely affecting dissolution and bioavailability. (27) In vivo experimental studies have shown that not all surfactants can enhance bioavailability. (27) This highlights the complexity of the impact of surfactants on ASDs. (28−30) Meanwhile, human intestinal fluids are known to contain a wide array of bile salts and phospholipids. These endogenous surfactants may influence the performance of orally administered ASDs. (31−37) Determining how to select a surfactant that can ensure the desired performance of ASDs under both in vitro and in vivo conditions, while effectively enhancing dissolution and ultimately improving bioavailability, remains a significant challenge. (38,39) At present, this can only be achieved through trial-and-error experimentation and screening.

To sum up, the judicious application of surfactants is crucial for the development of ASDs. This review focuses on the impact of surfactants on ASDs and provides the latest progress. Investigating the impact of surfactants on the performance of amorphous drugs in various states can guide the selection of suitable surfactants for ASD formulation.

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Jie Zhang, Luna Zhang, Minzhuo Liu, and Zhihong Zeng, Impact of Surfactants as Formulation Additives and Media Components on the Performance of Amorphous Solid Dispersions, Crystal Growth & Design Article ASAP, DOI: 10.1021/acs.cgd.5c00417