Recent Advances in Amorphous Solid Dispersions: Preformulation, Formulation Strategies, Technological Advancements and Characterization

Abstract

Amorphous solid dispersions (ASDs) are among the most popular and widely studied solubility enhancement techniques. Since their inception in the early 1960s, the formulation development of ASDs has undergone tremendous progress. For instance, the method of preparing ASDs evolved from solvent-based approaches to solvent-free methods such as hot melt extrusion and Kinetisol^®. The formulation approaches have advanced from employing a single polymeric carrier to multiple carriers with plasticizers to improve the stability and performance of ASDs. Major excipient manufacturers recognized the potential of ASDs and began introducing specialty excipients ideal for formulating ASDs. In addition to traditional techniques such as differential scanning calorimeter (DSC) and X-ray crystallography, recent innovations such as nano-tomography, transmission electron microscopy (TEM), atomic force microscopy (AFM), and X-ray microscopy support a better understanding of the microstructure of ASDs. The purpose of this review is to highlight the recent advancements in the field of ASDs with respect to formulation approaches, methods of preparation, and advanced characterization techniques

Introduction

Aqueous solubility and permeability across iological membranes are essential prerequisites for effective oral absorption [1]. Around 70–90% of all new chemical entities (NCEs)/drug molecules under development were reported to possess poor aqueous solubility; hence, they elong to the Biopharmaceutics Classification System (BCS) class II or class IV drugs [2,3]. This phenomenon of poor solubility is due to the structure and functional groups identified during the drug discovery phase. In an attempt to improve the poor solubility of NCEs, approaches such as modifying the structure–activity relationship (SAR) were tried during the preclinical development stage [4]. However, the use of these approaches on NCEs is often limited, due to the requirement of a lipophilic nature to bind iological targets or to cross iological membranes [5]. Therefore, this resulted in an increased number of poorly aqueous soluble NCEs in the preclinical development, posing a challenge during formulation development [6]. Based on physicochemical properties such as melting point, logP, molecular weight and aqueous solubility, NCEs were classified as either ‘brick-dust’ molecules or ‘grease-ball’ molecules [7,8]. The former name indicates solid-state limited solubility (due to orderly arranged crystalline lattices) and the latter denotes solvation-limited solubility (due to high lipophilicity) [9]. Therefore, as mentioned earlier, aqueous solubility and membrane permeability were found to e pivotal in the pipeline of successful formulation development. Depending on the inherent solubility and permeability of drug molecules, researchers have explored various formulation approaches for improvement [10]. Based on the methods reported in the literature, lipid-based drug delivery, micronization, use of polymorphs, co-crystals, salt formation, prodrug, nanocrystal dispersion, cyclodextrin complexation, inding to ion exchange resins, and amorphization were found to e effective [11–14]. Among these solubility enhancement technologies, amorphous solid dispersions (ASDs) have attracted tremendous importance in the last decade with numerous marketed products. Sekiguchi and Obi [15] first proposed the concept of solid dispersions in 1961. By definition, in ASDs, the drug homogenously disperses in an excipient carrier in amorphous state. The amorphous form of API enhances solubility y lacking crystalline lattices and having an inherently disordered arrangement. Apart from improving the solubility, ASDs enhance the wettability, rate of dissolution, and supersaturation of drugs, thereby promoting the membrane flux, ultimately leading to improved oral bioavailability [16]. The combination of a rapidly dissolving and supersaturating “spring” with precipitation retarding “parachute” is employed as an efficient formulation strategy for ASDs to improve the rate and extent of oral absorption [17]. Since then, solid dispersion (SD) technology has attracted the scientific community, leading to extensive research in the field of ASDs. At this time, nearly >25 ASD formulations are commercially available on the market [18]. Table 1 summarizes the Food and Drug Administration (FDA)-approved ASDs along with the polymers used in the formulation. However, ASDs are susceptible to thermodynamic instability (conversion from an amorphous state to a crystalline state) due to the higher free energy associated with the amorphous state [19,20]. Numerous factors such as the improper selection of formulation components, thermal stress, environmental stress (humidity), and manufacturing stress contribute to the physical instability of ASD. The proper selection of formulation ingredients, manufacturing process, process parameters, and packaging components are deemed essential to obtain a stable ASD drug product [21].

Table 1. Examples of FDA-approved amorphous solid dispersions products. Adapted from [18] under Creative Commons Attribution (CC BY-NC-ND 4.0) license, (https://creativecommons.org/licenses/by/4.0/).

Trade Name	Chemical Name	BCS Class	Manufacturing Technique	Polymers Used	Company	Year of Approval
Cesamet®	Nabilone	II	Solvent evaporation	Povidone	Meda Pharmaceuticals	1985
Isoptin SR	Verapamil HCl	II	Melt extrusion	Hypromellose	Ranbaxy Laboratories	1987
Sporanox	Itraconazole	II	Fluid bed bead layering	Hypromellose, Polyethylene glycol	Janssen	1922
Prograf	Tacrolimus	II	Spray drying	Hypromellose	Astellas Pharma	1994
NuvaRing	Etonogestrel/Ethinyl Estradiol	II	Melt extrusion	Ethylene vinylacetate copolymer	Merck	2001
Kaletra	Lopinavir/Ritonavir	IV/IV	Melt extrusion	Co-povidone	AbbVie	2007
Intelence	Etravirine	IV	Spray drying	Hypromellose	Janssen	2008
Modigraf	Tacrolimus	II	Spray drying	Hypromellose	Astellas Pharma	2009
Zortress	Everolimus	III	Spray drying	Hypromellose	Novartis	2010
Norvir Tablet	Ritonavir	IV	Melt extrusion	Co-povidone	AbbVie	2010
Onmel	Itraconazole	II	Melt extrusion	Hypromellose	Merz Pharma	2010
Incivek	Telaprevir	II	Spray drying	Hypromellose acetate succinate	Vertex	2011
Zelboraf	Vemurafenib	IV	Solvent/anti-solvent precipitation	Hypromellose	Roche	2011
Kalydeco	Ivacaftor	II	Spray drying	Hypromellose acetate succinate	Vertex	2012
Noxafil	Posaconazole	II	Melt extrusion	Hypromellose acetate succinate	Merck	2013
Harvoni	Ledipasvir/Sofosbuvir II/III Spray drying Co-povidone Gilead Sciences 2014	II/III	Spray drying	Co-povidone	Gilead Sciences	2014
ViekiraXR™	Dasabuvir/Ombitasvir/Paritaprevir/Ritonavir	II/IV/IV/IV	Melt extrusion	Co-povidone	AbbVie	2014
Epclusa	Sofosbuvir/Velpatasvir	III/IV	Spray drying	Co-povidone	Gilead Sciences	2016
Orkambi	Lumacaftor/Ivacaftor	II/II	Spray drying	Hypromellose acetate succinate, Povidone	Vertex	2016
Venclexta	Venetoclax	IV	Melt extrusion	Co-povidone	AbbVie	2016
Zepatier	Elbasvir/Grazoprevir	II/II	Spray drying	Vitamin E polyethylene glycol succinate, Co-povidone, Hypromellose	Merck	2016
Stivarga	Regorafenib	II	Solvent evaporation	Povidone	Bayer	2017
Mavyret™	Glecaprevir/Pibrentasvir	IV/IV	Melt extrusion	Hypromellose, Co-povidone	AbbVie	2017
Lynparza	Olaparib	IV	Melt extrusion	Co-povidone	AstraZeneca	2018
Erleada	Apalutamide	II	Spray drying	Hypromellose acetate succinate	Janssen	2018
Trikafta	Elexacaftor (Crystalline)/Ivacaftor/Tezacaftor	II or IV	Spray drying	Hypromellose, Hypromellose acetate succinate	Vertex	2019
Symdeko	Tezacaftor/Ivacaftor and Ivacaftor	II/II or IV	Spray drying	Hypromellose, Hypromellose acetate succinate	Vertex	2019
Braftovi	Encorafenib	II	Melt extrusion	Co-povidone, Poloxamer 188	Pfizer	2020
Oriahnn™	Elagolix/estradiol/norethindrone acetate	III/II/NA	Melt extrusion	Co-povidone, Hypromellose	AbbVie	2020

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Tambe, S.; Jain, D.; Meruva, S.K.; Rongala, G.; Juluri, A.; Nihalani, G.; Mamidi, H.K.; Nukala, P.K.; Bolla, P.K. Recent Advances in Amorphous Solid Dispersions: Preformulation, Formulation Strategies, Technological Advancements and Characterization. Pharmaceutics 2022, 14, 2203.
https://doi.org/10.3390/pharmaceutics14102203