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