Trends in amorphous solid dispersion drug products approved by the U.S. Food and Drug Administration between 2012 and 2023

Abstract

Forty-eight (48) drug products (DPs) containing amorphous solid dispersions (ASDs) have been approved by the U.S. Food and Drug Administration in the 12-year period between 2012 and 2023. These DPs comprise 36 unique amorphous drugs. Ten (10) therapeutic categories are represented, with most DPs containing antiviral and antineoplastic agents. The most common ASD polymers are copovidone (49%) and hypromellose acetate succinate (30%), while spray drying (54%) and hot melt extrusion (35%) are the most utilized manufacturing processes to prepare the ASD drug product intermediate (DPI). Tablet dosage forms are the most common, with several capsule products available. Line extensions of several DPs based on flexible oral solids and powders for oral suspension have been approved which provide patient-centric dosing to pediatric and other patient populations. The trends in the use of common excipients and film coating types are discussed. Eighteen (18) DPs are fixed-dose combinations, and some contain a mixture of amorphous and crystalline drugs. The DPs have dose/unit of amorphous drug ranging from <5 mg up to 300 mg, with the majority being ≤100 mg/unit. This review details several aspects of DPI and DP formulation and manufacturing of ASDs, as well as trends related to therapeutic category, dose, and patient-centricity.

2.5.2. Excipients

The excipients used to formulate ASD DPs from the three main categories of diluent, disintegrant, and lubricant are detailed in Fig. 9. In order to formulate and manufacture tablets and capsules at commercial scale, diluent excipients are added to impart mechanical strength, flowability characteristics, and increase the bulk of the tablet (Yu and Hoag, 2024). Disintegrants are included to promote de-aggregation of the solid dosage form upon contact with an aqueous environment (Berardi et al., 2022). Lubricants are an essential formulation component for reducing friction of the dosage form components with processing equipment during preparation of tablets and capsules (Paul and Sun, 2018). Other excipient types such as flow aids (e.g., silicon dioxide) or pH modifying agents are occasionally included in the ASD DP formulation, but will not be discussed in detail, as their use is less frequent. Excipients that serve as surfactants/plasticizers such as d-α-tocopherol polyethylene glycol 1000 succinate, sodium lauryl sulfate, or poloxamer are also found in many DPs. In most cases, these may be formulated within the DPI to improve wetting, dissolution rate, or serve as processing aid

Several diluent excipients were found in our dataset of ASD DPs (Fig. 9a). The majority of ASD tablets contain MCC (66.7%), as its high compressibility provides for high tablet tensile strength of ASD tablet formulations (Dinunzio et al., 2012; Yu and Hoag, 2024). Diluents may also be needed to prevent gelation of ASD tablets (Zhang et al., 2021). Lactose was the second most common diluent (41.7%). Most DPs are formulated with only MCC or lactose, but not both (n = 26 of 48), with those containing MCC only being more common. In many cases, multiple diluents are selected to optimize mechanical and disintegration properties. Thirteen (13) DPs contain both MCC and lactose, and five (5) DPs contain both MCC and mannitol. Nine (9) ASD DPs do not contain either lactose or MCC (Lynparza, Norvir oral powder, Noxafil PowderMix, Paxlovid (ASD tablet), Technivie, Tolsura, Venclexta, Viekira PAK (ASD tablet), Viekira XR). The diluent used in Lynparza is mannitol, while the diluent in Paxlovid (ASD tablet) and Venclexta is dibasic calcium phosphate (DCP). Norvir oral powder, Noxafil PowderMix, Technivie, Tolsura, Viekira PAK (ASD tablet) and Viekira XR do not contain diluent.

Disintegrants are found in the majority of ASD DPs in our dataset (79.2%) (Fig. 9b). Croscarmellose sodium (CCS) was the most commonly used disintegrant and is found in 32 DPs. This was followed by crospovidone (xPVP) found in three (3) DPs, sodium starch glycolate (SSG) found in two (2) DPs, and low-substituted hydroxypropyl cellulose (L-HPC) found in one (1) DP. Use of salts such as sodium chloride as part of the disintegrant system is found with several DPs (e.g., Qulipta, Tukysa, Ubrelvy, Zepatier) formulated with neutral polymers. This disintegrant system strategy is done to reduce disintegration time of ASDs formulated with neutral polymers by disrupting gelation (Xi et al., 2020). There are several tablet DPs that do not contain a disintegrant. For Astagraf XL, Envarsus XR, and Viekira XR, the absence of a disintegrant can be rationalized based on their matrix tablet design for extended-release, where the tablets are designed to release the drug over an extended period of time through gradual erosion of the tablet matrix. DPs such as Lynparza, Technivie, and Venclexta are also designed to release the drug through an erosion mechanism, albeit over an immediate-release timeframe.

Lubricants found in our dataset of ASD DPs are either magnesium stearate (MgSt) (70.8%) or sodium stearyl fumarate (SSF) (18.8%) (Fig. 9c). For Viekira XR, only the ER layer, which contains the crystalline drug dasabuvir, has a lubricant added (MgSt), but the IR ASD layer does not contain a lubricant. The other DPs that do not contain a lubricant are Orkambi granules, as well as the three (3) powders/granules for oral suspension (Norvir, Noxafil, Prograf).

2.5.3. Film coating

A majority of ASD DPs in our dataset are film coated (79.1%) as shown in Fig. 10. Film coatings are widely used to impart aesthetics or functionality such as taste masking, controlled release, or improved mechanical integrity (Felton and Porter, 2013). The prevalence of coating types is split between HPMC-based (n = 15) and PVA-based (n = 17). PVA-based film coatings are known to impart improved moisture barrier properties (Yang et al., 2019), suggesting a possible reason for their prevalence within ASD DPs. Coating components may impart additional crystallization inhibition properties to the supersaturated solution (Sakai et al., 2018), but may also induce risk of crystallization due to migration of plasticizers that are in direct contact with ASD particles or hygroscopicity (Punia et al., 2023). Additionally, the coating process should be carefully designed to protect the ASD from phase separation or crystallization that may be induced by solvent/water exposure (Boel and Van den Mooter, 2023).

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Dana E. Moseson, Trong Bien Tran, Bharathi Karunakaran, Rohan Ambardekar, Tze Ning Hiew, Trends in amorphous solid dispersion drug products approved by the U.S. Food and Drug Administration between 2012 and 2023, International Journal of Pharmaceutics: X, 2024, 100259, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2024.100259.

Read also our introduction article on Mannitol here: