**1. Introduction**

Most drugs fail to reach the market during development due to poor water solubility, even though they have desirable safety and efficacy profiles [1,2]. Several approaches were employed to enhance solubility and dissolution. These include chemical modification, particle size reduction, and formulation development [3,4]. Chemical modification of the drug results in significant changes in safety and efficacy profile that may result in elimination of potential lead compounds [3]. Particle size reduction improves dissolution rate but may not increase extent of crystalline solubility of drugs, even with an increase in surface-to-volume ratio [5,6]. Among the formulation development strategies, co-amorphous dispersion (CAD) and amorphous solid dispersion (ASD) are commonly used approaches for a poorly soluble drug where a crystalline drug is transformed into an amorphous form [7–12]. Dissolution of crystalline drugs includes disruption of the crystalline lattice, solvation/hydration, and breakdown of hydrogen bonds [13]. This approach exploits solubility advantage of an amorphous drug over a crystalline one due to lack of lattice order [14]. However, lack

**Citation:** Mohamed, E.M.; Dharani, S.; Nutan, M.T.H.; Cook, P.; Arunagiri, R.; Khan, M.A.; Rahman, Z. Application of Sucrose Acetate Isobutyrate in Development of Co-Amorphous Formulations of Tacrolimus for Bioavailability Enhancement. *Pharmaceutics* **2023**, *15*, 1442. https://doi.org/10.3390/ pharmaceutics15051442

Academic Editor: Ana Isabel Fernandes

Received: 10 March 2023 Revised: 5 May 2023 Accepted: 6 May 2023 Published: 9 May 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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of lattice order increases free energy, making the amorphous form thermodynamically unstable. The amorphous drug reverts to stable crystalline form after high temperature and humidity exposure. The amorphous drug is stabilized to a certain extent against crystallization by adding a high melting/glass transition temperature polymer to form an ASD, which increases the glass transition temperature of the drug. The polymer also provides means of dosage form development and manufacturability [15]. CAD is formed when the polymer is replaced by a small molecule [7,8,11]. Small molecules stabilize the amorphous drugs through intermolecular interactions, e.g., hydrogen bonds, π–π, or even ionic etc. This technique is widely used for solubility, dissolution, and oral bioavailability enhancement of poorly water-soluble drugs [16,17]. The CAD and ASD can be formulated into tablet and or capsule dosage forms. FDA has approved many ASD since 2007 [18].

Tacrolimus (TAC) is a BCS class II drug, meaning solubility and dissolution is the rate-limiting step in its absorption [19]. The ASD of TAC has been reported to increase the oral bioavailability of the drug [9,20]. Immediate release ASD dosage form of TAC has been reported using hydroxypropyl cellulose [21], polyvinyl pyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose (HPMC), [22], Eudragit® [23], HPMC and sodium lauryl sulfate [24]. Similarly, extended-release ASD of TAC has also been reported using HPMC and ethyl cellulose [25,26]. Among all the reported polymers for ASD, HPMC was the most effective in maintaining supersaturation during in vitro and in vivo dissolution, thus, enhancing oral bioavailability [22]. Therefore, FDA approved immediate and extended-release ASD dosage forms of TAC. However, immediate and extended-release ASD formulations of TAC have been recalled due to failure to meet dissolution specification during stability testing [27,28]. This could be related to drug crystallization during stability if the formulation composition is not optimized, the manufacturing method is incorrect, and/or the packaging is defective, etc. Drug crystallization is a long-standing problem in ASD dosage forms [9,20]. This dictates to search for a new polymer or excipient that may inhibit or reduce the drug crystallization while maintaining supersaturation during dissolution and in vivo absorption. In this paper, an attempt was made to develop CAD of TAC using sucrose acetate isobutyrate (SAIB) as a new carrier and characterize for physicochemical, stability, and pharmacokinetic attributes and compared with HPMC-based ASD formulation. SAIB is a pale straw glassy solid at room temperature that liquefies at 60 ◦C. It is synthesized by controlled esterification of sucrose with acetic anhydride and isobutyric anhydride. The molecular formula and weight of SAIB are C40H62O19 and 846.9 g/mL, respectively (Figure 1A). It is insoluble in water and soluble in most organic solvents with a LogP ranging from 3.4 to 7. The calculated hydrogen donor and acceptor counts in the molecule is zero and 19, respectively [29]. The physicochemical properties of TAC are similar to SAIB (Figure 1B). The molecular weight and LogP values of the drug are 804.0 and 2.7, respectively. Unlike SAIB, TAC has eleven hydrogen acceptor and three hydrogen donor counts. Reported solubility of TAC in SAIB was 115 mg/gm [29]. It is possible that both molecules may form CAD by hydrogen and hydrophobic interactions based on structural and physicochemical attributes. SAIB has never been reported in the literature for CAD formulation development.

**Figure 1.** (**A**) Structure of SAIB, (**B**) Structure of Tacrolimus.
