# Oxidative Thermolysis of Sulfobutyl-Ether-Beta-Cyclodextrin Sodium Salt: A Kinetic Study
## 1 Introduction  
In the ever-evolving landscape of pharmaceutical formulations, the solubility and bioavailability of active pharmaceutical ingredients (APIs) remain critical challenges. Many promising drug candidates exhibit poor water solubility, which can hinder their therapeutic effectiveness and limit their clinical applications [1]. To address this, novel excipients suchas sodium salt of sulfobutyl-ether-beta-cyclodextrintrim (SBECD) have emerged as powerful tools to improve drug solubility and stability [2; 3]. SBECD stands out due to its unique chemical structure, which includes negatively charged sulfobutyl groups attached to the beta-cyclodextrinrin core [4]. This modification not only improves the water solubility of hydrophobic drugs but also provides a safer and more biocompatible profile compared to traditional solubilizing agents [4; 5]. When inclusion complexes are formed with APIs, SBECD can significantly enhance the dissolution rate, protect drugs from degradation, and reduce irritation in sensitive tissues. These attributes make it a versatile excipient in various dosage forms [6], including injectables [7], oral tablets [8; 9], and ophthalmic solutions and gels [10]. In the realm of parenteral formulations [11], SBECD plays a critical role in increasing the solubility of intravenous drugs, thereby making it suitable for this pathway of administration. Also, it seems that formulations containing SBECD showed reduced nephrotoxicity, and even if decreased renal function causes reduced SBECD clearance and increased exposure, this compound continues to exhibit a good safety and tolerability profile in intravenous formulations [7; 12]. In oral dosage forms, it improves drug absorption by enhancing solubility in the gastrointestinal tract, leading to better therapeutic outcomes. Additionally, its ability to reduce drug toxicity and improve patient tolerance underscores its value in designing safer and more effective pharmaceuticals [12; 13]. The structural formula of SBECD is presented in Figure 1, along with the structure of the parent compound, the naturally occurring beta-cyclodextrinrin. According to Cyclolab [14], there are currently 13 APIs on the market (voriconazole, carfilzomib, amiodarone, ziprasidone, maropintant, aripiprazole, posaconazole, carbamazepine, melphalan, delafloxacin, brexanolone, remdesivir, fosphenytoin) and at least 150 further in development in formulations containing SBECD. Some physico-chemical properties of SBECD are reported in the literature, as well as in the certificates of analysis that are emitted by the producers of this modified cyclodextrin. The composition of SBECD can be typically denoted as C\({}_{42}\)H\({}_{70-n}\)O\({}_{35}\)(C\({}_{4}\)H\({}_{8}\)SO\({}_{3}\)Na)\({}_{n}\), where  
Figure 1: Structural formula of parent compound beta-cyclodextrinrin (R = H) and SBECD (R = [(CH\({}_{2}\))\({}_{4}\)SO\({}_{3}\)–Na\({}^{+}\)]\({}_{n}\) and (H)\({}_{21-n}\), with n = 6.5 for DexolveTM. \"n\" represents the degree of substitution [15], which can be modified by choosing an adequate synthesis protocol [16]. The molecular mass of SBECD varies depending on the degree of substitution, typically ranging from approximately 2000 to 3000 daltons [15]. The stability of SBECD and its decomposition are reported in several scientific papers, but also on the website of Cyclolab. It seems that in solution, SBECD starts decomposing at pH values of around 4.2-4.4, being more rapid as the pH decreases under 4.0 [14]. Regarding the solid state, it seems that SBECD showed no degradation when stored for 2 weeks in an inert atmosphere at 70 \({}^{\circ}\)C [14]. Kinetic studies were carried out in solution for the hydrolytic degradation of cefixime in the presence of Captisol(r) (a SBECD produced by Ligand Pharmaceuticals) [17], suggesting the strong stabilizing influence of the cefixime-Captisol complexation against aqueous-mediated degradation [18], and for the aqueous degradation of Salinosporamide A, where Captisol(r) had a similar stabilizing effect [19].