Preparation, Characterization, and Selection of Optimal Forms of (S)-Carvedilol Salts for the Development of Extended-Release Formulation

Abstract

Metrics & MoreArticle RecommendationsABSTRACT: (S)-carvedilol (S-CAR) is the dominant pharmacodynamic conformation of carvedilol, but its further development for extended-release formulation is restricted by its poor solubility. This study aimed to prepare and screen S-CAR salts that could be used to improve solubility and allow extended release. Five salts of S-CAR with well-known acid counterions (i.e., phosphate, hydrochloride, sulfate, fumarate, and tartrate) were produced using similar processes. However, these salts were obtained with water contents of 1.60−12.28%, and their physicochemical properties differed. The melting points of phosphate, hydrochloride, and tartrate were 1.1−1.5 times higher than that of the free base. The solubility of S-CAR salts was promoted to approximately 3−32 times higher than that of the free base at pH 5.0−8.0. Typical pH-dependent solubilities were evidently observed in S-CAR salts, but considerable differences in solubility properties among these salts were observed. S-CAR phosphate and hydrochloride possessed high melting points, considerable solubility, and excellent chemical and crystallographic stabilities. Accordingly, S-CAR phosphate and hydrochloride were chosen for further pharmacokinetic experiments and pharmaceutical study. S-CAR phosphate and hydrochloride extended-release capsules were prepared using HPMC K15 as the matrix and presented extended release in in vitro and in vivo evaluations. Results implied that water molecules in the hydrated salt were a potential threat to the achievement of crystal stability and thermostability. S-CAR phosphate and hydrochloride are suitable for further development of the extended-release formulation.

The Incorporated Drug Affects the Properties of Hydrophilic Nanofibers

“…Significantly higher moisture content in nanofibers after exposure to 46% relative humidity at room temperature for 24 h was observed for nanofibers with carvedilol and paracetamol ( Figure 5 ). Given that paracetamol and carvedilol are known to sorb moisture from the environment [ 89 , 90 ], a characteristic not shared by ibuprofen and metformin [ 91 , 92 ], it can be concluded that the hygroscopic properties of nanofibers are significantly influenced by the hygroscopic nature of the incorporated drug. The significant difference between formulation CAR and formulation PAR in moisture sorption capacity could be attributed to the more pronounced hygroscopic properties of paracetamol compared to carvedilol [ 89 , 90 ].…”

“…Given that paracetamol and carvedilol are known to sorb moisture from the environment [ 89 , 90 ], a characteristic not shared by ibuprofen and metformin [ 91 , 92 ], it can be concluded that the hygroscopic properties of nanofibers are significantly influenced by the hygroscopic nature of the incorporated drug. The significant difference between formulation CAR and formulation PAR in moisture sorption capacity could be attributed to the more pronounced hygroscopic properties of paracetamol compared to carvedilol [ 89 , 90 ]. Since the drugs were incorporated into a matrix of hygroscopic polymers [ 85 ] and since the drug-free nanofibers also demonstrated the ability to sorb moisture from the environment, it can be concluded that the hygroscopic behavior of nanofibers is a consequence of the hygroscopicity of the polymers and the drugs.…”

Pharmaceutical Salts of Carvedilol with Increased Solubility as an Approach for Enhancing the Drug Action

“…Thus, their diffraction patterns are distinct. Furthermore, they differ from one of the enantiopure CVD sulfate salts, 13 highlighting the supramolecular differences between the racemic and enantiopure forms. The CVD-MLN salt, which exhibits different salt ratio stoichiometry from its preparation, displays a good agreement between calculated and experimental patterns, corroborating the absence of impurities from the starting materials.…”

“…It is worth remembering that, as a BCS class II intestinal, absorption is primarily dependent on API solubility. To accredit this argument, we quote the work published by Zhang et al, 13 who have demonstrated an enhancement in the CVD plasmatic concentration through the preparation of more soluble salts. Considering lipophilicity, which can be expressed by the drug's log P, significantly impacts passive absorption and consequently influences oral bioavailability.…”

“…11,12 Despite its efficacy, the product development and the antihypertensive therapeutic value of CVD are limited by pharmacokinetic issues. 13 The very low solubility of CVD renders this API unsuitable for extendedrelease formulations and challenges its repurposing process to treat other diseases. CVD is a BCS class II drug that exhibits low and pH-dependent solubility, 14,15 as well as high permeability.…”