Racemic Salts and Solid Solutions of Enantiomers of the Antihypertensive Drug Carvedilol

被引:17
|
作者
Diniz, Luan F. [1 ,2 ]
Carvalho Jr, Paulo S. [3 ]
Mussel, Wagner da Nova [2 ]
Yoshida, Maria Irene [2 ]
Diniz, Renata [2 ]
Fernandes, Christian [1 ]
机构
[1] Univ Fed Minas Gerais, Lab Controle Qualidade Med & Cosmet, Dept Prod Farmaceut, Fac Farmicia, BR-31270901 Belo Horizonte, MG, Brazil
[2] Univ Fed Minas Gerais, Inst Ciencias Exatas ICEx, Dept Quim, BR-31270901 Belo Horizonte, MG, Brazil
[3] Univ Fed Mato Grosso do Sul, Inst Quim, BR-79074460 Campo Grande, MS, Brazil
关键词
INCREASING DISSOLUTION RATES; STRUCTURAL ASPECTS; GASTROINTESTINAL ABSORPTION; PHARMACEUTICAL SALTS; EUTECTIC MIXTURES; INTERMOLECULAR INTERACTIONS; CRYSTALLIZATION; CONGLOMERATE; COCRYSTALS; SYSTEM;
D O I
10.1021/acs.cgd.9b00263
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The R and S enantiomers of the antihypertensive drug carvedilol (CVD) can display remarkable miscibility in the crystalline state allowing this active pharmaceutical ingredient (API) to form a solid-solution of enantiomers (SSEs) as well as racemic compounds. Although rare and still little explored, these intriguing systems can also be used to design racemic multicomponent crystal forms toward the improvement of undesirable pharmaceutical properties of APIs. In this study, aiming to understand why there is miscibility between the enantiomers during the supramolecular recognition and crystallization processes of the CVD in the presence of salt formers, two SSEs and one racemic salt were prepared from the reaction of CVD with pharmaceutically acceptable HCl, HBr, and oxalic acids. Two monohydrated isostructural salts, hydrochloride (CVD-HCl-H2O) and hydrobromide (CVD-HBr-H2O), crystallize as racemic SSEs. These unique systems are formed from the miscibility of the R center dot center dot center dot R and S center dot center dot center dot S homochiral units that propagate into enantiomerically enriched one-dimensional chains through H-bonds with water molecules along the crystal. The oxalate salt (CVD-OXA), in turn, crystallizes as a standard racemic compound since the oxalate anions, which lie in the inversion center, are directly H-bonded to both R and S CVD enantiomers, forming racemic ionic units that extend along the structure. Complementary to the crystallographic study, conformational and Hirshfeld surface analysis were also performed based on the single-crystal X-ray diffraction data. The salt formations were confirmed from the Fourier transform infrared spectroscopy as well as powder X-ray diffraction patterns, and their thermal behaviors were investigated by a combination of differential scanning calorimetry, thermogravimetric, and hot-stage microscopy techniques.
引用
收藏
页码:4498 / 4509
页数:12
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