Cocrystal and Salt Forms of an Imidazopyridazine Antimalarial Drug Lead.
J Pharm Sci
; 108(7): 2349-2357, 2019 07.
Article
en En
| MEDLINE
| ID: mdl-30817923
ABSTRACT
Cocrystallization and salt formation were used to produce new multicomponent forms of a novel antimalarial imidazopyridazine drug lead (MMV652103) that displayed improved physicochemical properties. The drug lead had earlier shown good in vitro potency against multidrug resistant (K1) and sensitive (NF54) strains of the human malaria parasite Plasmodium falciparum, and high in vivo efficacy in both Plasmodium berghei and Plasmodium falciparum mouse models. A major drawback of MMV652103 is its limited aqueous solubility. Various new supramolecular products, including several multicomponent solid forms, are reported here, namely 3 cocrystal forms with the dicarboxylic acid coformers adipic acid, glutaric acid, and fumaric acid, and a salt form with malonic acid. These were characterized by thermal methods and their structures elucidated by single-crystal X-ray diffraction. A customized solubility experiment was performed in fasted-state simulated intestinal fluid for comparison of the solubility behavior of each new form of the drug lead with that of the untreated starting material. All of the multicomponent forms showed an improvement in the maximum concentrations (Cmax) attained by the drug lead and the rate at which it dissolved. The recorded Cmax values exceeded the concentration of the untreated compound by factors in the range 4.6-5.6.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
3_ND
Problema de salud:
3_malaria
/
3_neglected_diseases
Asunto principal:
Piridinas
/
Cloruro de Sodio
/
Imidazoles
/
Antimaláricos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Pharm Sci
Año:
2019
Tipo del documento:
Article
País de afiliación:
Sudáfrica