Computational prediction of drug solubility in fasted simulated and aspirated human intestinal fluid.
Pharm Res
; 32(2): 578-89, 2015 Feb.
Article
em En
| MEDLINE
| ID: mdl-25186438
ABSTRACT
PURPOSE:
To develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).METHODS:
Measured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.RESULTS:
Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R(2) = 0.61) or HIF (R(2) = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R(2) = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R(2) = 0.69 and RMSEte of 0.77; HIF, R(2) = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.CONCLUSION:
Computational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Simulação por Computador
/
Preparações Farmacêuticas
/
Química Farmacêutica
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Jejum
/
Secreções Intestinais
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Pharm Res
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Suécia