Titre du document / Document title

Characterization of the molecular distribution of drugs in glassy solid dispersions at the nano-meter scale, using differential scanning calorimetry and gravimetric water vapour sorption techniques

Auteur(s) / Author(s)

VAN DROOGE D. J. ⁽¹⁾ ; HINRICHS W. L. J. ⁽¹⁾ ; VISSER M. R. ⁽¹⁾ ; FRIJLINK H. W. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Groningen University Institute of Drug Exploration (GUIDE), Department of Pharmaceutical Technology and Biophannacy, Groningen, PAYS-BAS

Résumé / Abstract

The molecular distribution in fully amorphous solid dispersions consisting ofpoly(vinylpyrrolidone) (PVP)-diazepam and inulin-diazepam was studied. One glass transition temperature (Tg), as determined by temperature modulated differential scanning calorimetry (TMDSC), was observed in PVP-diazepam solid dispersions prepared by fusion for all drug loads tested (10-80 wt.%). The Tg of these solid dispersions gradually changed with composition and decreased from 177°C for pure PVP to 46 °C for diazepam. These observations indicate that diazepam was dispersed in PVP on a molecular level. However, in PVP-diazepam solid dispersions prepared by freeze drying, two T_g's were observed for drug loads above 35 wt.% indicating phase separation. One Tg indicated the presence of amorphous diazepam clusters, the other T_g was attributed to a PVP-rich phase in which diazepam was dispersed on a molecular level. With both the value of the latter Tg and the ACp of the diazepam glass transition the concentrations of molecular dispersed diazepam could be calculated (27-35 wt.%). Both methods gave similar results. Water vapour sorption (DVS) experiments revealed that the PVP-matrix was hydrophobised by the incorporated diazepam. TMDSC and DVS results were used to estimate the size of diazepam clusters in freeze dried PVP-diazepam solid dispersions, which appeared to be in the nano-meter range. The inulin-diazepam solid dispersions prepared by spray freeze drying showed one Tg for drug loads up to 35 wt.% indicating homogeneous distribution on a molecular level. However, this T_g was independent of the drug load, which is unexpected because diazepam has a lower T_g than inulin (46 and 155 °C, respectively). For higher drug loads, a T_g of diazepam as well as a T_g of the inulin-rich phase was observed, indicating the formation of amorphous diazepam clusters. From the ACp of the diazepam glass transition the amount of molecularly dispersed diazepam was calculated (12-27 wt.%). In contrast to the PVP-diazepam solid dispersions, DVS-experiments revealed that inulin was not hydrophobised by diazepam. Consequently, the size of diazepam clusters could not be estimated. It was concluded that TMDSC enables characterization and quantification of the molecular distribution in amorphous solid dispersions. When the hygroscopicity of the carrier is reduced by the drug, DVS in combination with TMDSC can be used to estimate the size of amorphous drug clusters.

Revue / Journal Title

International journal of pharmaceutics   ISSN 0378-5173   CODEN IJPHDE 

Source / Source

2006, vol. 310, n^o1-2, pp. 220-229 [10 page(s) (article)] (31 ref.)

Langue / Language

Anglais

Editeur / Publisher

Elsevier, Amsterdam, PAYS-BAS  (1978) (Revue)

Mots-clés anglais / English Keywords

Dosage form ; Pharmacokinetics ; Pharmaceutical technology ; Suspension ; Solution ; Incorporation ; Water sorption ; Differential scanning calorimetry ; Solid dispersion ; Drug ; Distribution ; Characterization ;

Mots-clés français / French Keywords

Forme pharmaceutique ; Pharmacocinétique ; Technologie pharmaceutique ; Suspension ; Solution ; Incorporation ; Sorption eau ; Calorimétrie différentielle balayage ; Dispersion solide ; Médicament ; Distribution ; Caractérisation ;

Mots-clés espagnols / Spanish Keywords

Forma farmacéutica ; Farmacocinética ; Tecnología farmacéutica ; Suspensión ; Solución ; Incorporación ; Sorción agua ; Análisis calorimétrico barrido exploración ; Dispersión sólida ; Medicamento ; Distribución ; Caracterización ;

Mots-clés d'auteur / Author Keywords

Mode of incorporation ; Amorphous drug clusters ; Solid solution ; Solid suspension ; Molecular incorporation ; Carrier ; Non-proportional water vapour sorption ;

Localisation / Location

INIST-CNRS, Cote INIST : 16510, 35400013308680.0280