Salt formation in solid dispersions consisting of polyacrylic acid as a carrier and three basic model compounds resulting in very high glass transition temperatures and constant dissolution properties upon storage.
The purpose of the study was to investigate the suitability of polyacrylic acid (PAA) as a carrier in solid dispersions, with the aim to delay crystallization of basic drugs and improve their dissolution behaviour. The physicochemical properties were investigated in order to link the physical state of some model compounds to their dissolution properties. Loperamide and two structurally related substances were selected as model compounds. Solid dispersions were prepared by spray drying. The amount of residual solvents and water was determined with gas chromatography (GCS: S: solvent) and thermogravimetric analysis (TGA). The drug loading of the dispersions was determined using high performance liquid chromatography (HPLC). ADSC (alternating or temperature modulated DSC), XRD and FT-IR-spectroscopy were used to evaluate the physical state and in vitro dissolution tests were performed to measure the dissolution properties. IR-measurements demonstrated the formation of a salt between the COOH-groups of the polymer and the amino-groups of the compounds. This phenomenon results in high T(g)-values of the dispersions, suppression of crystallization of the fragment molecules during preparation and an increase of the dissolution rate. Furthermore, the stability study conducted on the dispersions with loperamide showed that both, the amorphous state of the drug and the dissolution behaviour are stable under the applied storage conditions. Hence, from the experimental results it could be concluded that PAA is a suitable carrier in the formulation of stable solid dispersions for the basic compounds that were investigated.
Weuts
Ilse
I
Laboratorium voor Farmacotechnologie en Biofarmacie, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Kempen
Dieter
D
Verreck
Geert
G
Peeters
Jef
J
Brewster
Marcus
M
Blaton
Norbert
N
Van den Mooter
Guy
G
D000180:Acrylic Resins / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage / Q000379:methods; D008139:Loperamide / Q000031:analogs & derivatives / Q000737:chemistry*; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors; D044366:Transition Temperature
D000180:Acrylic Resins; D004337:Drug Carriers; D010880:Piperidines; C074930:4-(4'-chlorophenyl)-4-piperidinol; C006903:carbopol 940; D008139:Loperamide