Physical stability of the amorphous state of loperamide and two fragment molecules in solid dispersions with the polymers PVP-K30 and PVP-VA64.

The purpose of the present study was to investigate the impact of intermolecular forces on the stability of the amorphous state of loperamide and two of its fragment molecules (4-dimethylamino-N,N-dimethyl-2,2-diphenyl-butyramide (F1) and 4-(4-chlorophenyl)-4-piperidinol (F2)) in solid dispersions with PVP-K30 and PVP-VA64. The stability of originally homogeneous and amorphous dispersions was investigated under different storage conditions. The chemical stability of the compounds was evaluated with HPLC. TGA-analysis was used in order to assess the amount of water in the samples, whereas MT-DSC-measurements were performed to investigate changes in the physical state of the compounds caused by the storage procedure. TGA-analysis reveals a higher uptake of water in humid conditions of the dispersions with PVP-K30 in comparison to those with PVP-VA64, hereby reflecting the more hydrophilic nature of the former polymer. This water acts as a plasticizing agent resulting in an increased mobility and decreased glass transition temperature. Since the degree of supersaturation and the molecular mobility have an influence on the stability of the amourphous state, both parameters were assessed. With respect to the degree of supersaturation of the compounds in the dispersions, the materials seem to be very much alike. Therefore it was postulated that the induction of crystallization in the F1/polymer dispersions stored at high RH (52%) is due to higher molecular mobility of this compound in the dispersions in comparison to F2. The hydrogen bonds that are being formed between F2 and the polymers reduce its mobility and secure this compound from crystallization upon storage, thus indicating the importance of specific interactions with respect to stability issues of solid dispersions. No hydrogen bonds are formed between F1 and the polymers. As a result, the stability of the amorphous state of the compound is being compromised and crystallization takes place. Loperamide, that also does not form hydrogen bonds with the polymers, is less susceptible to crystallization due to its intrinsic good glass forming properties.