Search

Co-processing an active pharmaceutical ingredient (API) with a low Tg excipient has been previously reported to be an effective strategy for preventing drug amorphisation on milling. This technique relies on the ability of the excipient to form a molecular dispersion with the amorphous API during the milling process. The presence of the excipient within the amorphous phase induces a reduction of the Tg. Hence, the molecular dispersion becomes less stable than the amorphous API alone and recrystallises upon milling. The objective of this study was to develop a screening method for the selection of suitable excipients to prevent amorphisation, based on two criteria: the Tg of the excipient and the solubility of the excipient in the amorphous API. The ability of the excipients to induce Tg reduction was first assessed by measuring the Tg of the amorphous composite by thermal analysis and comparing it with that of the pure API (griseofulvin). A predicted ability for mitigation of amorphisation upon milling was then deduced from these observations for each excipient and assessed against experimental results. The same excipients were then studied with regard to their expected solubility in another amorphous API (budesonide) by Hildebrand solubility parameter calculations in order to evaluate their capacity to form an amorphous composite with the drug. The predicted effects of the excipients on comilling were compared with the amorphous content of the processed API. The screening method as applied to both APIs showed good agreement with the experimental results and were shown to be efficient for the selection of the most appropriate excipient. This approach revealed that the two key parameters involved are the Tg of the excipient and the ability of the API to form an amorphous molecular dispersion with the excipients. This work confirms and completes our previously published results on the mitigation of the amorphisation by comilling with low Tg excipients and constitutes the first report of the use of a polymeric additive for this purpose. [ABSTRACT FROM AUTHOR]

Pharmaceutical applications which require knowledge of the solubility of a crystalline compound in an amorphous matrix are abundant in the literature. Several methods that allow the determination of such data have been reported, but so far have only been applicable to amorphous polymers above the glass transition of the resulting composites. The current work presents, for the first time, a reliable method for the determination of the solubility of crystalline pharmaceutical compounds in high and low molecular weight amorphous matrices at the glass transition and at room temperature (i.e. below the glass transition temperature), respectively. The solubilities of mannitol and indomethacin in polyvinyl pyrrolidone (PVP) K15 and PVP K25, respectively were measured at different temperatures. Mixtures of undissolved crystalline solute and saturated amorphous phase were obtained by annealing at a given temperature. The solubility at this temperature was then obtained by measuring the melting enthalpy of the crystalline phase, plotting it as a function of composition and extrapolating to zero enthalpy. This new method yielded results in accordance with the predictions reported in the literature. The method was also adapted for the measurement of the solubility of crystalline low molecular weight excipients in amorphous active pharmaceutical ingredients (APIs). The solubility of mannitol, glutaric acid and adipic acid in both indomethacin and sulfadimidine was experimentally determined and successfully compared with the difference between their respective calculated Hildebrand solubility parameters. As expected from the calculations, the dicarboxylic acids exhibited a high solubility in both amorphous indomethacin and sulfadimidine, whereas mannitol was almost insoluble in the same amorphous phases at room temperature. This work constitutes the first report of the methodology for determining an experimentally measured solubility for a low molecular weight crystalline solute in a low molecular weight amorphous matrix. [ABSTRACT FROM AUTHOR]

Abstract: The unintentional generation of amorphous character in crystalline active pharmaceutical ingredients (APIs) is an adverse consequence of mechanical activation during dosage form manufacture. In this study, we assess and compare the ability of low glass transition temperature (T g) dicarboxylic acids to mitigate amorphisation of a model API, salbutamol sulphate (SS), on both co-milling and co-mixing. SS processed alone, as well as co-milled and co-mixed composites of the API with glutaric acid (GA), adipic acid (AA) and pimelic acid (PA) were characterised by powder X-ray diffraction (pXRD), differential scanning calorimetry (DSC) and dynamic vapour sorption (DVS). Milling and dry mixing of SS both resulted in pXRD amorphous materials. No amorphous content of SS was detected by DVS on co-milling with 50% (w/w) GA, while amorphisation was more than halved, relative to the API milled alone, on co-milling with 50% (w/w) AA and PA, respectively. Co-mixing with each excipient also resulted in a decrease in API amorphicity, although the extent of reduction was considerably less compared to the co-milling experiments. The solubility (Solexcipient) of each excipient in amorphous SS was determined by thermal methods. No further reduction in API amorphisation was achieved on co-mixing with 50% (w/w) excipient, compared to concentrations corresponding to the solubility of each excipient in the amorphous API (SolGA =36%, SolAA =21%, SolPA =22%). PXRD confirmed gradual dissolution over time of GA in amorphous SS on co-mixing. In contrast to co-mixing, co-milling SS at excipient weight fractions above their respective solubilities in the amorphous drug resulted in further reductions in API amorphisation. This is thought to be due to the generation of a molecular dispersion of amorphous API, supersaturated with excipient, thereby leading to a more pronounced composite T g lowering effect. The results indicate that co-processing with low T g excipients is an effective strategy at minimising amorphisation of an API on mechanical activation. [Copyright &y& Elsevier]