Concurrent Product and Process Refinement

Mannitol, dextran and sucrose were subsequently employed as stabilising excipients at 50 mg ml levels. 

Calorimetric analysis was performed by a modified differential scanning calorimetry (DSC) procedure.HPLC was used to analyse the reconstituted solutions. After freeze-drying, the DSC traces of the three formulations shown in Table 1 displayed the three states that are typically encountered in freeze-dried solutions, namely complete crystallisation, partial crystallisation and complete amorphisation (glass formation). 

Exhaustive reformulation, thermal cycling and annealing studies with addition of the excipients at several concentrations led to the following Tg data lactate and dextran containing solutions — 19°C mannitol containing solutions ca. —30°C. On reheating, mannitol invariably crystallised, and the phenomenon of vial cracking, already earlier reported,was observed. 

This discussion demonstrates how a logical rehnement of acceptable chemical formulation parameters against measured thermomechanical properties of the dried preparations will aid in the development of stable products. Thus, the often-repeated dictum, even by those who should know better, that acceptable products can only be obtained by trial-and-error methods is outdated and should be discarded. 

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