Application of resonant acoustic mixing in the synthesis of vitamin C-nicotinamide variable stoichiometry cocrystals.

The use of resonant acoustic mixing (RAM) to synthesize variable stoichiometry cocrystals of nicotinamide and vitamin C was investigated. Liquid assisted RAM (LA-RAM) was used to generate two polymorphs, Form I and II, of the 1 : 1 cocrystal of nicotinamide and vitamin C at a 700 mg scale using ethanol and methanol respectively as the liquid additives. LA-RAM was used to scale up polymorphs I and II of the 1 : 1 cocrystal to 20 grams. Finally, LA-RAM used was to produce a high purity 3 : 1 cocrystal of nicotinamide and vitamin C when either methanol or ethanol was used as the liquid additive. LA-RAM is demonstrated to be a scalable, environmentally friendly, ball-free method to make variable stoichiometry cocrystals.

Evaluation of Time Consolidation Effect of Pharmaceutical Powders.

PURPOSE: We aim to perform a systematic study of the time consolidation effect, i.e. the reduction of powder flowability resulting from at-rest storage, on a diverse array of pharmaceutical powders under different stress, humidity, and length of time. METHODS: A ring shear cell-based methodology was employed. An instantaneous flow function was obtained, followed immediately by at-rest consolidation at precisely controlled humidity, stress, and duration. The consolidated powder was then subjected to shear-cell measurement. The difference in flowability between the immediate and consolidated specimens were attributed to the time consolidation effect. RESULTS: Among the six excipients tested, three exhibited time consolidation at varying extents. Citric acid and starch underwent time consolidation only at high relative humidity (RH = 75%), promoted by vapor condensation and liquid bridge formation. For both materials, the flowability decreased with time, and the extent of time consolidation was not sensitive to the stress applied (0.4-2 kPa). Importantly, mannitol was found to time consolidate under both 50% and 75% RH. Given time, mannitol formed cake, giving rise to flow function below unity. Inverse gas chromatography analysis indicated that mannitol possesses high total surface energy among known pharmaceutical powders. CONCLUSION: While time consolidation is prevalent among pharmaceutical powders, most can be mitigated by controlling the RH to below 75%. Notably, for materials possessing high surface energy, such as mannitol, time consolidation could occur at ambient humidity. Therefore, it is desirable to consider in-depth time consolidation evaluation for high surface energy powders, e.g. those subjected to milling or of amorphous nature.

Determination of BET Specific Surface Area of Hydrate-Anhydrate Systems Susceptible to Phase Transformation Using Inverse Gas Chromatography.

Specific surface area (SSA) is an important parameter in drug development that affects other downstream pharmaceutical properties of interest such as reactivity, stability, dissolution, and ultimately bioavailability. Traditionally, the Brunauer-Emmett-Teller (BET) SSA of pharmaceutical powders is measured via gas adsorption (nitrogen or krypton) that is preceded by a prolonged degassing step under low pressure. This degassing step may not be suitable for certain pharmaceutical hydrates that are susceptible to dehydration and phase transformation under reduced pressure and humidity conditions. Therefore, inverse gas chromatography (IGC) was explored as a reliable alternate technique for determining the SSA of model anhydrate-hydrate systems (trehalose and thiamine hydrochloride) that are prone to such phase transformation during SSA measurement. Both trehalose dihydrate and thiamine HCl non-stoichiometric hydrate were found to undergo partial phase transformation to anhydrous forms during BET analysis via degassing and gas adsorption. In contrast, these hydrates remained stable during surface area analysis using IGC owing to measurements under controlled relative humidity. Thus, IGC proved to be a viable technique for SSA measurement of pharmaceutical hydrates without compromising their physical stability.