Reducing mechanical activation-induced amorphisation of salbutamol sulphate by co-processing with selected carboxylic acids

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 (Tg) 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 Tg lowering effect. The results indicate that co-processing with low Tg excipients is an effective strategy at minimising amorphisation of an API on mechanical activation.

Interactions Between Paracetamol and Hypromellose in the Solid State

“…As reported in the literature, other physical interactions are also possible, e.g., formation of eutectic mixtures (Bi et al, 2003), solid dispersions (Jahangiri et al, 2015), dissolution of paracetamol in hypromellose (Tian et al, 2015), reduction of paracetamol crystallinity in the presence of microcrystalline cellulose (de Oliveira et al, 2017) and amorphization or polymorphic transformation (Salunkhe et al, 2018). The risk of initiating interactions between ingredients is greater when homogenization of the mixtures is carried out using a pestle (Byard et al, 2005; Curtin et al, 2013).…”

Role of Lattice Disorder in Water-Mediated Dissociation of Pharmaceutical Cocrystal Systems

“…In an industrial setup, an API and an excipient may be “co-processed” necessitating studies on how this may impact the product performance. , When solid mixtures are milled, the extent of lattice disorder in each phase is expected to be influenced by its properties as well as the mixture composition. , In order to study the impact of comilling on cocrystal dissociation, CAFOXA and DCPA were mixed first and then milled together (“comilled mixture”). Milling together may result in an increase in the inter-particulate contact area amongst materials.…”

Physical stability of dry powder inhaler formulations

“…A co-milling method may also prevent changes to the solid-state property of the API upon exposure to elevated humidity. For example, the crystallization inhibitors, a-lactose monohydrate (LAC), adipic acid (AA) and magnesium stearate (MgSt) prevented crystallization of salbutamol sulphate [63,64,65].…”