Investigation of the Capacity of Low Glass Transition Temperature Excipients to Minimize Amorphization of Sulfadimidine on Comilling

Abstract

The co-processing of active pharmaceutical ingredient (API) with an excipient which has a high glass transition temperature (Tg) is a recognised strategy to stabilise the amorphous form of a drug. This work investigates whether co-processing a model API, sulfadimidine (SDM) with a series of low Tg excipients prevents or reduces amorphisation of the crystalline drug. It was hypothesised that these excipients could exert a Tg lowering effect, resulting in composite Tg values lower than that of the API alone and promote crystallisation of the drug. Milled SDM and co-milled SDM with glutaric acid (GA), adipic acid (AA), succinic acid (SA) and malic acid (MA) were characterised with respect to their thermal, X-Ray diffraction, spectroscopic and vapour sorption properties.SDM was predominantly amorphous when milled alone, with an amorphous content of 82 %.No amorphous content was detected by dynamic vapour sorption (DVS) on co-milling SDM with 50 % w/w GA, and amorphous content of the API was reduced by almost 30 %, relative to the API milled alone, on co-milling with 50 % w/w AA. In contrast, amorphisation of SDM was promoted on co-milling with 50 % w/w SA and MA, as indicated by near infrared (NIR) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 spectroscopy. Results indicated that the API was completely amorphised in the SDM:MA comilled composite.The saturated solubility of GA and AA in the amorphous API was estimated by thermal methods.It was observed that the Tg of the co-melt quenched composites reached a minimum and levelled out at this solubility concentration. Maximum crystallinity of API on co-milling was reached at excipient concentrations comparable to the saturated concentration solubility of excipient in the API. Moreover, the closer the Hildebrand solubility parameter of the excipient to the API, the greater was the inhibition of API amorphisation on co-milling.The results reported here indicate that an excipient with a low Tg coupled with high solubility in the API can prevent or reduce the generation of an amorphous phase on co-milling.

In vitro/in vivo evaluation of an optimized fast dissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylic acids

“…Co-milling and freeze drying with hydrophilic polymers were used to form amorphous glass solutions and hot-melt extrusion of drugs using mixtures of low-melting polymers and surfactants were also employed for co-amorphization (Zhang et al, 2014). Some di and tricarboxylic acids have the ability to adjust the glass transition temperature of the composite solid dispersion by the antiplasticizing effects thus protecting the amorphous state of the resulting dispersion (Curtin et al, 2012). In this study, solvent evaporation under vacuum was used for the preparation of solid dispersions of OL and poly carboxylic acids followed by incorporation of successful co-amorphous dispersions into different film formulations, followed by incorporation in different film formulations.…”

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals

“…Particle engineering and solid form modification of APIs and functional excipients can occur during spray drying [66,67], crystallization [68], milling [69,70], wet extrusion, wet granulation and hot melt extrusion [71]. Multiparticulate systems and tablet dosage forms can be coated by functional excipients to modify drug release [72], to avoid chemical degradation [73] and to reduce irritation of parts of the gastrointestinal tract [74].…”

Effects of the Glass-Forming Ability and Annealing Conditions on Cocrystallization Behaviors via Rapid Solvent Removal: A Case Study of Voriconazole

“…Without an obvious sign of recrystallization, the diacids with relatively low T g s, i.e., MAE (4.6 • C) and MAL (−20 • C), on the other hand, resulted in Class III GFA behavior [16,40]. It has been shown that for co-milling and spray-drying, which are also major sources of inducing amorphization, high T g excipients confer functional advantages for stabilizing the amorphous drugs [41][42][43][44][45]. However, the opposite trend was observed in our study, i.e., the crystallization tendency was positively correlated with the T g of the coformer (Figure 2).…”