Predictive identification of co-formers in co-amorphous systems

Co-Amorphous Drug Formulations in Numbers: Recent Advances in Co-Amorphous Drug Formulations with Focus on Co-Formability, Molar Ratio, Preparation Methods, Physical Stability, In Vitro and In Vivo Performance, and New Formulation Strategies

“…Table 2 gives an overview of different outcomes It can be seen in Table 2 that the drug carvedilol could not form a CAMS upon ball milling [29,41,54,103] or using liquid-assisted grinding (LAG) [103] with the amino acid co-formers aspartic acid or glutamic acid but could form a CAMS upon spray drying [72,103,104]. The same behavior using different preparation pathways could be seen for indomethacin with the amino acid co-former histidine, which became co-amorphous upon spray drying [105,106] but not upon ball milling [29,41,54,103]. Interestingly, the exact opposite could be shown for the drug simvastatin and the amino acid co-former tryptophan, which became co-amorphous after ball milling [29,41,54] but not after spray drying [111].…”

“…Apart from the above-mentioned co-former classes, other types of small molecules have been applied in the preparation of CAMS, for example urea [41,44,45] and nicotinamide [41,43,[45][46][47][48][49]. These CAMS contribute 17.5% of the total.…”

“…In other words, it is unclear if the behavior of those five drugs in CAMS with respect to co-formability, physical stability, and dissolution behavior can be directly translated to other drugs. ents to form strong molecular interactions with basic drugs (for example in [25,[31][32][33][34][35][36][37][38][39][40][41][42][43]). The organic acids used as co-formers differ in their number of carboxylic acid groups, which was hypothesized to lead to salt formation with a basic drug at different molar ratios.…”

“…Considerations of bioactivity, structural characteristics of drug and co-former, and physicochemical properties of co-formers on the one hand and consideration of combination therapy on the other hand accounted for 18.1% and 6.8%, respectively. However, a systematic co-former screening was only performed in 21.8% of the reported studies [29,36,41,[50][51][52][53][54][55][56][57]. Therefore, systematic, predictive, and computational screening methods for co-former selections are still largely unexplored (see also a review: [27]).…”

“…The model showed a clear separation of the co-amorphous and the not co-amorphous samples and underlined that amino acids with non-polar side chains were dominating the co-amorphous system class. Recently, a further step was taken to optimize and expand the application of this method by reducing the number of variables from 36 to 7 and testing other co-formers (rather than only amino acids) [41]. The method showed potential to predict the co-formability of different co-formers with a high accuracy.…”