Preparation of Amorphous Solid Dispersions by Cryomilling: Chemical and Physical Concerns Related to Active Pharmaceutical Ingredients and Carriers.

In this work, a chemical (and physical) evaluation of cryogenic milling to manufacture amorphous solid dispersions (ASDs) is provided to support novel mechanistic insights in the cryomilling process. Cryogenic milling devices are considered as reactors in which both physical transitions (reduction in crystallite size, polymorphic transformations, accumulation of crystallite defects, and partial or complete amorphization) and chemical reactions (chemical decomposition, etc.) can be mechanically triggered. In-depth characterization of active pharmaceutical ingredient (API) (content determination) and polymer (viscosity, molecular weight, dynamic vapor sorption, Fourier transform infrared spectroscopy, dynamic light scattering, and ANS and thioflavin T staining) chemical decomposition demonstrated APIs to be more prone to chemical degradation in case of presence of a polymer. A significant reduction of the polymer chain length was observed and in case of BSA denaturation/aggregation. Hence, mechanochemical activation process(es) for amorphization and ASD manufacturing cannot be regarded as a mild technique, as generally put forward, and one needs to be aware of chemical degradation of both APIs and polymers.

Drug-carrier binding and enzymatic carrier digestion in amorphous solid dispersions containing proteins as carrier.

In order to further explain the ability of gelatin 50PS and bovine serum albumin (BSA) to generate supersaturation of a series of poorly soluble drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole, naproxen, phenylbutazone and phenytoin), drug-polymer binding was investigated using solution NMR and equilibrium dialysis experiments. Binding characteristics of the biopolymers were compared to those of PVP, PVPVA and HPMC. Since both biopolymers are prone to enzymatic digestion, we evaluated the influence of proteolytic enzymes like pepsin and pancreatin on the dissolution properties of poorly soluble compounds when formulated as amorphous solid dispersions with gelatin 50PS and BSA. Evidence is being presented that supports the importance of drug-polymer binding in inducing and stabilizing supersaturation of poorly soluble drugs and enhancing dissolution from ASDs. In fact, BSA displayed drug binding with nearly all tested model drugs while in case of gelatin 50PS binding was observed for 5 out of 12 drugs. Addition of pepsin or pancreatin during dissolution of the biopolymer-containing ASDs leads to a drop in the concentration of the drug pointing to enzymatic digestion of the gelatin and BSA. However, after digestion, these formulations still outperformed their crystalline counterparts.