Mitigating unwanted amorphisation: A screening method for the selection of suitable excipients

Abstract

Co-processing an active pharmaceutical ingredient (API) with a low Tg excipient has been previously reported to be an effective strategy for preventing drug amorphisation on milling.This technique relies on the ability of the excipient to form a molecular dispersion with the amorphous API during the milling process. The presence of the excipient within the amorphous phase induces a reduction of the Tg. Hence, the molecular dispersion becomes less stable than the amorphous API alone and recrystallises upon milling. The objective of this study was to develop a screening method for the selection of suitable excipients to prevent amorphisation, based on two criteria: the Tg of the excipient and the solubility of the excipient in the amorphous API. The ability of the excipients to induce Tg reduction was first assessed by measuring the Tg of the amorphous composite by thermal analysis and comparing it with that of the pure API (griseofulvin). A predicted ability for mitigation of amorphisation upon milling was then deduced from these observations for each excipient and assessed against experimental results.The same excipients were then studied with regard to their expected solubility in another amorphous API (budesonide) by Hildebrand solubility parameter calculations in order to 2 evaluate their capacity to form an amorphous composite with the drug. The predicted effects of the excipients on comilling were compared with the amorphous content of the processed API.The screening method as applied to both APIs showed good agreement with the experimental results and were shown to be efficient for the selection of the most appropriate excipient. This approach revealed that the two key parameters involved are the Tg of the excipient and the ability of the API to form an amorphous molecular dispersion with the excipients. This work confirms and completes our previously published results on the mitigation of the amorphisation by comilling with low Tg excipients and constitutes the first report of the use of a polymeric additive for this purpose.

Glass Transition Dynamics and Physical Stability of Amorphous Griseofulvin in Binary Mixtures with Low-Tg Excipients

“…In some early reports, one can find that a high- T g matrix does not necessarily guarantee the greater physical stability of the amorphous systems. , The molecular factors, involving hydrogen bonding, ionic interactions, steric hindrances, and so on, can also affect the overall crystallization tendency of the coamorphous mixtures. ,, Here, it is worthy to mention the plasticization effect, which is always associated with reduced T g values, enhanced molecular mobility, and eventually facilitated crystallization . Nevertheless, it has also been reported in the literature that a low- T g polymer, such as poly­(ethylene oxide) (PEO), could exert selective accelerating effects on the crystallization kinetics of different polymorphs of indomethacin (IMC) .…”

“…10,17,18 Here, it is worthy to mention the plasticization effect, which is always associated with reduced T g values, enhanced molecular mobility, and eventually facilitated crystallization. 19 Nevertheless, it has also been reported in the literature that a low-T g polymer, such as poly(ethylene oxide) (PEO), could exert selective accelerating effects on the crystallization kinetics of different polymorphs of indomethacin (IMC). 20 Moreover, our recent work found that the crystallization of amorphous nifedipine (NIF, T g = 317 K and with a large tendency to recrystallize from the supercooled state) can be effectively suppressed by its structural analogue, nimodipine (NIM, T g = 289 K), at both ambient and elevated pressures, indicating that the plasticizers might be also useful in stabilization of the amorphous APIs.…”

Insights on the Physical State Reached by an Active Pharmaceutical Ingredient upon High-Energy Milling

“…15−18 Yet, understanding these transformations is of practical value for the pharmaceutical industry. Controlling the milling process would prevent the formation of undesired physical states 19 (poorly soluble crystalline forms, unstable amorphous substances, etc.) and establish innovative and suitable formulations enabling pharmaceutical ingredients to be placed into therapeutically efficient states.…”

“…High-energy milling, for all those reasons, is a valuable candidate to become an efficient manufacturing method of amorphous substances, preserving the chemical completeness when it is not accompanied by excessive heating. − Although observed in numerous compounds of pharmaceutical interest, phase transformations upon milling have still not been investigated thoroughly to rationalize experimentally encountered situations. − Yet, understanding these transformations is of practical value for the pharmaceutical industry. Controlling the milling process would prevent the formation of undesired physical states (poorly soluble crystalline forms, unstable amorphous substances, etc.) and establish innovative and suitable formulations enabling pharmaceutical ingredients to be placed into therapeutically efficient states .…”

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).…”