The Flory-Huggins interaction parameter has been shown to be useful in predicting the thermodynamic miscibility of a polymer and a small molecule in a binary mixture. In the present paper, this concept was extended and evaluated to determine whether or not the Flory-Huggins interaction parameter can be applied to small molecule binary mixtures and if this parameter can predict the phase stability of such amorphous binary mixtures. This study was based on the assumption that a thermodynamically miscible binary system is stable and cannot crystallize, and that phase separation is essential before the individual components can crystallize. The stabilization of a binary system is thought to derive from molecular interactions between components in a solid dispersion, which are characterized by the Flory-Huggins interaction parameter. Based on DSC experiments, drug molecules (39) in the present study were classified into three different categories according to their crystallization tendency; i.e., highly crystallizing, moderately crystallizing and noncrystallizing compounds. The Flory-Huggins interaction parameter was systematically calculated for each drug pair. The validity of this approach was empirically verified by hot-stage polarized light microscopy. If both compounds in the pair belonged to the category of highly crystallizing compound, the Flory-Huggins interaction predicted an amorphous or crystalline phase with approximately 88% (23 out of 26) confidence. If one or both compounds of the pair were either moderately crystallizing or noncrystallizing compounds, the binary mixture remained in the amorphous phase during the cooling phase regardless of the interaction parameter. The Flory-Huggins interaction parameter was found to be a reasonably good indicator for predicting the phase stability of small molecule binary mixtures. The method described can enable fast screening of the potential stabilizers needed to produce a stable amorphous binary mixture.

For almost two decades there has been intense debate about whether the amorphous solid state form could resolve the solubility problems and subsequent bioavailability issues of many small molecule drugs. Since the amorphous form is a high energy and unstable state of solid matter, any material in that form requires stabilization. Areas covered: This review examines the technologies being exploited to stabilize the amorphous state in co-amorphous formulations. The review emphasizes the importance of the appropriate selection criteria of stabilizing excipient and focuses on the mechanisms of stabilization. Expert opinion: An extensive literature review has revealed that the current research seeking to achieve stabilization of an amorphous form tends to be conducted on a case-by-case basis. This kind of approach is very inefficient since it can rarely be transferred to other cases. The greatest weakness in the selection of stabilizing excipient for co-amorphous formulations is that modern computational tools have rarely been utilized as a predictive tool in the selection of the excipient. It is evident that more research needs to be done to study larger datasets with modern in silico tools, chemometrics and advanced statistical tools to achieve a more predictive, and systematic approach for the screening of stabilizing excipients to be incorporated into co-amorphous formulations.

Combinatorial chemistry has enabled the production of very potent drugs that might otherwise suffer from poor solubility and low oral bioavailability. One approach to increase solubility is to make the drug amorphous, which leads to problems associated with drug stability. To improve stability, one option is to molecularly disperse the drug in a matrix. However, the primary reason for the failed stabilization with this approach is phase separation, which has been carefully studied in polymeric systems. Nevertheless, the amorphous-amorphous phase separation in coamorphous small molecule mixtures has not yet been reported. The goal of the present study was to experimentally detect the amorphous-amorphous phase separation between two small molecules. A modified in silico method for predicting miscibility by the Flory-Huggins interaction parameter is presented, where conformational variations of the studied molecules were taken into account. A series of drug-drug mixtures, with different mixture ratios, were analyzed by conventional differential scanning calorimetry (DSC(conv)) to detect possible amorphous-amorphous phase separations. The phase separation of coamorphous drug-drug mixtures was also monitored by temperature modulated DSC (MDSC) and Fourier transform infrared (FT-IR) imaging at temperatures above Tg for prolonged time periods. Amorphous-amorphous phase separation was not detected with DSC(conv), probably due to the slow kinetics of phase separation. However, the melting of the separated and subsequently crystallized phases was detected by MDSC. Furthermore, FT-IR imaging was able to detect the separation of the two amorphous phases, which demonstrates the ability of this method to detect small molecule phase separations.

The applicability of the computational docking approach was investigated to create a novel method for quick additive screening to inhibit the crystallization taking place in amorphous drugs. Surface energy and attachment energy were utilized to recognize the morphologically most important crystal faces. The surfaces (100), (001), and (010) were identified as target faces, and the estimated free energies of binding of additives on these surfaces were computationally determined. The molecule of the crystallizing compound was included in the group of the modeled additives as the reference and for the validation of the approach. Additives having a lower estimated free energy of binding than the reference molecule itself were considered as potential crystallization inhibitors. Salicylamide, salicylic acid, and sulfanilamide with computationally prescreened additives were melt-quenched, and the nucleation and crystal growth rates were subsequently monitored by polarized light microscopy. As a result, computationally screened additives decelerated the nucleation and crystal growth rates of the studied drugs while the pure drugs crystallized too fast to be measured. The use of a computational approach enabled fast and cost-effective additive selection to retard nucleation and crystal growth, thus facilitating the production of amorphous binary small molecular compounds with stabilized disordered structures.

No abstract