Abstract
The amorphous state is of particular interest in the pharmaceutical industry due to the higher solubility that amorphous active pharmaceutical ingredients show compared to their respective crystalline forms. Due to their thermodynamic instability, drugs in the amorphous state tend to recrystallize; in order to avoid crystallization, it has been a common strategy to add a second component to hinder the crystalline state and form a thermally stable co-amorphous system, that is to say, an amorphous binary system which retains its amorphous structure. The second component can be a small molecule excipient (such as a sugar or an aminoacid) or a second drug, with the advantage that a second active pharmaceutical ingredient could be used for complementary or combined therapeutic purposes. In most cases, the compositions studied are limited to 1:1, 2:1 and 1:2 molar ratios, leaving a gap of information about phase transitions and stability on the amorphous state in a wider range of compositions. In the present work, a study of novel co–amorphous formulations in which the selection of the active pharmaceutical ingredients was made according to the therapeutic effect is presented. Resistance against crystallization and behavior of glass transition temperature ( were studied through calorimetric measurements as a function of composition and shelf time. It was found that binary formulations with temperatures higher than those of pure components presented long-term thermal stability. In addition, significant increments of values, of as much as 15 C, were detected as a result of glass relaxation at room temperature during storage time; this behavior of glass transition has not been previously reported for co-amorphous drugs. Based on these results, it can be concluded that monitoring behavior of and relaxation processes during the first weeks of storage leads to a more objective evaluation of the thermomechanical stability of an amorphous formulation.
Highlights
It is well-known that the number of active pharmaceutical ingredients (APIs) with high therapeutic potential but low water solubility is constantly growing due to sustained drug discovery efforts
Two new binary co-amorphous systems were prepared, NIF-CIM and NIM-CAR, whose components were selected according to their therapeutic complementarity. These mixtures were prepared in a wide range of molar fractions to construct phase diagrams and to gather enough information to evaluate the effect of composition in the glass transition temperature and stability of the amorphous state
The measurements of the glass transition temperatures after a long storage time showed a significant increase in Tg compared to the values observed right after the preparation of the glass, indicating a structural relaxation process as a result of storage time
Summary
It is well-known that the number of active pharmaceutical ingredients (APIs) with high therapeutic potential but low water solubility is constantly growing due to sustained drug discovery efforts. The structure of an amorphous material is characterized by a long range disordered arrangement of its molecules leading to a higher chemical potential compared to the more stable crystalline form This higher chemical potential is the driving force for a higher dissolution rate and saturation concentration when dissolved in water [5,6], but it is the driving force for the crystallization process. A review of the current literature shows that efforts along this line are modest, there being around twenty drug–drug binary systems reported to be stable in the amorphous state that have been studied thermally and structurally [3,10] If we compare this number with the large number of poorly soluble drugs [11], there is a great area of opportunity to find new stable amorphous binary systems with increased solubility. Most of the studies on co-amorphous drugs report limited compositions of the binary systems, at most 1:1, 1:2 and 2:1 ratios, leaving a gap of information that needs to be filled by the exploration of a wider composition range to fully characterize the effects of the formulation on the stability and phase transitions of the mixtures, both in the crystalline and amorphous state
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