Luz María Martínez

Stabilization of amorphous paracetamol based systems using traditional and novel strategies.

There is a special interest in having pharmaceutical active ingredients in the amorphous state due to their increased solubility and therefore, higher bioavailability. Nevertheless, not all of them present stable amorphous phases. In particular, paracetamol is an active ingredient widely known for its instability when prepared in the amorphous state. In the present work thermally stable amorphous binary paracetamol based systems were obtained showing stability on a wide range of temperatures: below its glass transition temperature (Tg) as amorphous solids in the glassy state and above their glass transition temperature, where these materials exist as stable supercooled liquids. To achieve stabilization of the binary paracetamol based system several strategies were applied and optimized, being the selection of the container material a key and novel approach to control the mechanical stress during cooling, eliminating cracks which act as nucleation centers leading to crystallization.

Two-phase amorphous-amorphous solid drug dispersion with enhanced stability, solubility and bioavailability resulting from ultrasonic dispersion of an immiscible system

Graphical abstract Figure. No Caption available. Abstract Amorphization of active pharmaceutical ingredients (APIs) and the preparation of solid dispersions are strategies that can be synergized to improve the solubility of oral drugs. Immiscibility between an API and a carrier in the molten state that could be perceived as a problem in the preparation of solid dispersions, may actually introduce an advantage. In the present work, a two‐phase amorphous‐amorphous solid dispersion (AASD) was prepared by ultrasonicating a molten immiscible mixture of indomethacin (IND) and glucose (GLU) prior quenching. By introducing this novel ultrasound assisted method, the immiscible API particles were uniformly dispersed as microscopic glassy clusters of the drug in the solid amorphous GLU matrix; particle sizes of IND in the AASD range from 600 nm to 1.4 &mgr;m. As a result of the amorphization and particle size reduction of IND, its aqueous solubility increased to reach almost 40 ppm (8 times more soluble compared to indomethacin in its crystalline state). In addition, the oral bioavailability and its resistance against crystallization were also enhanced; AASD samples have remained amorphous for more than two years of storage.

Long-Term Stability of New Co-Amorphous Drug Binary Systems: Study of Glass Transitions as a Function of Composition and Shelf Time

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 (Tg were studied through calorimetric measurements as a function of composition and shelf time. It was found that binary formulations with Tg temperatures higher than those of pure components presented long-term thermal stability. In addition, significant increments of Tg 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 Tg and relaxation processes during the first weeks of storage leads to a more objective evaluation of the thermomechanical stability of an amorphous formulation.

Application of ATR-FTIR spectroscopy to the study of thermally induced changes in secondary structure of protein molecules in solid state

FTIR spectroscopy in combination with ATR sampling technique is the most accessible analytical technique to study secondary structure of proteins both in solid and aqueous solution. Although several studies have demonstrated the applications of ATR‐FTIR to study conformational changes of solid dried proteins due to dehydration, there are no reports that demonstrate the application of ATR‐FTIR in the study of thermally induced changes of secondary structure of biomolecules directly on the solid state. In this study, four biomolecules of pharmaceutical interest, lysozyme, myoglobine, chymotripsin and human growth hormone (hGH), were studied on the solid state before and after different thermal treatments in order to relate changes of secondary structure to partial or total thermal denaturation processes. The results obtained provide experimental evidence that protein thermal denaturation in the solid state can be detected by displacement of carbonyl bands which correspond to conformational transformations between α–helix to β‐sheet or intermolecular β‐sheet; the molecules studied undergo this transformation when exposed to a temperature close to their denaturation temperature which may become irreversible depending on the extent of the heating treatment. These findings demonstrate that ATR‐FTIR is an effective and time efficient technique that allows the monitoring of the protein thermal denaturation process of solid samples without further reconstitution or prior sample preparation.

Phase Transitions in Sugars and Protein Systems: Study of Stability of Lysozyme in Amorphous Sugar Matrices

In the last decades, development of products resulting from the application of molecular biology and biotechnology has demonstrated accelerated progress; as a result, the use of biological products such as proteins and enzymes has increased considerably in the food and pharmaceutical industry (Wanh 2000). Since most of these biomolecules, particularly enzymes, are extremely sensible to changes in temperature, pH, ionic force, and water concentration, scientists in these fields are in constant search of new methodologies and techniques to improve their stability. In industrial processes, biomolecules are obtained in aqueous solutions; however, in this medium their shelf life is relatively short. A remarkable improvement in the stability of protein based drugs has been obtained when these biomolecules are taken to a dry state; unfortunately, the freeze drying or spray-drying processes (which are the most common used techniques to obtain dry protein) expose these molecules to extreme conditions that cause a considerable decrease in their activity (Passot et al. 2005; Liao et al. 2004; Hinrichs et al. 2001; Heller et al. 1999).

Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia

The high index of simultaneous incidence of hypertension and hypercholesterolemia in the population of many countries demands the preparation of more efficient drugs. Therefore, there is a significant area of opportunity to provide as many alternatives as possible to treat these illnesses. Taking advantage of the solubility enhancement that can be achieved when an active pharmaceutical ingredient (API) is obtained and stabilized in its amorphous state, in the present work, new drug-drug co-amorphous formulations (Simvastatin SIM- Nifedipine NIF) with enhanced solubility and stability were prepared and characterized. Results show that the co-amorphous system (molar ratio 1:1) is more soluble than the pure commercial APIs studied separately. Aqueous dissolution profiles showed increments of solubility of 3.7 and 1.7 times for SIM and NIF, correspondingly, in the co-amorphous system. The new co-amorphous formulations, monitored in time, (molar fractions 0.3, 0.5 and 0.7 of SIM) remained stable in the amorphous state for more than one year when stored at room temperature and did not show any signs of crystallization when re-heating. Inspection on the remainder of a sample after six hours of dissolution showed no recrystallization, confirming the stability of co-amorphous system. The enhanced solubility of the co-amorphous formulations makes them promising for simultaneously targeting of hypertension and hypercholesterolemia through combination therapy.