Towards continuous production of pharmaceutical cocrystals

A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), using hot-melt extrusion by coprocessing the drug and conformer has been developed. Three model drugs were used, a coformer, and matrix, respectively. The MAC product containing 80:20 (w/w) cocrystal:matrix was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. A partial least squares (PLS) regression model was developed for quantifying the efficiency of cocrystal formation. The PLS model estimated that the MAC product was 78% (w/w) cocrystal (theoretical 80%), with ~ 0.3% mixture of free (unreacted) drug, and 21.6% Soluplus (theoretical 20%). A physical mixture (PM) of a reference cocrystal (RCC), prepared by precipitation from solution, and Soluplus resulted in faster dissolution relative to the pure RCC. However, the MAC product with the exact same composition resulted in considerably faster dissolution and higher maximum concentration (~5-fold) than those of the PM. The MAC product consists of high-quality cocrystals embedded in a matrix. The processing aspect of MAC plays a major role on the faster dissolution observed. The MAC approach offers a scalable process, suitable for the continuous production, manufacturing, and formulation of pharmaceutical cocrystals

Pharmaceutical and food surfaces of relevant composite materials and the characterization thereof

The main motivation is to understand surface-interface of materials in order to manipulate the systems and then get involved in technology. Particulate and composite materials, used in Pharmaceutical and Food, are subjected to structural modifications during the chain of steps of production and manufacturing processes. The processing objective is often to induce a macroscopic change in order to setup the material for the next processing step. One critical aspect is that the various unit operations meant to adjust the macroscopic properties that invariably induce structural changes at the microscopic scale on the materials. Being unintended, such microscopic changes are also uncontrolled and are the source of the often unpredictable and poorly understood bulk behavior of many particulate materials. It is therefore of critical relevance to develop a fundamental insight at the microscopic structure of such materials, by probing and mapping them at the nanoscale level. This study probes the interface and surfaces of stress-free and stress-induced materials with characterization thereof. Submicron particles are always produced during pharmaceutical and food processing in an uncontrolled and poorly understood manner. The high surface to volume ratio often makes them dominant on the bulk behavior of the in-process materials used for manufacturing. The structural properties controlling in-process response are size dependent, falling over the length scales ranging from nanometers to a few micrometers. In this domain, structural surface mapping is critical to the dispersion and agglomeration control to understand and enable bulk functionality of powders. Working with films has been demonstrated to be an effective way of immobilizing nanoparticulate systems in a dry and uniform manner. The use of polymer–particle composite films results in better reproducibility of in-process systems than the single component counterpart. Therefore, nanoscale mapping of surfaces of such composites results in a more systematic way of characterizing the critical processing attributes of food and pharmaceutical materials that will lead to a higher performance and acceptable shelf-life stability

Estimation of aqueous solubility of organic compounds.

The relationship between aqueous activity coefficients (log γ(w)) and different physico-chemical properties has been studied for a number of solutes by both empirical correlations as well as by applying existing theoretical models. The solute properties selected have been classified into three categories: geometrical, polar, and electrostatic. The solutes chosen were divided into two major groups: (a) Training Set. Structurally simple compounds, i.e., each containing only one functional group, and (b) Test Set. A series of drugs and pollutants covering a wide variety of functional groups. The Training Set is in turn formed by four sub-sets of structurally related solutes, each representative of typical data sets used in the literature for solubility studies. Linear relationships were found for polar and geometric parameters in agreement with those reported in the literature. However, although the overall correlations are good, the quality of the regressions among the sub-sets is not uniform. The generality of the relationships obtained with the Training Set was tested by applying the obtained expressions to estimate log γ(w) of the solutes of the Test Set. It was found that the parameters of the theoretical models are the only ones whose relationship with log γ(w) is maintained for both the Training and the Test sets. The theoretical models used are: octanol-water partition coefficient estimated by both Rekker's (parameter LOGP) and by Leo's (parameter PCLOGP) methods; the solubility group contributions method of Wakita et al. (1986) (parameter WAKITA); the Linear Solvation Energy Relationships model (parameter KAMLET), and the UNIFAC model. The theoretical approaches were evaluated based on two criteria: accuracy of predictions and range of applicability. The accuracy of predictions was quantitated by a prediction coefficient, P², which although analogous to regression coefficient (R²) is far less flexible. Prediction coefficient is sensitive not only to scatter of the predictions but also to the systematic errors of the model being tested. The range of applicability was quantitated by the fraction (f) of solutes within the data set for which estimates by the given methodology are possible. The Accuracy-Generality Product (AGP) defined as the product of P² and f was used as the overall criterion for evaluation. The results indicated that the quality of predictions of the theoretical models as determined by the AGP is PCLOGP > LOGP > WAKITA > UNIFAC > KAMLET, for both the Training and Test sets

Entropy of Mixing and the Glass Transition of Amorphous Mixtures

Different equations have been proposed for estimating the glass transition temperature of amorphous mixtures. All such expressions lack a term to account for the effect of the entropy of mixing on the glass transition. An entropy based analysis for the glass transition of amorphous mixtures is presented. The treatment yields an explicit mixing term in the expression for the glass transition temperature of a mixture. The obtained expression reduces to the Couchman-Karasz equation in the limiting case where the contribution of the entropy of mixing approaches zero. Equivalent expressions are obtained for the glass transition temperature of a mixture of two glass formers as for the effect of a plasticizing liquid diluent on the glass transition temperature of an amorphous material

Síntesis de N-succinil-quitosano y formación de nanomicelas para transporte de fármacos hidrófobos

En este artículo se presenta la síntesis y caracterizaciones del copolímero anfifílico, parcialmente hidrosoluble N-succinil-quitosano, el cual presenta una mayor solubilidad a un pH de 5, este se sintetiza a partir del polímero no soluble en agua quitosano de medio peso molecular. Esto con el fin de implementar este derivado del quitosano para la formación de nanomicelas transportadoras de fármacos hidrófobos, la cual se llevó a cabo a través del método de evaporación de solvente. Las caracterizaciones del polímero se realizaron empleando espectroscopia de infrarrojo y resonancia magnética nuclear, cuyo análisis de resultados indica que mediante el proceso de síntesis empleado se logró obtener el polímero N-succinil-quitosano soluble en agua a partir del quitosano de peso molecular medio. Las nanoparticulas poliméricas formadas a partir de éste, se caracterizaron a través de microscopía electrónica de transmisión obteniendo imágenes de nanomicelas de un tamaño medio de 70 nm