Rodolfo Pinal

Solubility of aromatic pollutants in mixed solvents

The solubility behavior of several aromatic and polynuclear aromatic pollutants was determined in a variety of water/cosolvent mixtures. The data was used to test a log-linear solubility model and develop a relationship for determining the slope of the log-linear solubility curve.

Hydrotropic solubilization of poorly water‐soluble drugs

The solubilizing ability of two aromatic hydrotropes, N,N-diethylnicotinamide (DENA) and N,N-dimethylbenzamide (DMBA), was investigated using a set of 13 poorly soluble, structurally diverse drugs. The number of aromatic rings in the solute molecule has a very strong effect on the solubility enhancement produced by either hydrotrope. However, although solubility enhancements in the order of 1000- to 10,000-fold were obtained with each of the hydrotropic agents, important differences were found between the two. DMBA is more hydrophobic and undergoes more extensive self-association than DENA, as determined by vapor osmometry. As a result, DMBA is generally a more powerful solubilizer of hydrophobic drugs. DENA, on the other hand, is more polar and its self-association is essentially limited to dimer formation. However, despite being less hydrophobic, DENA is an extremely powerful solubilizer of paclitaxel, a highly hydrophobic compound. Such a result is attributed to the higher hydrogen bonding ability of DENA over DMBA and the very high hydrogen bonding ability of paclitaxel. These observations in turn illustrate the strong interplay between specific and hydrophobic interactions on the observed solubilization by hydrotropic agents.

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.

Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs.

A novel method was developed to manufacture amorphous formulations of poorly soluble compounds that cannot be processed with existing methods such as spray drying and melt extrusion. The manufacturing process and the characterization of the resulting amorphous dispersion are presented via examples of two research compounds. The novel process is utilized N,N-dimethylacetamide (DMA) to dissolve the drug and the selected ionic polymer. This solution is then co-precipitated into aqueous medium. The solvent is extracted out by washing and the co-precipitated material is isolated by filtration followed by drying. The dried material is referred to as microprecipitated bulk powder (MBP). The amorphous form prepared using this method not only provides excellent in vitro and in vivo performance but also showed excellent stability. The stabilization of amorphous dispersion is attributed to the high T(g), ionic nature of the polymer that help to stabilize the amorphous form by possible ionic interactions, and/or due to the insolubility of polymer in water. In addition to being an alternate technology for amorphous formulation of difficult compounds, MBP technology provides advantages with respect to stability, density and downstream processing.

Effect of molecular symmetry on melting temperature and solubility

Molecular symmetry has a pronounced effect on the melting properties and solubility of organic compounds. As a general rule, symmetrical molecules in crystalline form have higher melting temperatures and exhibit lower solubilities compared with molecules of similar structure but with lower symmetry. Symmetry in a molecule imparts a positive amount of residual entropy in the solid phase (i.e., more possible arrangements leading to the same structure). This means that the entropy of a crystal of symmetric molecules is greater than the entropy of crystal of a similar, but non-symmetric molecule. An analysis is presented relating the enthalpy, entropy and temperature of melting for an idealised system of structural isomers of different molecular symmetries. The analysis presented helps explain why often, yet not always, the crystal of a more symmetric molecule, which has greater entropy to start (closer to that of the liquid), also exhibits a greater gain in entropy upon melting, compared with the crystal of a less symmetrical molecule. The residual entropy due to molecular symmetry has the direct effect of reducing the entropy gain upon melting (a negative effect). However, molecular symmetry also exerts indirect effects on both the entropy and enthalpy of melting. These indirect effects, imposed by the condition of equilibrium melting, are positive, such that it is the balance between the direct and indirect effects what determines the value observed for the entropy of melting of the symmetric molecules. When the indirect effect of molecular symmetry is greater than its direct effect, the observed entropy gain upon melting of the more symmetrical molecule is greater than that of a less symmetrical one.

Solubility enhancement of hydrophobic compounds by cosolvents: Role of solute hydrophobicity on the solubilization effect

Drug solubilization is an important aspect of drug development. We investigate the relationship between solute hydrophobicity on the solubilization properties of water-cosolvent mixtures. The solubilization in water-cosolvent mixtures of seven chemically unrelated drugs was determined. The set of solutes included hydrocortisone, sulfanilamide, acetophenetidine, benzocaine, indomethacin, thymol and ibuprofen. Two sets of water-cosolvent mixtures were used in the study. A group of polar cosolvents consisting of three aliphatic alcohols, and a group of the less polar cosolvents NMP, tetraglycol and labrasol. The hydrophobicity of the drug has a direct impact on the solubilization obtained in the water-cosolvent mixtures. However, the role of hydrophobicity is different in the case of the polar cosolvents compared with the less polar ones. In polar cosolvents, the solubilization behavior is typical of polarity match, where the collective trend of solubility enhancement decreases as the activity coefficient of the solute in the solvent mixture increases. The result is a linear profile comprising the combined data of all solutes and all solvents. On the other hand, while the less polar cosolvents exhibit greater positive deviations from the log-linear cosolvency model, the collective solubility enhancement in these systems exhibits no readily discernible pattern. However, by taking into account the hydrophobicity of the solutes, a systematic effect becomes clearly apparent. In this case, the hydrophobicity of the solute demarcates its region in the solubilization profile.

Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions.

We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days.

Hydrotropic polymer micelles as versatile vehicles for delivery of poorly water-soluble drugs

Polymer micelles have been used widely for delivery of poorly water-soluble drugs. Such drug delivery, however, has been based primarily on hydrophobic interactions. For better drug loading and improved stability, hydrotropic polymer micelles were used. To develop a versatile polymer micelle for solubilizing various poorly soluble drugs, two different hydrotropic agents were examined. The solubilizing properties of two hydrotropic agents, N,N-diethylnicotinamide (DENA) and N,N-dimethylbenzamide (DMBA), in polymeric form were investigated for their ability to solubilize five drugs with low aqueous solubility covering a wide range of hydrophobicity and molecular structures. The hydrotropes were covalently linked to the hydrophobic block of a block copolymer that also had a hydrophilic poly(ethylene glycol) (PEG) block. The solubilizing capacity of the polymeric hydrotropes was compared with that of the non polymeric hydrotropes, as well as of two conventional (non hydrotropic) copolymer systems. The solubilizing capacity of polymeric hydrotropes reflects combined effects of the micellar solubilization by the hydrophobic micelle core and hydrotropic solubilization. Because of the highly localized configuration, hydrotropes in the polymeric form are more powerful solubilizers than in the monomeric (non-polymeric) solution. It is possible to produce 1~3 orders of magnitude increase in solubility with polymeric hydrotropes at the 1% (w/v) level. Of the two hydrotropic polymeric systems in this study, the DENA-based system is highly specific, whereas the DMBA-based system is a general solubilizer of hydrophobic drugs. An additional advantage of polymeric hydrotropes over the non-polymeric form is absence of high concentrations of free hydrotropes in the formulation. Solubilization vehicles based on polymeric hydrotropes are expected to provide a new and versatile means of preparing formulations for various poorly soluble drugs and drug candidates without using organic solvents. This advantage is accompanied with the inherent controlled release property of the hydrotropic polymer micelles, making them ideal for pharmaceutical formulations used in drug candidate screening and toxicology studies.

Elucidating Raw Material Variability—Importance of Surface Properties and Functionality in Pharmaceutical Powders

The purpose of this study is to illustrate, with a controlled example, the influence of raw material variability on the excipient’s functionality during processing. Soluble starch was used as model raw material to investigate the effect of variability on its compaction properties. Soluble starch used in pharmaceutical applications has undergone a purification procedure including washing steps. In this study, a lot of commercially available starch was divided into two parts. One was left intact and the other was subjected to an extra washing step. The two resulting lots were subjected to a series of physical characterization tests typical of those used to qualify raw materials. The two resulting lots gave virtually identical results from the tests. From the physical testing point of view, the two lots can be considered as two equivalent lots of the same excipient. However, when tested for their functionality when subjected to a compaction process, the two lots were found to be completely different. The compaction properties of the two lots were distinctly different under all environmental and processing conditions tested. From the functionality point of view, the two lots are two very different materials. The similar physical testing results but different functionality can be reconciled by considering the surface properties of the powders. It was found that the washing step significantly altered the surface energetic properties of the excipient. The washed lot consistently produced stronger compacts. These results are attributable to the measurably higher surface energy of induced by the additional washing step.

Utility of Multivariate Analysis in Modeling the Effects of Raw Material Properties and Operating Parameters on Granule and Ribbon Properties Prepared in Roller Compaction

This article aimed to model the effects of raw material properties and roller compactor operating parameters (OPs) on the properties of roller compacted ribbons and granules with the aid of principal component analysis (PCA) and partial least squares (PLS) projection. A database of raw material properties was established through extensive physical and mechanical characterization of several microcrystalline cellulose (MCC) and lactose grades and their blends. A design of experiment (DoE) was used for ribbon production. PLS models constructed with only OP-modeled roller compaction (RC) responded poorly. Inclusion of raw material properties markedly improved the goodness of fit (R2 = .897) and model predictability (Q2 = 0.72).