Excipients are crucial components of most pharmaceutical formulations. In the case of a solid oral dosage formulation containing the salt form of a weakly ionizable drug, excipient selection is critical, as some excipients are known to cause salt disproportionation (conversion of salt to the free form). Therefore, robust formulation design necessitates an in-depth understanding of the factors impacting salt disproportionation during processing or storage as this can negatively impact product quality and performance. To date, there is an incomplete understanding of key excipient properties influencing salt disproportionation. Specifically, the potential roles of amorphous excipient glass transition temperature and excipient hygroscopicity, if any, on salt disproportionation are still not well understood. Furthermore, the relationship between the compression and the extent of salt disproportionation is an unknown factor. Herein, by utilizing various grades of polyvinylpyrrolidone (PVP), its copolymer, copovidone (PVPVA), and magnesium stearate, a systematic investigation of disproportionation was performed using pioglitazone HCl as a model salt of a weak base. It was observed that there was a poor correlation between excipient hygroscopicity and the rate and extent of disproportionation. However, powder compression into compacts enhanced the rate and extent of disproportionation. This work focused on disproportionation of the salt of a weak base, as basic drugs are more prevalent, however, salts of weak acids may have similar tendencies under relevant conditions. The knowledge gained from this study will help in understanding the role of various excipients with respect to salt disproportionation, paving the way for designing stable salt formulations.

Salt disproportionation is a major issue for pharmaceutical products containing a salt form of a weakly basic drug, because conversion to the free base during processing or storage in the presence of excipients may negatively impact stability and bioperformance of the drug product. Several factors influencing disproportionation tendency have been elucidated; however, a complete mechanistic understanding of this phenomenon is still lacking. Specifically, it is unclear if the crystal structure of the salt plays a role, beyond influencing the salt solubility. Herein, by utilizing model compounds with similar pK(a) and pH(max) values, and hence similar thermodynamic driving forces for disproportionation, we demonstrate that salt crystal structure appears to play a major role in influencing disproportionation tendency. Some salts with low pH(max) values were found to be resistant to disproportionation, while other systems transformed to the free base following contact with the basic excipient, magnesium stearate. For salts that converted to the free base, the new crystal phase was imaged using atomic force microscopy and scanning electron microscopy. Based on these images, it was concluded that conversion occurred via a nucleation and growth process; i.e., transformation involved considerable structural rearrangement. Extensive crystallographic analysis provided some insight, suggesting that the packing and intermolecular interactions around the salt bridge may influence the susceptibility of the salt to conversion to the free base when challenged with a basic microenvironment. Thus, evaluation of disproportionation risk requires consideration not only of pH,a, but also salt crystal structure, whereby different solid state forms of a given salt may present different risk levels for conversion to free base. Further studies of correlations between crystal structure and disproportionation tendency are clearly warranted to ensure the development of robust salt formulations.

Understanding the phase behavior of crystal forms is essential in drug formulation development, as physical stability of the active pharmaceutical ingredient (API) is critical to achieving the desired bioavailability. Solvents greatly impact the physical stability of crystalline solids, resulting in a variety of well-known phase transitions, such as hydrate/solvate formation. However, solvent incorporation may also result in the formation of a less-known crystalline solid solutions (CSSs). The identification and characterization of CSSs and their effect on API physicochemical properties have not been investigated. This is the first reported instance of a CSS for an API. An exhaustive study of the phase behavior of the enantiotropically related polymorphs, I and II, of Benzocaine in water and ethanol revealed that Form I formed a CSS with water below 294.5K. Construction of the phase diagrams of Forms I and II in water and ethanol revealed that CSS formation significantly decreased the phase transition temperature between Forms I and II in water. This change resulted from the increased disorder in the lattice of Form I due to the presence of water. This work demonstrates the importance of understanding the formation of CSSs on the thermodynamic behavior of crystalline pharmaceutical solids.

The ability to engineer biocompatible polymers with controllable properties is highly desirable. One such approach is to cross-link carbohydrate polymers using ionotropic gelation (IG). Previous studies have investigated the effect of curing time on alginate cross-linking. Herein, we discuss a novel study detailing the effect of IG residence time (IGRT) on the cross-linking of alginate with calcium ions (Ca2+) along with water migration (syneresis) and their subsequent impact on the pharmaceutical properties of alginate particles. IGRT was shown to have a significant effect on particle size, porosity, density, mechanical strength and swelling of calcium alginate particles as well as drug release mechanism. Furthermore, we describe a novel application of electron dispersive spectroscopy (EDS), in conjunction with Fourier Transform- infra red (FT-IR) spectroscopy, to analyze and monitor the changes in Ca2+ concentration during cross-linking. A simple procedure to determine the concentration and distribution of the surface and internal Ca2+ involved in alginate cross-linking was successfully developed.

A key challenge in rationally designing heterogeneous surfaces for controlling crystallization is overcoming the lack of understanding the influence of surface properties has on nucleation. Previous studies hay shown how surface chemistry, can be used to control both nucleation rate and polymorphism. However, these approaches are often empirical and lack any predictive capability. Herein, a novel method, PETI (Predicting Efficacy Through Intermolecular Interactions), for predicting the effectiveness of different polymer surfaces in promoting heterogeneous nucleation is described. PETI utilizes the Cambridge Structural Database to determine the likelihood of forming an intermolecular interaction between solute chemical moieties and polymer surfaces. The concept for PETI is the more likely a solute/polymer interaction, the faster the rate of heterogeneous nucleation. PETI was tested by studying the nucleation of model compounds, benzocaine and 1,1'-bi-2-naphthol, on different polymer surfaces. Results showed that PETIs predictions for the effectiveness of the different polymers at promoting nucleation were in good agreement with experimental observations. This study represents a highly novel approach to predicting the effectiveness of surfaces in promoting crystal nucleation and shows the potential utility of using knowledge of solid-state intermolecular interactions as a tool for the rational design of polymer surfaces for controlling heterogeneous nucleation.

Approximately 50% of solid oral dosage forms utilize salt forms of the active pharmaceutical ingredient (API). A major challenge with the salt form is its tendency to disproportionate to produce the un-ionized API form, decreasing the solubility and negatively impacting product stability. However, many of the factors dictating the tendency of a given salt to undergo disproportionation remain to be elucidated. In particular, the role of the solid-state properties of the salt on the disproportionation reaction is unknown. Herein, various solid forms of a model salt, miconazole mesylate (MM), were evaluated for their tendency to undergo disproportionation when mixed with basic excipients, namely tribasic sodium phosphate dodecahydrate (TSPd) and croscarmellose sodium (CCS), and exposed to moderate relative humidity storage conditions. It was observed that the rate and extent of salt disproportionation were significantly different for the various solid forms of MM. As expected, the amorphous salt was highly susceptible to disproportionation, while the dihydrate salt form was resistant to conversion under the conditions tested. In addition, binary excipient blends of amorphous and anhydrous forms exhibited a reduced extent of disproportionation at a higher relative humidity storage condition. This was due to the competitive kinetics between disproportionation to the free base and conversion to the dihydrate salt form. The results of this study provide important insights into the impact of solid-state form on susceptibility to disproportionation that can be utilized for rationally designing robust pharmaceutical formulations.

The ability to control crystal form is essential for the development of materials with desired properties. The rational design of heterosurfaces to control nucleation is one such approach. Heterosurfaces are commonly selected based on their chemistry and/or crystallography and/or morphology. However, the heterosurface is almost always considered to be in equilibrium with the crystallization medium during nucleation. This may lead to an inaccurate description of the epitaxial mechanisms responsible for controlling nucleation. Herein, we discuss controlling the surface equilibria of sparingly soluble crystals to control heterogeneous nucleation and crystal form. The heterogeneous crystallization of 3-aminobenzensulfonic acid (3-ABSA) on seeds of 1,5-diaminonaphthalene (DAN) was investigated. The DAN crystal faces were determined to be in a nonequilibrium state upon suspension in an aqueous solution of 3-ABSA, resulting in significant changes in surface morphology. Controlling the kinetics of surface equilibration resulted in DAN seeds with differing surface morphologies. Seeding with these different surface morphologies led to the nucleation of different crystal forms of 3-ABSA, including the so-called "disappeared" polymorph, Form I. Utilizing surface equilibria to control heterogeneous nucleation represents a highly novel approach to controlling the crystal form.

While polymer induced heterogeneous nucleation (PIHn) has been shown to be a powerful tool for crystallization control and polymorph screening the factors influencing PIHn, such as solvent selection, supersaturation and method of crystallization are not well understood. Herein, we report on the use of PIHn to selectively crystallize a new and rare crystal structure of vanillin. Nearly 65 years ago, Walter McCrone postulated vanillin to be trimorphic. However, only one crystal form, Form I, had been structurally characterized to this point. Form II crystallizes in the space group Pna21 with four molecules in the asymmetric unit. Achiral molecules exhibiting such crystal structures account for less than 0.008% of all organic entries in the Cambridge Structural Database. Polymorphic control by PIHn was observed to be highly dependent on the method of crystallization. In the presence of poly(acrylic acid) and poly(methyl methacrylate) micro-particles the thermodynamically stable Form I was crystallized from isopropanol by quench cooling, while metastable Form II was obtained by slow evaporation. To our knowledge this is the first deliberate study to highlight the influence of crystallization method on PIHn.

Paraoxonase 1 (PON1) is an HDL-associated enzyme and exhibits anti-inflammatory, anti-diabetic, and anti-atherogenic properties. Association of PON1 to HDL particles increases the stability and activity of PON1 and is important for the normal functioning of the enzyme. HDL particles are made up of lipid and protein constituents and apolipoprotein A-I (apoA-I) is a principal protein constituent of HDL that facilitates various biological activities of HDL. In many disease conditions the oxidized phospholipid (Ox-PL) content of HDL is found to be increased and an inverse correlation between the activity of PON1 and oxidation of the HDL is observed. However, the molecular details of the inhibitory action of the Ox-PL-containing HDL on the function of PON1 are not clear yet. In this study we have assembled reconstituted HDL (rHDL) particles with and without Ox-PL and compared their effect on the structure and function of (13)C-labeled recombinant PON1 ((13)C-rPON1) by employing attenuated total reflectance Fourier transformed infrared (ATR-FTIR) spectroscopy and enzymatic assay. Our results show that the presence of the Ox-PL in the rHDL particles alters the structure of rPON1 and decreases its lactonase activity.

High density lipoprotein (HDL) particles are made up of lipid and protein constituents and apolipoprotein A-I (apoA-I) is a principal protein component that facilitates various biological activities of HDL particles. Increase in Ox-PL content of HDL particles makes them 'dysfunctional' and such modified HDL particles not only lose their athero-protective properties but also acquire pro-atherogenic and pro-inflammatory functions. The details of Ox-PL-induced alteration in the molecular properties of HDL particles are not clear. Paraoxonase 1 (PON1) is an HDL-associated enzyme that possesses anti-inflammatory and anti-atherogenic properties; and many of the athero-protective functions of HDL are attributed to the associated PON1. In this study we have characterized the physicochemical properties of reconstituted HDL (rHDL) particles containing varying amounts of Ox-PL and have compared their PON1 stimulation capacity. Our results show that increased Ox-PL content (a) modifies the physicochemical properties of the lipid domain of the rHDL particles, (b) decreases the stability and alters the conformation as well as orientation of apoA-I molecules on the rHDL particles, and (c) decreases the PON1 stimulation capacity of the rHDL particles. Our data indicate that the presence of Ox-PLs destabilizes the structure of the HDL particles and modifies their function.

Apolipoprotein A-I (apoA-I) is a major protein constituent of high density lipoprotein (HDL) which plays a prominent role in reverse cholesterol transport as well as other functions of HDL. Oxidative stress in many inflammatory conditions leads to peroxidation of phospholipids resulting in the formation of oxidized HDL particles. Effect of oxidized phospholipids on the properties of HDL is not well characterized. In this study we have characterized the effect of oxidized phospholipids on the properties of reconstituted HDL particles. Reconstituted HDL particles containing varying amount of oxidized-PAPC were prepared by cholate dialysis method and purified using gel filtration chromatography. Purified rHDL particles were used for characterization. Our results indicate that presence of oxidized-PAPC not only modifies the lipidic environment of HDL particles but also drastically alters the secondary structure and stability of bound apoA-I and induces significant change in global conformation as well as orientation of bound apoA-I. We acknowledge financial support from NIPER, S.A.S. Nagar, India.