Engineering cocrystal solubility, stability, and pH max by micellar solubilization

Cocrystals offer great promise in enhancing drug aqueous solubilities, but face the challenge of conversion to a less soluble drug when in contact with solvent. This manuscript shows that differential solubilization of cocrystal components by micelles can impart thermodynamic stability to otherwise unstable cocrystals. The theoretical foundation for controlling cocrystal solubility and stability is presented by considering the contributions of micellar solubilization and ionization of cocrystal components. A surfactant critical stabilization concentration (CSC) and a solution pH (pH max ) where cocrystal and drug are thermodynamically stable are shown to characterize cocrystal stability in micellar solutions. The solubility, CSC, and pH max of carbamazepine cocrystals in micellar solutions of sodium lauryl sulfate predicted by the models are in very good agreement with experimental measurements. The findings from this work demonstrate that cocrystal CSC and pH max can be tailored from the selection of coformer and solubilizing additives such as surfactants, thus providing an unprecedented level of control over cocrystal stability and solubility via solution phase chemistry. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:5219–5234, 2011Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86984/1/22725_ftp.pd

Transformation pathways of cocrystal hydrates when coformer modulates water activity

An important attribute of cocrystals is that their properties can be tailored to meet required solubility and stability specifications. But before such practical uses can be realized, a better understanding of the factors that dictate co-crystal behavior is needed. This study attempts to explain the phase behavior of anhydrous/hydrated cocrystals when the coformer modulates both water activity and co-crystal solubility. Stability dependence on solution composition and water activity was studied for theophylline–citric acid (THP–CTA) anhydrous and hydrated cocrystals by both suspension and vapor equilibration methods. Eutectic points and associated water activities were measured by suspension equilibration methods to determine stability regions and phase diagrams. The critical water activity for the anhydrous–hydrate co-crystal was found to be 0.8. It is shown that (a) both water and coformer activities determine phase stability, and (b) excipients that alter water activity can profoundly affect the hydrate/anhydrous eutectic points and phase stability. Vapor phase stability studies demonstrate that cocrystals of highly water soluble coformers, such as citric acid, are predisposed to conversions due to moisture uptake and deliquescence of the coformer. The presence of such coformers as trace level impurities with co-crystal will alter hygroscopic behavior and stability. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3977–3985, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77537/1/22245_ftp.pd

Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34497/1/1_ftp.pd

Surfactant-facilitated crystallization of dihydrate carbamazepine during dissolution of anhydrous polymorph

The influence of two structurally different anionic surfactants on the anhydrous-to-dihydrate transformation of carbamazepine (CBZ) was investigated. The surfactants studied were sodium lauryl sulfate (SLS), a surfactant commonly used in compendial dissolution methods, and sodium taurocholate (STC), an important surfactant in the solubilization and absorption of drugs and lipids in the gastrointestinal tract. Results show that both surfactants promoted the crystallization of CBZ dihydrate [CBZ(D)] during dissolution of the anhydrous monoclinic polymorph [CBZ(A)]). Examination of crystal surfaces showed that SLS facilitated the surface-mediated nucleation of CBZ(D) on CBZ(A) crystals at surfactant concentrations below the critical micelle concentration (cmc). Solubilization of a dye and related color changes provided visual evidence for adsorbed SLS assemblies on CBZ(A) crystal faces below the cmc. Above the cmc, both surfactants promoted the transformation by increasing the bulk nucleation of CBZ(D). STC changed the crystal morphology of CBZ(D) from acicular to prismatic, depending on STC concentration. Such morphology changes originate from interactions between STC and molecular structures of CBZ(D) crystal faces that interfere with the formation of a hydrogen-bonded chain of water molecules and carboxamide dimers. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:449–460, 2004Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34510/1/10496_ftp.pd

Crystallization pathways and kinetics of carbamazepine–nicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy, and calorimetry studies

The work presented here was motivated by the premise that the amorphous state serves as a medium to study cocrystal formation. The molecular mobility inherent to amorphous phases can lead to molecular associations between different components such that a single crystalline phase of multiple components or cocrystal is formed. Cocrystallization pathways and kinetics were investigated from amorphous equimolar phases of carbamazepine and nicotinamide using hot-stage polarized microscopy (HSPM), hot-stage Raman microscopy (HSRM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). Nonisothermal studies revealed that amorphous phases generate cocrystals and that thermal history affects crystallization pathways in significant ways. Two different pathways to cocrystal formation from the amorphous phase were identified: (1) at low heating rates (3°C/min) a metastable cocrystalline phase initially nucleates and transforms to the more stable cocrystalline phase of CBZ–NCT, and (2) at higher heating rates (10°C/min) individual components crystallize, then melt and the stable cocrystalline phase nucleates and grows from the melt. Isothermal studies above the T g of the amorphous equimolar phase also confirm the nucleation of a metastable cocrystalline phase from the amorphous state followed by a solid phase mediated transformation to the stable cocrystalline phase. Cocrystallization kinetics were measured by image analysis and by thermal analysis from small samples and are described by the Avrami–Erofeev model. These findings have important implications for the use of amorphous phases in the discovery of cocrystals and to determine the propensity of cocrystallization from process-induced amorphization. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1147–1158, 2007Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55996/1/20945_ftp.pd

Effect of Initial Buffer Composition on pH Changes During Far-From-Equilibrium Freezing of Sodium Phosphate Buffer Solutions

Purpose. This study aims to assess the pH changes induced by salt precipitation during far-from-equilibrium freezing of sodium phosphate buffers as a function of buffer composition, under experimental conditions relevant to pharmaceutical applications—sample volumes larger than a few microliters, experiencing large degrees of undercooling and supersaturation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41483/1/11095_2004_Article_296795.pd

Rheological Characterization of Topical Carbomer Gels Neutralized to Different pH

Purpose . The primary objective of this study is to perform detailed and extensive rheological characterization of rheology of carbomer (Carbopol) microgels formulated using a solvent system typically used in topical gel formulations. Solvents like glycerin and propylene glycol can alter rheology and drug delivery characteristics of topical gels owing to their different viscosities and due to the change in solvent-polymer and solvent-solvent interactions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41505/1/11095_2004_Article_489401.pd

Prácticas sociales genocidas: El caso de los moriscos y el caso de los palestinos

En este artículo se analiza el caso de los moriscos en España y el caso de los palestinos en Israel desde la perspectiva de las “prácticas sociales genocidas”, que nos ofrece un marco de análisis habitualmente utilizado en el estudio del holocausto. La importancia de este análisis se centra en el proceso, que transcurre por unas fases que le dan una planificación, sistematización e intencionalidad, que se suponen terminan con éxito la tarea: la exterminación de una parte importante de la población.In this paper the case of the Moorish in Spain and the case of the Palestinians in Israel are analysed from the perspective of “genocide social practices”, which offers an analysis often used in the study of Holocaust. The importance of this analysis rely on the process, which is well organised, planned, and systematically and intentionally executed, in such a way to guaranty the success of the target: the extermination of a relevant part of the population

Formation and physicochemical properties of crystalline and amorphous salts with different stoichiometries formed between ciprofloxacin and succinic acid

YesMulti-ionizable compounds, such as dicarboxylic acids, offer the possibility of forming salts of drugs with multiple stoichiometries. Attempts to crystallize ciprofloxacin, a poorly water-soluble, amphoteric molecule with succinic acid (S) resulted in isolation of ciprofloxacin hemisuccinate (1:1) trihydrate (CHS-I) and ciprofloxacin succinate (2:1) tetrahydrate (CS-I). Anhydrous ciprofloxacin hemisuccinate (CHS-II) and anhydrous ciprofloxacin succinate (CS-II) were also obtained. It was also possible to obtain stoichiometrically equivalent amorphous salt forms, CHS-III and CS-III, by spray drying and milling, respectively, of the drug and acid. Anhydrous CHS and CS had melting points at ∼215 and ∼228 °C, while the glass transition temperatures of CHS-III and CS-III were ∼101 and ∼79 °C, respectively. Dynamic solubility studies revealed the metastable nature of CS-I in aqueous media, resulting in a transformation of CS-I to a mix of CHS-I and ciprofloxacin 1:3.7 hydrate, consistent with the phase diagram. CS-III was observed to dissolve noncongruently leading to high and sustainable drug solution concentrations in water at 25 and 37 °C, with the ciprofloxacin concentration of 58.8 ± 1.18 mg/mL after 1 h of the experiment at 37 °C. This work shows that crystalline salts with multiple stoichiometries and amorphous salts have diverse pharmaceutically relevant properties, including molecular, solid state, and solubility characteristics.Solid State Pharmaceutical Cluster (SSPC), supported by Science Foundation Ireland under grant number 07/SRC/ B1158