Stefan Ulvenlund

Hydration of microcrystalline cellulose and milled cellulose studied by sorption calorimetry.

The hydration of two different polymorphs of microcrystalline cellulose (cellulose I and II), as well as the hydration of amorphous cellulose was studied using water sorption calorimetry, gravimetric water vapor sorption, nitrogen sorption, and X-ray powder diffraction. Amorphous cellulose was prepared by means of ball-milling of microcrystalline cellulose (MCC). Whereas X-ray data showed the untreated MCC to consist of cellulose I, the amorphous cellulose was found to recrystallize into cellulose II after contact with water or water vapor at relative humidities (RHs) above 90%. Sorption isotherms show an increase of water sorption in the sequence cellulose I<cellulose II<amorphous cellulose. The enthalpy of water sorption becomes more exothermic in the same sequence. The specific area of cellulose is dramatically higher when calculated from the water adsorption than when calculated from nitrogen adsorption. A proposed mechanism of water sorption by MCC implies the adsorption of water molecules at solid-solid interfaces, i.e., between neighboring microfibrils, which explains the observed difference between water and nitrogen. The Brunauer-Emmett-Teller (BET) model is therefore not appropriate for the description of the hydration of cellulose. Rather, the Langmuir model represents a more accurate description of water sorption by MCC at low RH. At higher RH, the water adsorption competes with capillary condensation. The thickness of microfibrils, as calculated using the fitting of the sorption isotherm of MCC with the Langmuir equation, is about 4 nm. This value compares favorably with literature data.

Efficient synthesis of a long carbohydrate chain alkyl glycoside catalyzed by cyclodextrin glycosyltransferase (CGTase).

Alkyl glycosides with long carbohydrate groups are surfactants with attractive properties but they are very difficult to synthesize. Here, a method for extension of the carbohydrate group of commercially available dodecyl‐β‐d‐maltoside (DDM) is presented. DDM was converted to dodecyl‐β‐d‐maltooctaoside (DDMO) in a single step by using a CGTase as catalyst and α‐cyclodextrin (α‐CD) as glycosyl donor. The coupling reaction is under kinetic control and the maximum yield depends on the selectivity of the enzyme. The Bacillus macerans CGTase favored the coupling reaction while the Thermoanaerobacter enzyme also catalyzed disproportionation reactions leading to a broader product range. A high ratio α‐CD/DDM favored a high yield of DDMO and yields up to 80% were obtained using the B. macerans enzyme as catalyst. Biotechnol. Bioeng. 2009; 104: 854–861.

Formation of subvalent bismuth cations in molten gallium trichloride and benzene solutions

Liquid GaCl3 and GaCl3–NaCl mixtures oxidize bismuth metal to subvalent bismuth cations and such species are also formed in Bi–GaCl3–benzene and Bi–BiCl3–GaCl3–benzene solutions at room temperature. In Bi–GaCl3 and Bi–GaCl3–NaCl melts, 71Ga NMR, UV–VIS and Raman spectroscopy identify Ga+, halogallate(III) ions, Bi+ and the cluster Bi53+ as reaction products and Bi5(GaCl4)3 can be crystallized from Bi–GaCl3 melts. Furthermore, Raman spectra and powder diffraction data or quenched samples of the Bi–GaCl3 system give evidence for the formation of more reduced bismuth clusters at high formal bismuth concentrations. In benzene solution, Bi+ and Bi53+ are formed; no evidence for other, more reduced, species are found. In order to interpret the 71Ga NMR and Raman spectra of the Bi–GaCl3–benzene system properly, a detailed investigation of the Ga–GaCl3–benzene system was undertaken. The spectroscopic data from this system support the view that the chlorogallate (III) ion accompanying the subvalent ions Ga+ and Bi53+ in Bi–GaCl3–benzene solution is Ga3Cl10–. Liquid X-ray scattering (LXS) measurements confirm the speciation of the Bi–GaCl3–benzene system and show that the structure of Bi53+ is virtually identical with that in the solid state. Interactions between Bi53+ and the aromatic solvent are evident from a Raman band at 986 cm–1 next to the most intense band of C6H6 at 992 cm–1. However, LXS and 13C NMR are inconclusive as to the nature of this interaction. Upon dilution of Bi–GaCl3–benzene solutions by n-heptane, a new modification of Bi5(GaCl4)3 precipitates, as shown by powder diffraction. Rietveld analysis shows this modification to possess cubic symmetry (Fm3c, a= 17.114 A) and a high degree of structural disorder.

Oral-based controlled release formulations using poly(acrylic acid) microgels

Aim: To investigate the release of hydrophobic and hydrophilic substances from tablets containing Pemulen and Carbopol as excipients. Method: The dissolution patterns of a hydrophobic (diazepam) and a hydrophilic active substance (midodrine-HCl) from different tablet formulations containing a nonmodified polyacrylic microgel (Carbopol 981 F) or a hydrophobically modified polyacrylic microgel (Pemulen®) have been studied. Possible differences in dissolution in phosphate buffer (pH 6.8) and in 0.1 M HCl between tablets produced using wet granulation and direct compression were also investigated. Results: Tablets produced by wet granulation had a greater effect on the release of active substance from the tablets. No major differences were observed in the release patterns of the hydrophilic substance midodrine-HCl from wet granulated tablets based on Carbopol and Pemulen. However, the release pattern of the more hydrophobic drug substance, diazepam, differed considerably between the two polymers. Wet granulation gave reproducible release patterns. The release patterns from the polymers differed considerably at pH 6.8 but were similar at low pH. Conclusions: The release of the diazepam from the hydrophobic polymer Pemulen was very slow, and the release was close to zero order.

Using NMR Chemical Shift Imaging To Monitor Swelling and Molecular Transport in Drug-Loaded Tablets of Hydrophobically Modified Poly(acrylic acid): Methodology and Effects of Polymer (In)solubility

A new technique has been developed using NMR chemical shift imaging (CSI) to monitor water penetration and molecular transport in initially dry polymer tablets that also contain small low-molecular weight compounds to be released from the tablets. Concentration profiles of components contained in the swelling tablets could be extracted via the intensities and chemical shift changes of peaks corresponding to protons of the components. The studied tablets contained hydrophobically modified poly(acrylic acid) (HMPAA) as the polymer component and griseofulvin and ethanol as hydrophobic and hydrophilic, respectively, low-molecular weight model compounds. The water solubility of HMPAA could be altered by titration with NaOH. In the pure acid form, HMPAA tablets only underwent a finite swelling until the maximum water content of the polymer-rich phase, as confirmed by independent phase studies, had been reached. By contrast, after partial neutralization with NaOH, the polyacid became fully miscible with water. The solubility of the polymer affected the water penetration, the polymer release, and the releases of both ethanol and griseofulvin. The detailed NMR CSI concentration profiles obtained highlighted the clear differences in the disintegration/dissolution/release behavior for the two types of tablet and provided insights into their molecular origin. The study illustrates the potential of the NMR CSI technique to give information of importance for the development of pharmaceutical tablets and, more broadly, for the general understanding of any operation that involves the immersion and ultimate disintegration of a dry polymer matrix in a solvent.

Surfactants modify the release from tablets made of hydrophobically modified poly (acrylic acid)

Many novel pharmaceutically active substances are characterized by a high hydrophobicity and a low water solubility, which present challenges for their delivery as drugs. Tablets made from cross-linked hydrophobically modified poly (acrylic acid) (CLHMPAA), commercially available as Pemulen™, have previously shown promising abilities to control the release of hydrophobic model substances. This study further investigates the possibility to use CLHMPAA in tablet formulations using ibuprofen as a model substance. Furthermore, surfactants were added to the dissolution medium in order to simulate the presence of bile salts in the intestine. The release of ibuprofen is strongly affected by the presence of surfactant and/or buffer in the dissolution medium, which affect both the behaviour of CLHMPAA and the swelling of the gel layer that surrounds the disintegrating tablets. Two mechanisms of tablet disintegration were observed under shear, namely conventional dissolution of a soluble tablet matrix and erosion of swollen insoluble gel particles from the tablet. The effects of surfactant in the surrounding medium can be circumvented by addition of surfactant to the tablet. With added surfactant, tablets that may be insusceptible to the differences in bile salt level between fasted or fed states have been produced, thus addressing a central problem in controlled delivery of hydrophobic drugs. In other words CLHMPAA is a potential candidate to be used in tablet formulations for controlled release with poorly soluble drugs.

Synthesis of water soluble DTPA complexes with pendant uracil moieties capable of forming complementary hydrogen bonds

Two new DTPA (diethylenetriaminepentaacetic acid) functionalised bis(amides) with pendant uracil moieties have been synthesised from the condensation reaction between DTPA bis(anhydride) and 5-aminouracil or 5,6-diaminouracil. These ligands are representative of an increasing number of ligands capable of forming triple hydrogen bonds with complementary organic bases. However, these ligands are unusual since they form water soluble complexes with a variety of metal ions. In this paper, the syntheses of the two DTPA-uracil ligands, seven metal complexes and the crystal structure of the bismuth complex of DTPA bis(4,5-diamino-6-hydroxy-2-mercaptopyrimidine) L1 are reported. The most important feature of this solid state structure is that the two arms on which the uracil moieties are situated have a high degree of rotational freedom and this allows these groups to form multiple hydrogen bonds involving both uracil moieties on one side of the molecule.

Structural studies on volatile, air and moisture sensitive liquids at ambient and elevated temperatures using liquid X-ray scattering. The structure of liquid gallium (III) chloride systems

Abstract An X-ray scattering method is presented which provides accurate structural information on air and moisture sensitive liquids at ambient and elevated temperatures using a standard θ-θ X-ray diffractometer. The method utilizes capillary glass tubes as sample containers and requires no corrections for sample container absorption or scattering, as shown by structural studies of well-known systems such as benzene, carbon tetrachloride and antimony trichloride. Artefacts produced by the sample holder are insignificant and very easy to correct for. The major drawback of the method is the long time of experiment, due to the small (compared with the standard set-up) area/volume ratio of the liquid which contributes to the intensity of the scattered radiation. However, the time required is not unduly long except for liquids containing light elements only (very low scattering power) or very heavy ones (high liner absorptivity). Liquid GaCl 3 is shown to have a dimeric structure consisting of edge-sharing GaCl 4 tetrahedra. This structure is analogous to that previously found for GaCl 3 in the gaseous and solid state and for AlCl 3 in the gaseous and liquid state. Concentrated solutions of GaCl 3 in benzene have been shown to comprise monomeric GaCl 3 units with C 3v symmetry. However, it is suggested that such units form as a result of a radiolytically induced cleavage of the Ga 2 Cl 6 moieties. No GaC correlation is resolved, which is explained by assuming a σ-type complex GaCl 3 and benzene and/or an ill-defined interaction between the GaCl 3 unit and benzene. The former sitution would most probably produce too few GaC correlation to be observable by the present method, whereas the latter situation would produce a very broad GaC correlation difficult to separate from the background. However, the deviation from the D 3h symmetry adopted by GaCl 3 in the gas phase indicates a specific interation between GaCl 3 and benzene.

Synthesis of main-group metal clusters in organic solvents

Oxidation of bismuth metal by GaIII in GaCl3–benzene solution produces the subvalent species Bi+ and Bi53+, which are characterized by liquid X-ray scattering, Raman and UV–VIS spectroscopy.

Arene solutions of gallium chloride Part 3: A quantum chemical evaluation of structural models derived from X-ray scattering and vibrational spectroscopy

Abstract Experimental results from X-ray scattering vibrational spectroscopy of solutions of GaCl3 and mixed-valence salts Ga(GanCl3n+1) in benzene and mesitylene are rationalized using applied theoretical calculations at Hartree-Fock and 2nd-order Moller-Plesset levels. The interaction between the aromatic molecules and Ga(III) is strongly suggested to be of 1π type. Benzene is indicated to form a mono-bridged Ga2Cl6(C6H6) complex, whereas the stronger donor mesitylene seems to also form monomeric GaCl3(C9H12) complexes in equilibrium with the mono-bridged, Ga2Cl6-mesitylene dimer complex. Ga2Cl7− is shown to have a preferred bent configuration with a GaClGa angle about 120°. However, the potential surface is found to be very flat and weak interactions or packing effects in solid compounds are very likely to influence its conformation.