Solvent driven phase transitions of acyclovir-the role of water and solvent polarity

Acyclovir, an antiviral purine derivative listed on the WHO's Model List of Essential Medicines, is commonly used in several different dosage forms from tablets to gels, oleogels and suspensions. Although temperature driven phase transitions of its commercially available 3 : 2 hydrate have been known since 2011, information on the solvent driven phase transitions of this drug has been limited. This study identifies the pathways of transformations of acyclovir forms I and V induced by organic solvents and water using the method of solution mediated phase transformation. The 3 : 2 hydrate, form V, undergoes dehydration to anhydrous form I in methanol, ethanol and N,N-dimethylformamide. Form I converts to anhydrous form II in dry methanol and N,N-dimethylformamide, while increased water content in the solvent prevents the transformation of form I to form II. Both forms I and V yield a gel-like material in dimethyl sulfoxide, composed of highly crystalline form II and reported here for the first time. Furthermore, significant differences in the thermal dehydration process of forms V and VI were observed using VT FTIR, including the first time report on a novel metastable ACV form VII formed upon dehydration of ACV dihydrate (form VI). High resolution solid-state NMR spectra of two anhydrous polymorphs (forms I and II) and two hydrates (forms V and VI) supported by DFT calculations using the CASTEP code are also presented

Mechanically robust gels formed from hydrophobized cellulose nanocrystals

Cellulose nanocrystals (CNCs) that bind to each other through associative hydrophobic interactions have been synthesized by modifying sulfated CNCs (sCNCs) with hydrophobic moieties. These octyl-CNCs form gels at significantly lower concentrations than parent sCNCs, producing extremely strong hydrogels. Unlike sCNCs, these octyl-CNCs do not form ordered liquid crystalline phases indicating a random association into a robust network driven by hydrophobic interactions. Furthermore, involvement of the octyl-CNCs into multicomponent supramolecular assembly was demonstrated in combination with starch. AFM studies confirm favorable interactions between starch and octyl-CNCs, which is thought to be the source of the dramatic increase in gel strength

Unravelling cationic cellulose nanofibril hydrogel structure: NMR spectroscopy and small angle neutron scattering analyses

Stiff, elastic, viscous shear thinning aqueous gels are formed upon dispersion of low weight percent concentrations of cationically modified cellulose nanofibrils (CCNF) in water. CCNF hydrogels produced from cellulose modified with glycidyltrimethylammonium chloride, with degree of substitution (DS) in the range 10.6(3)–23.0(9)%, were characterised using NMR spectroscopy, rheology and small angle neutron scattering (SANS) to probe the fundamental form and dimensions of the CCNF and to reveal interfibrillar interactions leading to gelation. As DS increased CCNF became more rigid as evidenced by longer Kuhn lengths, 18–30 nm, derived from fitting of SANS data to an elliptical cross-section, cylinder model. Furthermore, apparent changes in CCNF cross-section dimensions suggested an “unravelling” of initially twisted fibrils into more flattened ribbon-like forms. Increases in elastic modulus (7.9–62.5 Pa) were detected with increased DS and 1H solution-state NMR T1 relaxation times of the introduced surface –N+(CH3)3 groups were found to be longer in hydrogels with lower DS, reflecting the greater flexibility of the low DS CCNF. This is the first time that such correlation between DS and fibrillar form and stiffness has been reported for these potentially useful rheology modifiers derived from renewable cellulose

Thermosensitive supramolecular and colloidal hydrogels via self-assembly modulated by hydrophobized cellulose nanocrystals

Utilization of reversible non-covalent interactions is a versatile design strategy for the development of stimuli responsive soft materials. In this study, hydrophobic interactions were harnessed to assemble water-soluble macromolecules and nanoparticles into a transient hybrid network forming thermosensitive hydrogels with tunable rheological properties. Hybrid hydrogels were built of biopolymer derived components: cellulose nanocrystals (CNCs), nanoparticles of high aspect ratio, and hydroxypropyl methylcellulose (HPMC). To enable polymer/CNC assembly via hydrophobic interactions, the surface of highly hydrophilic CNCs was modified by binding octyl moieties (octyl-CNCs). The amphiphilicity of octyl-CNCs was confirmed by surface tension measurements. The molecular and particulate amphiphiles assemble into hybrid networks, which result in stiffer and stronger hydrogels compared to HPMC hydrogels and hydrogels reinforced with hydrophilic CNCs. Hybrid hydrogels retain the ability of HPMC hydrogels to flow under applied shear stress. However, significantly higher viscosity was achieved for HPMC/octyl-CNCs compared with HPMC/CNCs hydrogels. The inherent thermal response of rheological properties of HPMC hydrogels was further amplified in combination with octyl-CNCs due to temperature-induced polymer/nanoparticle association via hydrophobic interactions. Saturation transfer difference NMR spectroscopy demonstrated the growth of network-bound water with an increase in temperature, which correlates with the increase of stiffness and viscosity of hydrogels upon heating. Rheological properties of these hybrid hydrogels are defined by the content of the soluble polymer and the CNCs, and it is shown that they can be finely adjusted for a required application

Starch hydrogels as targeted colonic drug delivery vehicles

Targeted colonic drug delivery systems are needed for the treatment of endemic colorectal pathologies, such as Crohn's disease, ulcerative colitis, and colorectal cancer. These drug delivery vehicles are difficult to formulate, as they need to remain structurally intact whilst navigating a wide range of physiological conditions across the upper gastrointestinal tract. In this work we show how starch hydrogel bulk structural and molecular level parameters influence their properties as drug delivery platforms. The in vitro protocols mimic in vivo conditions, accounting for physiological concentrations of gastrointestinal hydrolytic enzymes and salts. The structural changes starch gels undergo along the entire length of the human gastrointestinal tract have been quantified, and related to the materials' drug release kinetics for three different drug molecules, and interactions with the large intestinal microbiota. It has been demonstrated how one can modify their choice of starch in order to fine tune its corresponding hydrogel's pharmacokinetic profile

Rapid determination of the acidity, alkalinity and carboxyl content of aqueous samples by 1H NMR with minimal sample quantity

The titratable acidity, alkalinity, and carboxylate content are fundamental properties required for the understanding of aqueous chemical systems. Here, we present a set of new methods that allow these properties to be determined directly by 1H NMR without the labor, cost, and sample quantity associated with running separate potentiometric or conductometric titrations. Our methods require only the measurement of the pH-sensitive 1H chemical shifts of indicator molecules and do not require the tedious titration of reagents into a sample. To determine the titratable acidity, an excess of 2-methylimidazole (2MI) is added to a sample and the quantity of protons absorbed by 2MI is determined from its 1H chemical shifts. The titratable alkalinity of a sample can be similarly determined using acetic acid. To determine the concentration of deprotonated carboxylates, a sample is acidified with HCl, and the quantity of H+ absorbed is determined from the 1H chemical shift of methylphosphonic acid. We validate our methods by demonstrating the measurement of the acidity of fruit-flavored drinks, the alkalinity of tap water, and the carboxylate content of nanocellulose dispersions

Structure and Mobility of Lactose in Lactose/Sodium Montmorillonite Nanocomposites

This study aims at investigating the molecular level organization and molecular mobility in montmorillonite nanocomposites with the uncharged organic low-molecular-weight compound lactose commonly used in pharmaceutical drug delivery, food technology, and flavoring. Nanocomposites were prepared under slow and fast drying conditions, attained by drying at ambient conditions and by spray-drying, respectively. A detailed structural investigation was performed with modulated differential scanning calorimetry, powder X-ray diffraction, solid-state nuclear magnetic resonance, scanning electron microscopy, microcalorimetry, and molecular dynamic simulations. The lactose was intercalated in the sodium montmorillonite interlayer space regardless of the clay content, drying rate, or humidity exposure. Although, the spray-drying resulted in higher proportion of intercalated lactose compared with the drying under ambient conditions, non-intercalated lactose was present at 20 wt% lactose content. This indicates limitations in maximum load capacity of nonionic organic substances into the montmorillonite interlayer space. Furthermore, a fraction of the intercalated lactose in the co-spray-dried nanocomposites diffused out from the clay interlayer space upon humidity exposure. Also, the lactose in the nanocomposites demonstrated higher molecular mobility than that of neat amorphous lactose. This study provides a foundation for understanding functional properties of nanocomposites, such as loading capacity and physical stability

Luminescent SiO2 nanoparticles for cell labeling: combined water dispersion polymerization and 3D condensation controlled by oligoperoxide surfactant-initiator

Hybrid polymer coated silica nanoparticles (NPs) were synthesized using low temperature graft (co)polymerization of trimethoxysilane propyl methacrylate (MPTS) initiated by surface-active oligoperoxide metal complex (OMC) in aqueous media. These NPs were characterized by means of kinetic, solid-state NMR, TEM and FTIR techniques. Two processes, namely the radical graft-copolymerization due to presence of double bonds and 3D polycondensation provided by the intra- or/and intermolecular interaction of organosilicic fragments, occurred simultaneously. The relative contribution of the reactions depending on initiator concentration and pH value leading to the formation of low cured polydisperse microparticles or OMC coated SiO2 NPs of controlled curing degree was studied. The availability of free-radical forming peroxide fragments on the surface of SiO2 NPs provides an opportunity for seeded polymerization leading to the formation of the functional polymer coated NPs with controlled particle structure, size, and functionality. Encapsulation of the luminescent dye (Rhodamine 6G) in SiO2 core of functionalized NPs provided a noticeable increase in their resistance to photo-bleaching and improved biocompatibility. These luminescent NPs were not only attached to murine leukemia L1210 cells but also tolerated by the mammalian cells. Their potential use for labeling of the mammalian cells is considered

Understanding heat driven gelation of anionic cellulose nanofibrils: Combining Saturation Transfer Difference (STD) NMR, Small Angle X-ray Scattering (SAXS) and rheology

A novel mechanism of heat-triggered gelation for oxidised cellulose nanofibrils (OCNF) is reported. We demonstrate that a synergistic approach combining rheology, small-angle X-ray scattering (SAXS) and saturation transfer difference NMR (STD NMR) experiments enables a detailed characterisation of gelation at different length scales. OCNF dispersions experience an increase in solid-like behaviour upon heating as evidenced by rheological studies, associated with enhanced interfibrillar interactions measured using SAXS. Interactions result in an increased fibrillar overlap and increased population of confined water molecules monitored by STD NMR. In comparison, cationic cellulose nanofibrils (produced by reaction of cellulose with trimethylglycidylammonium chloride) were found to be heat-unresponsive

Supramolecular Amino Acid Based Hydrogels: Probing the Contribution of Additive Molecules using NMR Spectroscopy

Supramolecular hydrogels are composed of self-assembled solid networks that restrict the flow of water. l-Phenylalanine is the smallest molecule reported to date to form gel networks in water, and it is of particular interest due to its crystalline gel state. Single and multi-component hydrogels of l-phenylalanine are used herein as model materials to develop an NMR-based analytical approach to gain insight into the mechanisms of supramolecular gelation. Structure and composition of the gel fibres were probed using PXRD, solid-state NMR experiments and microscopic techniques. Solution-state NMR studies probed the properties of free gelator molecules in an equilibrium with bound molecules. The dynamics of exchange at the gel/solution interfaces was investigated further using high-resolution magic angle spinning (HR-MAS) and saturation transfer difference (STD) NMR experiments. This approach allowed the identification of which additive molecules contributed in modifying the material properties