Solution Stability Studies Research Articles

Solubility and solution stability studies of different amino acid prodrugs of bromhexine

Objective: The aim of the present study was to prepare the amino acid prodrugs of bromhexine hydrochloride to improve its solubility.Methods: All the prodrugs were synthesized by first reacting bromhexine with tert-butoxycarbonyl (Boc) protected amino acid and then deprotection was carried out by using trifluoroacetic acid. These prodrugs were characterized by their melting points, NMR, mass and FTIR spectroscopy. Solubility and partition coefficient of bromhexine and various prodrugs were determined. The solution stability of various prodrugs was also determined in various buffers of pH ranging from 2 to 10. Degradation rate constants and half-life were also determined at various pH.Results and discussion: The structures of all the synthesized prodrugs were confirmed by NMR, mass and FTIR spectra. The prodrug 2-N-l-alanyl-bromhexine hydrochloride showed maximum solubility and minimum partition coefficient value. These prodrugs may hydrolyze by one or more mechanisms. The order of decreasing rates of hydrolysis was 2-N-l-prolyl-bromhexine hydrochloride > 2-N-glycyl-bromhexine hydrochloride > 2-N-l-alanyl-bromhexine hydrochloride. All the prodrugs exhibited maximum stability in the acidic pH range and undergo base catalyzed hydrolysis.Conclusion: Solubility studies and partition coefficient values indicated that the synthesized prodrug, 2-N-l-alanyl-bromhexine hydrochloride, was least lipophilic as compared to other synthesized prodrugs. Solution stability studies showed that this prodrug undergo minimum hydrolysis at 37°C. So, it is concluded that 2-N-l-alanyl-bromhexine hydrochloride exhibits better solubility and stability as compared to other synthesized prodrugs.

Validation of a dissolution method with RP-HPLC analysis for Perindopril erbumine and Indapamide combination tablet

A Dissolution method with high performance liquid chromatography (HPLC) analysis was validated for perindopril erbumine and indapamide in combination tablet formulation. The method was validated to meet requirements for a global regulatory filing and this validation included specificity, linearity, accuracy, precision, range, robustness and solution stability studies. The dissolution method, which uses USP apparatus 1 with basket rotating at 100 rpm, 1000 ml of phosphate buffer pH 6.8 as the dissolution medium, and reversed-phased HPLC was carried out at 50?C on a 4.6mm?250mm 5?m cyano column that contained USP packing L1 with acetonitrile: buffer pH 2.8::40:60 (v/v), as mobile phase. UV detector was set at 225 nm. A method was found to be selective, linear, accurate and precise in the specified ranges. Intra-day and inter-day variability for method was <2% RSD. This method was successfully used for quantification of perindopril erbumine and indapamide combination tablet formulations.

Investigation into omacetaxine solution stability for in vitro study

Omacetaxine is a natural product extract originating from Chinese medicine and finding therapeutic use as a potent myelosuppressive agent in leukemia. When planning in vitro cell biology experiments to assess omacetaxine activity against primary leukemic stem cells, it became apparent that the literature rarely describes the in vitro stability of the molecule, although accessible chromatographic methods have been published. Clearly whole organisms vs their component cells will differ in the way in which they handle xenobiotics, with the latter more dependent on physiochemical parameters such as pH and temperature in the absence of active metabolism or excretion. This could impact on the cells' experience of drug in culture. We therefore report here on examination of a modified, high-performance liquid chromatography (HPLC) method with assessment of degradant production from a 72 h solution stability study, clearly demonstrating that omacetaxine is highly stable in representative cell culture conditions (37 °C, neutral pH) and persists for many days in marked contrast to its short-half life in vivo.

Crystal Structure and Physicochemical Properties of Crystalline Form of 2′-O-{3-[(7-chloro-4-quinolinyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A

The intent of the study was to prepare and characterize crystalline form of 2'-O-{3-[(7-chloro-4-quinolinyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (1), a novel 15-membered azalide derivative with antimalarial activity. The crystalline material was prepared by crystallization from acetonitrile reproducible in high yield and purity. Single crystal X-ray studies, X-ray powder diffractometry, differential scanning calorimetry, thermogravimetric analysis, moisture adsorption, Karl Fischer titration, gas chromatography, scanning electron microscopy, optical microscopy, solubility, and solid-state and solution stability were conducted to investigate physicochemical properties of the existing crystalline form. Crystalline 1 is not hygroscopic, does not contain solvents, is physicochemically stable in solid state for up to 4 weeks, and is highly soluble at pH values below 6 and in biorelevant media (simulated gastric fluid, fed simulated intestinal fluid, and fasted simulated intestinal fluid). Solution stability studies (buffers and biorelevant media) indicated that this compound is stable in solutions at pH values 5-6, and that stability is influenced by pH and temperature.

Electrochemically activated water as an alternative to chlorine for decentralized disinfection

Research Article| June 01 2011 Electrochemically activated water as an alternative to chlorine for decentralized disinfection K. Ghebremichael; K. Ghebremichael 1Department of Urban Water and Sanitation, UNESCO-IHE, Westvest 7, PO Box 3015, 2601 DA Delft, The Netherlands E-mail: k.ghebremichael@unesco-ihe.org Search for other works by this author on: This Site PubMed Google Scholar E. Muchelemba; E. Muchelemba 1Department of Urban Water and Sanitation, UNESCO-IHE, Westvest 7, PO Box 3015, 2601 DA Delft, The Netherlands Search for other works by this author on: This Site PubMed Google Scholar B. Petrusevski; B. Petrusevski 1Department of Urban Water and Sanitation, UNESCO-IHE, Westvest 7, PO Box 3015, 2601 DA Delft, The Netherlands Search for other works by this author on: This Site PubMed Google Scholar G. Amy G. Amy 2Water Desalination and Reuse Center, Kaust, Saudi Arabia Search for other works by this author on: This Site PubMed Google Scholar Journal of Water Supply: Research and Technology-Aqua (2011) 60 (4): 210–218. https://doi.org/10.2166/aqua.2011.034 Article history Received: June 28 2010 Accepted: January 24 2011 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Cite Icon Cite Permissions Search Site Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsThis Journal Search Advanced Search Citation K. Ghebremichael, E. Muchelemba, B. Petrusevski, G. Amy; Electrochemically activated water as an alternative to chlorine for decentralized disinfection. Journal of Water Supply: Research and Technology-Aqua 1 June 2011; 60 (4): 210–218. doi: https://doi.org/10.2166/aqua.2011.034 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex Electrochemically activated (ECA) water is being extensively studied and considered as an alternative to chlorine for disinfection. Some researchers claim that ECA is by and large a chlorine solution, while others claim the presence of reactive oxygen species such as ozone and hydroxyl radicals in addition to chlorine. This study compares sodium hypochlorite (NaOCl) and ECA in terms of disinfection efficacy, trihalomethanes (THMs) formation, stability and composition. The studies were carried out under different process conditions (pH 5, 7 and 9, disinfectant concentrations of 2–5 mg/L and dissolved organic carbon (DOC) concentration of 2–4 mg/L). The results indicated that in the presence of low DOC (<2 mg/L) ECA showed better disinfection efficacy for Escherichia coli inactivation, formed lower THM and had better stability compared with NaOCl at both pH 5 and 7. Stability studies of stock solutions showed that over a period of 30 days, ECA decayed by only 5% while NaOCl decayed by 37.5% at temperatures of 4 °C. In a fresh ECA of 200 mg/L chlorine, about 5.3 mg/L ozone and 36.9 mg/L ClO2 were detected. The study demonstrates that ECA could be a suitable alternative to NaOCl where decentralized production and use are required. anolyte, disinfection, ECA, E. coli, sodium hypochlorite, THM This content is only available as a PDF. © IWA Publishing 2011 You do not currently have access to this content.

Approaches to improve the stability of the antiviral agent UC781 in aqueous solutions

In this work, we evaluated the chemical stability profiles of UC781 based solutions to identify excipients that stabilize the microbicidal agent UC781. When different antioxidants were added to UC781 in sulfobutylether-β-cyclodextrin (SBE-β-CD) solutions and subjected to a 50 °C stability study, it was observed that EDTA was a better stabilizing agent than sodium metabisulfite, glutathione or ascorbic acid. Some antioxidants accelerated the degradation of UC781, suggesting metal-catalyzed degradation of UC781. Furthermore, we observed substantial degradation of UC781 when stored in 1% Tween 80 and 1% DMSO solutions alone or in those with 10 mM EDTA. On the other hand, improved stability of UC781 in the presence of 100 and 200 mM of EDTA was observed in these solutions. The addition of both EDTA and citric acid in the stock solutions resulted in recovery of more than 60% of UC781 after 12 weeks. Generally, 10% SBE-β-CD in the presence of EDTA and citric acid stabilized UC781 solutions: the amount of UC781 recovered approaching 95% after 12 weeks of storage at 40 °C. We also showed that the desulfuration reaction of the UC781 thioamide involves oxygen by running solution stability studies in deoxygenated media. Improved stability of UC781 in the present study indicates that the incorporation of EDTA, citric acid and SBE-β-CD and the removal of oxygen in formulations of this drug will aid in increasing the stability of UC781 where solutions of the drug are required.

Solution stability and thermal degradation of some cyclic dithiocarbamates

Although cyclic dithiocarbamates (DTC) present better solution and solid state stability when compared to aliphatic analogues, relatively few thermo-analytical and solution stability studies have so far been reported which concern these important substances. In solution, the degradation of dithiocarbamates undergoes via a protonated intermediate and is very fast in acidic media. A spectrophotometric method based on diode array detection has been proposed for a fast and accurate determination of pK a and degradation kinetic constants of these cyclic DTC's and is discussed here. Thermal analytical data were also collected regarding ammonium, sodium, potassium salts as well as for zinc, cadmium, lead, cobalt, nickel, copper, mercury, silver, iron and manganese complexes of pyrrolidinedithiocarbamate (pyr), piperidinedithiocarbamate (pip), morpholinedithiocarbamate (mor) and hexamethyleneiminedithiocarbamate (hex) and are summarized in this article. Differences in the decomposition intermediates permitted to conclude that structural differences make the decomposition to occur by specific pathways, depending on the number and nature of members of the aminic ring.

Lower semicontinuity of the solution map to a parametric vector variational inequality

This paper is concerned with the study of solution stability of a parametric vector variational inequality, where mappings may not be strongly monotone. Under some requirements that the operator of a unperturbed problem is monotone or it satisfies degree conditions then we show that the solution map of a parametric vector variational inequality is lower semicontinuous.

Rapid structure elucidation of drug degradation products using mechanism-based stress studies in conjunction with LC–MS n and NMR spectroscopy: identification of a photodegradation product of betamethasone dipropionate

Betamethasone dipropionate is an active pharmaceutical ingredient (API) that is used in various dosage forms of finished products for the treatment of inflammatory disorders. An unknown degradant was observed during a solution stability study of betamethasone dipropionate. An approach that combines LC–MS n , mechanism-based stress studies, semi-preparative HPLC purification and structure elucidation by NMR spectroscopy was used to identify the unknown species. The key step of this approach is the design of relevant stress studies based on the plausible degradation mechanism that is revealed by the informative LC–MS n analysis. The appropriately designed mechanism-based stress studies not only verify the degradation mechanism but also produce enough quantities of the unknown species for further structure elucidation/confirmation by NMR spectroscopy. With this strategy, the unknown degradant was rapidly identified as lumibetametasone dipropionate, a photodegradation product of betamethasone dipropionate.

Optimization of a series of 4,6-bis-anilino-1 H-pyrrolo[2,3- d]pyrimidine inhibitors of IGF-1R: Elimination of an acid-mediated decomposition pathway

Initial evaluation of a series 4,6-bis-anilino-1 H-pyrrolo[2,3- d]pyrimidines revealed a C(1′) carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1′) carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1 H-pyrrolo[2,3- d]pyrimidine template.

Comparison of the Crystal Chemistry, the Process Conditions for Crystallization and the Relative Structural Stability of Two Polymorphic Forms of NG-monomethyl-l-arginine Hydrochloride

Crystal structures of two conformational polymorphs (Form A and Form D) of NG-monomethyl-l-arginine hydrochloride, a drug developed to treat septic shock, are presented. Form A is orthorhombic in a tetra-molecular unit cell and Form D is monoclinic in a bimolecular unit cell (space groups P212121 and P21, respectively). The two forms display differences in the conformation of the terminal N-methyl group, which is cis in Form D and trans in Form A. Structural energy calculations demonstrate that Form D has a lower lattice energy compared to Form A (−134.7 and −128.8 kcal/mol, respectively). This is supported by solution stability studies where the potential for solution-mediated phase transformation was investigated and Form D is found to be the more stable polymorphic structure at room temperature. The melting behavior of forms A and D indicates a monotropic phase transformation relationship between the two polymorphic forms albeit their melting points (215.7 and 203.7 °C for forms A and D, respectively) ...

Lower Semicontinuity of the Solution Map to a Parametric Generalized Variational Inequality in Reflexive Banach Spaces

This paper is concerned with the study of solution stability of a parametric generalized variational inequality in reflexive Banach spaces. Under the requirements that the operator of a unperturbed problem is of class (S) + and operators under consideration are pseudo-monotone and demicontinuous, we show that the solution map of a parametric generalized variational inequality is lower semicontinuous. The obtained results are proved without conditions related to the degree theory and the metric projection.

Effects of solution conditions and surface chemistry on the adsorption of three recombinant botulinum neurotoxin antigens to aluminum salt adjuvants

Botulinum neurotoxin (BoNT) is a biological warfare threat. Protein antigens have been developed against the seven major BoNT serotypes for the development of a recombinant protein vaccine. This study is an evaluation of adsorption profiles for three of the recombinant protein antigens to aluminum salt adjuvants in the development of a trivalent vaccine against BoNT. Adsorption profiles were obtained over a range of protein concentrations. The results document that charge-charge interactions dominate the adsorption of antigen to adjuvant. Optimal conditions for adsorption were determined. However, potency studies and solution stability studies indicated the necessity of using aluminum hydroxide adjuvant at low pH. To improve the adsorption profiles to AlOH adjuvant, phosphate ions were introduced into the adsorption buffers. The resulting change in the adjuvant chemistry led to an improvement of adsorption of the BoNT antigens to aluminum hydroxide adjuvant while maintaining potency. Competitive adsorption profiles were also determined, and showed changes in maximum adsorption from mixed solutions compared to adsorption from individual protein solutions. The adsorption profiles for each protein varied due to differences in adsorption mechanism and affinity for the adjuvant surface. These results emphasize the importance of evaluating competitive adsorption in the development of multivalent vaccine products.

Validation of the LC-MS/MS method for the quantification of mevalonic acid in human plasma and determination of the matrix effect

A simple, specific, and sufficiently sensitive liquid chromatography-tandem mass spectrometry (negative-ion electrospray ionization) methodology to determine mevalonic acid (MVA) in human plasma is described, and its application to the analysis of rat plasma MVA levels after rosuvastatin administration is demonstrated. The method was validated over the linearity range of 0.5-50.0 ng/ml (r(2) > 0.99) using deuterated MVA as an internal standard. The lower limit of quantification was 0.5 ng/ml. The assay procedure involved the isolation of MVA from plasma samples using solid-phase extraction. Chromatographic separation was achieved on a HyPurity Advance column with a mobile phase consisting of ammonium formate buffer (10 mM, pH 8.0) and acetonitrile (70:30, v/v). Excellent precision and accuracy were observed. MVA and deuterated mevalonolactone were stable in water and plasma under different storage and processing conditions. The recovery observed was low, which was attributable to a significant matrix effect. A significant decrease (30-40%; P < 0.05) was observed in rat plasma MVA levels after rosuvastatin administration.

Synthesis, Characterization, Solution Stability Studies, Electrochemistry, and DNA‐Binding Behavior of Cu(II) Complexes of D‐Gluconic Acid

The chemistry of saccharides has emerged as a new subarea of pharmaceuticals. Condensation reactions of D‐gluconic acid with [M(en)2]Cl2/[M(ea)2]Cl2 where M=Cu, Ni, en=ethylenediamine, and ea=ethanolamine were carried out and a new series of chiral complexes have been isolated and characterized. Molar conductance measurements show that the complexes are ionic, and the spectral data are indicative of octahedral geometry of the complexes [Cu(D‐GlcCO2H en*)2 (H2O)2] · Cl2 (1b), [Cu(D‐GlcCO2H ea*) (H2O)2] · Cl2 (3b) and [Ni(D‐GlcCO2H ea*) (H2O)2] · Cl2 (4), and the square planar geometry of complex [Ni(D‐GlcCO2H en*)2] · Cl2 (2b). Polarimetric data along with CD spectra establish the chiral nature of complexes. Solution stabilities of these complexes were evaluated by cyclic voltammetric techniques as a function of pH. Electrochemical behavior of the complexes was studied in aqueous solution and showed an irreversible CuII/CuI couple. Kinetic studies of complex 1b and 3b with calf thymus DNA have been investigated spectrophotometrically under pseudo‐first order conditions, and k obs values have been evaluated. Circular dichroism, cyclic voltammetry determinations, and viscosity measurements have also been carried out to authenticate the binding of DNA with metal complexes. Complexes 1b and 3b bind to DNA by covalent bond formation.

A Comparison of Trehalose Dihydrate and Mannitol as Stabilizing Agents for Dicalcium Phosphate Dihydrate Based Tablets

This study investigated the possible utility of trehalose dihydrate (TD) as a tablet stabilizing agent. Acetylsalicylic acid was used as the model hydrolyzable drug and dicalcium phosphate dihydrate (DCPD) as the base excipient, because it is well documented that ASA/DCPD tablets are unstable during storage at low temperature and high relative humidity; DCPD is usually combined with mannitol in order to improve tablet stability.Tablets comprising DCPD, 10% ASA, and 0%, 10%, or 20% w/w of TD were prepared by direct compression and stored at 35°C and 82.9% relative humidity for 6 months. Additionally, control tablets with DCPD and ASA, only, or with DCPD, ASA and 20% mannitol, were also evaluated. At predetermined time intervals, formulations were tested for drug content, mechanical, microstructural, and drug dissolution properties. Additionally, thermal analyses and ASA solution stability studies were carried out. Results reveal that both TD and mannitol significantly reduce degradation of ASA included in DCPD-based tablets, but neither effectively protects against the marked decline in tablet mechanical properties on aging. The ASA stabilization effects of TD and mannitol were also observed in solution, indicating an interaction between these sugars and ASA.

In vitro and in vivo evaluation of a sulfobutyl ether β‐cyclodextrin enabled etomidate formulation

In this study, we report the formulation and in vivo evaluation of etomidate in an aqueous solution using sulfobutyl ether‐7 β‐cyclodextrin (SBE‐CD, Captisol®) as a solubilizing agent. The phase‐solubility behavior of etomidate as a function of SBE‐CD concentration was evaluated, and accelerated solution stability studies of 2mg/mL etomidate in a 5% w/v SBE‐CD solution were conducted. The intravenous administration of the SBE‐CD etomidate formulation in dogs was compared with Amidate®, the commercial etomidate drug product formulated with propylene glycol as a cosolvent. The etomidate plasma concentration‐time data were fit to a three‐compartment mamillary model and the derived standard pharmacokinetic parameters were not statistically different between the two formulations (n = 4, p > 0.050). Concurrent pharmacodynamic analysis provided statistically equivalent maximum effects and median inhibitory concentrations for the two formulations. In vivo hemolysis after intravenous administration of Amidate® was 10‐fold higher than the SBE‐CD formulation. Whereas Amidate® cannot be given subcutaneously because of the cosolvent in the formulation, a 12mg/mL aqueous solution of etomidate in 20% (w/v) SBE‐CD was well tolerated by this route. The results suggest that the SBE‐CD formulation is a viable clinical drug product with a reduced side‐effect profile.

Aggregation of Lignin Derivatives under Alkaline Conditions. Kinetics and Aggregate Structure

The kinetics of kraft lignin (KL) aggregation at alkaline conditions was studied by quasi-elastic light scattering (QELS) and turbidity measurements. Stability ratios (W) for KL were obtained at 70 °C and various concentrations of sodium chloride. By analyzing the early-time evolution data of aggregate growth obtained from QELS, fractal dimensions of flocs formed in both reaction-limited cluster−cluster aggregation regimes and diffusion-limited cluster−cluster aggregation regimes were determined. Correlations between the fractal dimension and the W-ratio were found in accordance to recent studies of a system containing monodisperse polystyrene colloids. By cryogenic transmission electron microscopy, the fractality of KL aggregate structures in the system was also shown. It was seen from stability studies of KL solutions that the effects of specific co- and counterions follow the Hofmeister series. From the outcome of the investigation, different modes of aggregation occurring in a KL system are proposed. Starting from the macromolecular state of KL and evolving through larger aggregates, the KL clusters finally exhibit a supramolecular structure similar to what earlier has been proposed for native softwood lignin.

Inhibition of microbial growth, study of solution stability, growth and characterization of potassium fluoride mixed l-arginine phosphate single crystals

In order to alleviate the major problem of microbial growth and colouration in l-arginine phosphate (LAP), the use of potassium fluoride (KF), a new additive having higher dipole moment, has been proposed. The stabilities of the pure and KF mixed LAP solution at different temperatures have been determined. Pure and KF mixed LAP crystals were grown by the temperature lowering technique. The presence of potassium in the crystal was identified by inductively coupled plasma analysis (ICP). The lattice parameters for the grown crystals were determined from X-ray powder diffraction. The molecular vibration and thermal behaviour of KF mixed LAP were found from Fourier transform infrared (FTIR) spectroscopy and thermal analysis (DTA &TGA) respectively.

Transition metal saccharide chemistry and biology: syntheses, characterization, solution stability and putative bio-relevant studies of iron–saccharide complexes

A number of Fe(III) complexes of saccharides and their derivatives, and those of ascorbic acid were synthesized, and characterized by a variety of analytical, spectral (FT-IR, UV–Vis, EPR, Mössbauer and EXAFS), magnetic and electrochemical techniques. Results obtained from various methods have shown good correlations. Data obtained from EPR, magnetic susceptibility and EXAFS techniques could be fitted well with the mono-, di- and trinuclear nature of the complexes. The solution stability of these complexes has been established using UV–Vis absorption and cyclic voltammetric techniques as a function of pH of the solution. Mixed valent, Fe(II,III) ascorbate complexes have also been synthesized and characterized. Reductive release of Fe(II) from the complexes using sodium dithionite has been addressed. In vitro absorption of Fe(III)–glucose complex has been studied using everted sacs of rat intestines and the results have been compared with that of simple ferric chloride. Fe(III)–saccharide complexes have shown regular protein synthesis even in hemin-deficient rabbit reticulocyte lysate indicating that these complexes play a role that is equivalent to that played by hemin in order to restore the normal synthesis of protein. These complexes have exhibited enhanced DNA cleavage properties in the presence of hydrogen peroxide with pUC-18 DNA plasmid.