Maleic Acid Salt Research Articles

Green Technology for Salt Formation: Slurry Reactive Crystallization Studies for Papaverine HCl and 1:1 Haloperidol–Maleic Acid Salt

Papaverine HCl was successfully suspended by slurry reactive crystallization with the use of isopropyl alcohol (IPA) at 25 °C, a solid-to-liquid ratio of 0.19 g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 200–400 μm, and the value for enthalpy of fusion of 154.5 J/g. The poor solubility of papaverine in IPA and better solubility of papaverine HCl in water-containing IPA had made the homogeneous nucleation of papaverine HCl dominate. Crystal size and crystallinity of papaverine HCl were time and temperature dependent. However, the 1:1 haloperidol–maleic acid salt was also successfully suspended and generated by slurry reactive crystallization with the use of water at 25 °C, a solid-to-liquid ratio of 0.18 g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 500–1000 μm, and the value for enthalpy of fusion of 84.9 J/g. The poor solubility of haloperidol and 1:1 haloperidol–maleic acid salt in water had made the heterogeneous nucleation of 1:1 haloperidol–maleic acid sal...

Salt formation improved the properties of a candidate drug during early formulation development

The purpose of this study was to investigate if AZD5329, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development as an oral immediate release (IR) solid dosage form as a final product. The neutral form of AZD5329 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Crystalline material of a maleic acid salt and a fumaric acid salt of AZD5329 were obtained. X-ray powder diffractiometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the two salts. The fumarate salt of AZD5329 is anhydrous, the crystallization is reproducible and the hygroscopicity is acceptable. Early polymorphism assessment work using slurry technique did not reveal any better crystal modification or crystallinity for the fumarate salt. For the maleate salt, the form isolated originally was found to be a solvate, but an anhydrous form was found in later experiments; by suspension in water or acetone, by drying of the solvate to 100–120 °C or by subjecting the solvate form to conditions of 40 °C/75%RH for 3 months. The dissolution behavior and the chemical stability (in aqueous solutions, formulations and solid-state) of both salts were also studied and found to be satisfactory. The compound displays sensitivity to low pH, and the salt of the maleic acid, which is the stronger acid, shows more degradation during stability studies, in line with this observation. The presented data indicate that the substance fulfils basic requirements for further development of an IR dosage form, based on the characterization on crystalline salts of AZD5329.

Development of a Practical Synthesis of a Peripherally Selective Noradrenaline Reuptake Inhibitor Possessing a Chiral 6,7-trans-Disubstituted-1,4-oxazepane as a Scaffold

A practical synthesis of a peripherally selective noradrenaline reuptake inhibitor that has a chiral 6,7-trans-disubstituted-1,4-oxazepane as a new class of scaffold is described. The amino alcohol possessing the desired stereochemistry was obtained with excellent dr and ee, starting from a commercially available aldehyde via a Morita–Baylis–Hillman reaction, Michael addition, isolation as maleic acid salt, reduction, and diastereomeric salt formation with (+)-10-camphorsulfonic acid. The desired single stereoisomer obtained at an early stage of the synthesis was used for seven-membered ring formation in fully telescoped processes, providing the chiral 6,7-trans-disubstituted-1,4-oxazepane efficiently. In addition to controls of dr and ee of the chiral 1,4-oxazepane, and control of N,O-selectivity in SN2 reaction of the intermediate mesylate with a pyridone derivative, finding appropriate intermediates that were amenable to isolation and upgrade of purity enabled a practical chiral HPLC separation-free, c...

Emulsion polymerization of styrene with amphiphilic random copolymer as surfactant: Predominant droplet nucleation

AbstractAmphiphilic random copolymer consisting of monomeric units of poly (butyl acrylate) and poly (maleic acid salt) was synthesized and characterized. The emulsion polymerization kinetics of styrene stabilized by this copolymer was investigated. The influencing factors, including polymeric surfactant concentration, initiator concentration and polymerization temperature, were systematically studied. The kinetic data show that the polymerization rate (RP) increased with the increase of the polymeric surfactant concentration ([S]) and polymerization temperature (T). At the higher [S], droplets nucleation and micelle nucleation coexisted in the polymerization system; at the lower [S], only the droplets nucleation process existed. The polymerization did not follow Smith‐Ewart Case II kinetics. Dynamic light scatter and transmission electron microscope were utilized to measure the sizes and shapes of the particles, respectively. It would be speculated that a kind of large heterogeneous particles with multiple‐active‐sites was formed in the polymerization system. The increasing of RP with increasing initiator concentration ([KPS]) was rapid at a medium [KPS], but the slowly increasing was observed at a lower or higher [KPS]. It was attributed to the barrier effect of the polymeric surfactant around the monomer droplets. The polymerization activation energy was 60.29 kJ/mol. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009

Synthesis and characterization of polyaniline–maleic acid salt

Polyaniline–maleic acid (PANI–MAc) salts have been prepared at various maleic acid concentrations. The salts are characterized by using infrared (IR), UV/VIS Spectroscopy, thermogravimetric analysis and conductivity measurements. Blends of PANI–MAc were made with styrene–butyl acrylate (ST–BuA) copolymer and percolation threshold determined.

Nephrotoxicity of Pravadoline Maleate (WIN 48098-6) in Dogs: Evidence of Maleic Acid-Induced Acute Tubular Necrosis

Nephrotoxicity of Pravadoline Maleate (WIN 48098-6) in Dogs: Evidence of Maleic Acid-Induced Acute Tubular Necrosis. Everett, R. M., Descotes, G., Rollin, M., Greener, Y., Bradford, J. C., Benziger, D. P., and Ward, S. J. (1993). Fundam. Appl. Toxicol. 21, 59-65.Single oral administration of pravadoline maleate (WIN 48098-6), the maleic acid salt of WIN 48098, induced acute tubular necrosis (ATN) in male and female beagle dogs at dosages ⩾40 mg/kg (WIN 48098 base (31 mg/kg) and maleic acid (9 mg/kg)). Subsequent oral studies were conducted with equimolar dosages of maleic acid and WIN 48098-7, the ethanesulfonate salt of WIN 48098, to determine the nephrotoxic moiety of WIN 48098-6. ATN was observed for dogs given only maleic acid at single oral dosages ⩾9 mg/kg. This result provided evidence that maleic acid was responsible for the nephrotoxicity observed in dogs given single oral dosages of WIN 48098-6. The induction of maleic acid-related nephrotoxicity in dogs may confound the interpretation of toxicologic studies of maleic acid salts of basic pharmaceutics, if the dosage of test article results in the delivery of dosages of maleic acid ⩾9 mg/kg. Furthermore, the results of these studies underscore the importance of establishing maximum no-observed-effect dosages and target organ toxicity profiles for acids and bases that are commonly used in the development of salts of pharmaceutics.

Chemotaxis of Bracken Spermatozoids

ABSTRACT Fern spermatozoids respond chemotactically to concentration gradients of malic or maleic acid salts (Pfeffer, 1884). They respond weakly to salts of a few other dicarboxylic acids, but do not respond to succinate or fumarate (Shibata, 1911; Rothschild, 1956). Previous workers concluded, without adequate justification, that the malate ion, and not the undissociated malic acid molecule, is chemotactically active; but no consideration has been given to the possibility that the bimalate ion may be the active species.