Methods for making prodrugs of trepreostinil and treprostinil derivatives are provided. Specifically, methods are provided herein for producing prostacyclin compounds comprising treprostinil covalently linked to a linear C.sub.5-C.sub.18 alkyl, branched C.sub.5-C.sub.18 alkyl, linear C.sub.2-C.sub.18 alkenyl, branched C.sub.3-C.sub.18 alkenyl, aryl, aryl-C.sub.1-C.sub.18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide). The linkage, in one embodiment, is via an amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. The compounds provided herein can be used to treat pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension.

Methods for making prodrugs of trepreostinil and treprostinil derivatives are provided. Specifically, methods are provided herein for producing prostacyclin compounds comprising treprostinil covalently linked to a linear C.sub.5-C.sub.18 alkyl, branched C.sub.5-C.sub.18 alkyl, linear C.sub.2-C.sub.18 alkenyl, branched C.sub.3-C.sub.18 alkenyl, aryl, aryl-C.sub.1-C.sub.18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide). The linkage, in one embodiment, is via an amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. The compounds provided herein can be used to treat pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension.

An integrated microfluidic device for carrying out a series of fluidic operations includes a housing including a plurality of n microfluidic conduits, wherein n is at least three, and a rotating valve having an internal channel with an entrance port and an exit port that are angularly separated. The rotating valve is positionable in a first position to connect two of the n fluidic conduits via the internal channel, and upon rotating the valve to a second position, two other of the n fluidic conduits are connected by the internal channel. The device further may include one or more fluidic chambers in fluid communication with respective fluidic conduits. Fluid contained in one fluidic chamber is transferrable by application of positive or negative gas pressure through associated fluidic conduits into another fluidic chamber via the internal channel. The device may be utilized to perform a variety of fluidic operations.

An integrated microfluidic device for carrying out a series of fluidic operations includes a housing including a plurality of n microfluidic conduits, wherein n is at least three, and a rotating valve having an internal channel with an entrance port and an exit port that are angularly separated. The rotating valve is positionable in a first position to connect two of the n fluidic conduits via the internal channel, and upon rotating the valve to a second position, two other of the n fluidic conduits are connected by the internal channel. The device further may include one or more fluidic chambers in fluid communication with respective fluidic conduits. Fluid contained in one fluidic chamber is transferrable by application of positive or negative gas pressure through associated fluidic conduits into another fluidic chamber via the internal channel. The device may be utilized to perform a variety of fluidic operations.

The present invention provides a method of producing an aqueous solution containing bis(N.sup.ε-lauroyl lysine)dicarboxylic acid diamide and/or a salt thereof, and having a pH of 9-11, which includes a first step of reacting N.sup.ε-lauroyl lysine and/or a salt thereof with dicarboxylic acid dichloride in a water solvent having a pH of 12-14 to form bis(N.sup.ε-lauroyl lysine)dicarboxylic acid diamide and/or a salt thereof, a second step of adjusting the aqueous solution obtained in the first step to pH 7.5-8.5, a third step of adding N.sup.ε-lauroyl lysine to the aqueous solution obtained in the second step and filtering the mixture, and a fourth step of adjusting the aqueous solution obtained in the third step to pH 9-11.

The present invention provides a method of producing an aqueous solution containing bis(N.sup.ε-lauroyl lysine)dicarboxylic acid diamide and/or a salt thereof, and having a pH of 9-11, which includes a first step of reacting N.sup.ε-lauroyl lysine and/or a salt thereof with dicarboxylic acid dichloride in a water solvent having a pH of 12-14 to form bis(N.sup.ε-lauroyl lysine)dicarboxylic acid diamide and/or a salt thereof, a second step of adjusting the aqueous solution obtained in the first step to pH 7.5-8.5, a third step of adding N.sup.ε-lauroyl lysine to the aqueous solution obtained in the second step and filtering the mixture, and a fourth step of adjusting the aqueous solution obtained in the third step to pH 9-11.

The present invention provides a method of producing an aqueous solution containing bis(N.sup.ε-lauroyl lysine)dicarboxylic acid diamide and/or a salt thereof, and having a pH of 9-11, which includes a first step of reacting N.sup.ε-lauroyl lysine and/or a salt thereof with dicarboxylic acid dichloride in a water solvent having a pH of 12-14 to form bis(N.sup.ε-lauroyl lysine)dicarboxylic acid diamide and/or a salt thereof, a second step of adjusting the aqueous solution obtained in the first step to pH 7.5-8.5, a third step of adding N.sup.ε-lauroyl lysine to the aqueous solution obtained in the second step and filtering the mixture, and a fourth step of adjusting the aqueous solution obtained in the third step to pH 9-11.

An N-acylglucamide compound of the formula (I)

##STR00001## where R.sub.2 is a linear or branched alkyl group or an aryl group; X is a moiety R.sub.1, which is a linear or branched alkyl group comprising 8 to 18, carbon atoms, which is substituted by one hydroxy group; or X is a moiety R.sub.1, which is a linear or branched, mono- or polyunsaturated alkenyl group comprising 8 to 18 carbon atoms, which is substituted by one hydroxy group, And blends and aqueous surfactant solutions comprising it.

An N-acylglucamide compound of the formula (I)

##STR00001## where R.sub.2 is a linear or branched alkyl group or an aryl group; X is a moiety R.sub.1, which is a linear or branched alkyl group comprising 8 to 18, carbon atoms, which is substituted by one hydroxy group; or X is a moiety R.sub.1, which is a linear or branched, mono- or polyunsaturated alkenyl group comprising 8 to 18 carbon atoms, which is substituted by one hydroxy group, And blends and aqueous surfactant solutions comprising it.

An N-acylglucamide compound of the formula (I)

##STR00001## where R.sub.2 is a linear or branched alkyl group or an aryl group; X is a moiety R.sub.1, which is a linear or branched alkyl group comprising 8 to 18, carbon atoms, which is substituted by one hydroxy group; or X is a moiety R.sub.1, which is a linear or branched, mono- or polyunsaturated alkenyl group comprising 8 to 18 carbon atoms, which is substituted by one hydroxy group, And blends and aqueous surfactant solutions comprising it.