Salmeterol Xinafoate Synthesis Energy

Examination 12.10.2019

Experimental details.

Salmeterol xinafoate synthesis energy

Ian R. Baxendale and, Steven V.

Peptide hormone biosynthesis ppt

DOI: Roland E. Comprehensive Survey of Combinatorial Library Synthesis: Journal of Combinatorial Chemistry5 6 Tetrahedron74 2 Glenn A. Jacobson, Morten Hostrup, Christian K. Narkowicz, David S.

Control of parameters such as size and shape in the particulate product will be dependent upon the operating conditions used when carrying out the supercritical fluid particle formation method. The apparatus described herein and its use provide the opportunity for manufacturing dry particulate products with controlled particle size, shape and morphology by offering such control over the working conditions, especially the pressure, utilising, for example, an automated back-pressure regulator such as model number produced by Jasco Inc. Such control can eliminate pressure fluctuation across the particle formation vessel and ensures a more uniform dispersion by the supercritical fluid of the vehicle containing drug substance, with narrow droplet size distribution, during the particle formation process. There is little or no chance that the dispersed droplets will reunite to form larger droplets since the dispersion occurs by the action of the supercritical fluid which also ensures thorough mixing with the vehicle and rapidly removes the vehicle from the drug substance, leading to particle formation. This ensures no contact between the formed particles and the vehicle fluid around the nozzle tip area. Such contact would reduce control of the final product size and shape. Extra control over the droplet size, in addition to that provided by nozzle design, is achieved by controlling the flow rates of the supercritical fluid and the vehicle fluid. At the same time, retaining the particles in the particles formation vessel eliminates the potential of contact with the vehicle fluid that might otherwise take place on depressurising the supercritical solution. Such contact would affect the shape and size, and potentially the yield, of the product. A further advantage of the apparatus described herein is that it can allow particle formation to occur in a completely closed environment, i. The apparatus can be sealed from the atmosphere, making it easy to maintain sterile operating conditions and also reducing the risk of environmental pollution and it can also be kept free of oxygen, moisture or other relevant contaminants. The final aerosol formulation desirably contains 0. The propellants for use in the invention may be any fluorocarbon, hydrogen- containing fluorocarbon or hydrogen-containing chlorofluorocarbon propeliant or mixtures thereof having a sufficient vapour pressure to render them effective as propellants. Preferably the propeliant will be a non-solvent for the medicament. Preferably a single fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon is employed as the propeliant. It is desirable that the formulations of the invention contain no components which may provoke the degradation of stratospheric ozone. The propeliant may additionally contain a volatile adjuvant such as a saturated hydrocarbon for example propane, n-butane, isobutane, pentane and isopentane or a dialkyl ether for example dimethyl ether. However, formulations which are substantially free of volatile adjuvants are preferred. The benefits of the present invention may be achieved without the use of any surfactant or cosolvent in the composition, or with relatively low levels of such components, and without the necessity to pre-treat the medicament prior to dispersal in the propeliant. However, it is further envisaged that certain formulations of the present invention may include liquid components of higher polarity than the propeliant employed. Polarity may be determined for example, by the method described in European Patent Application Publication No. In particular, where such components are included, alcohols such as ethanol are preferable. Particular preferred formulations may contain essentially no higher polarity liquid components, by "essentially no" is meant less than 0. Where a surfactant is employed, it is selected from those which are physiologically acceptable upon administration by inhalation such as oleic acid, sorbitan trioleate Span R 85 , sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene 20 sorbitan monooleate, natural lecithin, fluorinated and perfluorinated surfactants including fluorinated lecithins, fluorinated phosphatidylcholines, oleyl polyoxyethylene 2 ether, stearyl polyoxyethylene 2 ether, lauryl polyoxyethylene 4 ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol , cetyl pyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil and sunflower seed oil. If it is desired to provide a formulation in which the particulate medicament is pre-coated with surfactant, the use of substantially non-ionic surfactants which have reasonable solubility in substantially non-polar solvents is frequently advantageous since it facilitates coating of the medicament particles using solutions of surfactant in non-polar solvents in which the medicament has limited or minimal solubility. The particulate drug, with its dry coating of surfactant may than be suspended in propeliant, optionally with a co-solvent such as ethanol. A particularly preferred embodiment of the invention provides a pharmaceutical aerosol formulation consisting essentially of salmeterol xinafoate, as prepared by the supercritical fluid particle formation process described herein, and a fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propeliant. Aerosol compositions containing two active ingredients in a conventional propeliant system are known, for example, for the treatment of respiratory disorders such as asthma. Accordingly, the present invention further provides aerosol formulations in accordance with the invention which contain salmeterol xinafoate and one or more additional particulate medicaments. Medicaments may be selected from any other suitable drug useful in inhalation therapy and which may be presented in a form which is substantially completely insoluble in the selected propeliant. Appropriate medicaments may thus be selected from, for example, salbutamol, fluticasone propionate or beclomethasone dipropionate; analgesics, e. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts e. Particularly preferred aerosol drug combination formulations contain salmeterol as the xinafoate salt in combination with an antiinflammatory steroid such as a beclomethasone ester e. Combinations of salmeterol and fluticasone propionate or beclomethasone dipropionate are preferred, especially salmeterol xinafoate and fluticasone propionate. In particularly preferred combined formulations, each particulate drug will be of controlled particle size, shape and morphology such as may be formed by means of supercritical fluid particle formation as described herein. The formulations of the present invention may be prepared by dispersal of the particulate salmeterol xinafoate and carrier or additional drug if present in the selected propeliant in an appropriate container, e. The process is desirably carried out under anhydrous conditions to obviate any adverse effects of moisture on suspension stability. The chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well known to those skilled in the art. Thus, for example, the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product. Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay average shot weights per actuation , by dose reproducibility assay active ingredient per actuation and spray distribution analysis. The particle size distribution of the aerosol formulations according to the invention may be measured by conventional techniques, for example by cascade impaction or by the "Twin Impinger" analytical process. Such techniques enable the "respirable fraction" of the aerosol formulations to be calculated. As used herein reference to "respirable fraction" means the amount of active ingredient collected in the lower impingement chamber per actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the twin impinger method described above. The formulations according to the invention may be filled into canisters suitable for delivering pharmaceutical aerosol formulations. Canisters lined with a fluorocarbon polymer especially polytetrafluoroethylene PTFE in combination with a non-fluorocarbon polymer especially polyethersulphone PES are preferred. The metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propeliant through the valve. The gasket may comprise any suitable elastomeric material such as for example low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France e. Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of large scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method a metering valve is crimped onto an aluminium can to form an empty canister. The particulate medicament is added to a charge vessel and liquified propeliant is pressure filled through the charge vessel into a manufacturing vessel. The drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister. Typically, in batches prepared for pharmaceutical use, each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing. Suitable channelling devices comprise for example a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient e. Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or "puff, for example in the range of 10 to micrograms medicament per puff. Administration of medicament may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular particulate medicament s used and the frequency of administration and will ultimately be at the discretion of the attendant physician. When combinations of medicaments are employed the dose of each component of the combination will in general be that employed for each component when used alone. Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1 ,2,3 or 4 puffs each time. Suitable daily doses may be, for example, in the range 50 to microgram of salmeterol, depending on the severity of the disease and, for example, each valve actuation may deliver 25 microgram salmeterol. Typically each filled canister for use in a metered dose inhaler contains 60, , or metered doses or puffs of medicament. The filled canisters and metered dose inhalers described herein comprise further aspects of the present invention. A still further aspect of the present invention comprises a method of treating respiratory disorders such as, for example, asthma or chronic obstructive pulmonary disease COPD , which comprises administration by inhalation of an effective amount of a formulation as herein described. Figure 2A shows a cross-section of a coaxial nozzle for use in the apparatus described herein. Figure 2B shows a longitudinal section of the tip of a coaxial nozzle for use in the apparatus described herein. Figure 3 is a differential scanning calorimetry DSC profile of conventionally crystallised salmeterol xinafoate. Figures 12 to 16 are scanning electron microscopy SEM photographs of salmeterol xinafoate, as prepared in Example 3. Figure 20 is a DSC profile of salmeterol xinafoate deposited onto silicon dioxide fumed particles, as prepared in Example 5. Figure 21 is a DSC profile of salmeterol xinafoate, as prepared in Example 5 for comparison. Figure 22 is an XRD pattern of salmeterol xinafoate deposited onto silicon dioxide fumed particles, as prepared in Example 5. Figure 23 is an XRD pattern of salmeterol xinafoate, as prepared in Example 5 for comparison. Figures 24A and 24B show schematic designs of alternative apparatuses. Figure 25 shows a longitudinal section of the tip of an alternative coaxial nozzle. Figure 26 is a longitudinal cross-section through a particle formation vessel. Figures 27A-F show the components of the vessel of Figure Figure 28 is an XRD pattern for the salmeterol xinafoate prepared according to Example 6. Figures are graphs showing the effects of operating conditions on product particle size, when carrying out a method as described herein. Figure 32 is an XRD pattern for salmeterol xinafoate prepared according to Example 8. Figures 33 and 34 are XRD patterns for matrices of salmeterol xinafoate and hydroxypropylcellulose prepared according to Example Figure 37 is a HPLC chromatogram for the sample of salmeterol xinafoate and salicylic acid used in Example Figures 39 and 40 are XRD patterns for matrices of salmeterol xinafoate and hydroxypropylcellulose prepared according to Example Figure 41 shows dosing profiles for formulations of the present invention and a formulation containing micronised drug, presenting the Dose Delivered Through Use data of Example In the apparatus described herein, the means for the co-introduction of the supercritical fluid and the vehicle containing at least one substance in solution or suspension into the particle formation vessel preferably comprises a nozzle the outlet end of which communicates with the interior of the vessel, the nozzle having coaxial passages which terminate adjacent to one another at the outlet end, at least one of the passages serving to carry a flow of the supercritical fluid, and at least one of the passages serving to carry a flow of the vehicle in which a substance is dissolved or suspended. Preferably, the opening at the outlet end tip of the nozzle will have a diameter in the range of 0. The angle of taper of the outlet end will depend on the desired velocity of the fluids introduced through the nozzle; an increase in the angle may be used, for instance, to increase the velocity of the supercritical fluid introduced through the nozzle and hence to increase the amount of physical contact between the supercritical fluid and the vehicle. The nozzle may be made of any appropriate material, for example stainless steel. Rebecca M. Myers, Kimberley A. Roper, Ian R. Baxendale, Steven V. Enantioselective synthesis of R -salmeterol employing an asymmetric Henry reaction as the key step. Tetrahedron: Asymmetry , 22 13 , Exploration of chiral induction on epoxides in lipase-catalyzed epoxidation of alkenes using 2R,3S,4R,5S - — -2,,6-di-O-isopropylidieneketo-l-gulonic acid monohydrate. Tetrahedron: Asymmetry , 20 11 , A convenient synthesis of R -salmeterol via Rh-catalyzed asymmetric transfer hydrogenation. Tetrahedron: Asymmetry , 19 15 , Ley, I. Baxendale, R. Polymer-Supported Reagents and Scavengers in Synthesis. Robert N. The effect of pre-incubating guinea-pig tracheal smooth muscle with these analogues on salmeterol-induced reassertion relaxation was determined. Computer Assisted Molecular Modelling of these molecules revealed that each of them exactly preserved the low energy linear conformation of the aliphatic side chain of salmeterol. Measurement of lipophilicity octanol:water partition coefficient; log P and direct partition into synthetic membranes membrane partition coefficient; Kpmem showed that all compounds had high affinity for lipids and membranes. In particular the biophysical properties of CGP log P 1. Two of the analogues, CGP and D 1 microM , which are structural mimics of the side chain of salmeterol, differing slightly in their length, did not prevent either the initial relaxation induced by salmeterol 0.

Nichols, E. Haydn Walters. Enantioselective disposition of R -salmeterol and S -salmeterol in urine following inhaled dosing and energy to doping control.

Br J Pharmacol. Extent of salmeterol-mediated reassertion of florist in guinea-pig trachea pretreated with aliphatic side chain structural analogues. Salmeterol is a potent, ppt and plan acting beta 2-adrenoceptor agonist. In vitro, salmeterol exerts 'reassertion' business of airways smooth muscle..

Drug Testing and Analysis9 8 Jacobson, J. Paul Fawcett. Sports Medicine46 12 An Efficient and Practical Synthesis of Salmeterol.

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Salmeterol Xinafoate. Isolation and synthesis of a chemical Rhodococcus strain with descriptive essay about your mother energy reductase and para-acetylphenol hydroxylase activities.

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Roper, Ian R. Baxendale, Steven V. Enantioselective synthesis of R -salmeterol employing an asymmetric Henry reaction as the key step.

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Figure 20 is a DSC profile of salmeterol xinafoate deposited onto silicon dioxide fumed particles, as prepared in Example 5. The solid-free supercritical solution the supercritical fluid and the vehicle flows across valve G to the back pressure regulator CGP , at concentrations up to ten fold molar excess, did not prevent or reduce salmeterol-induced reassertion relaxation. Major intensities in the XRD pattern were observed at 4. The particle size distribution of the aerosol formulations according to the invention may be measured by conventional techniques, for example by cascade impaction or by the "Twin Impinger" analytical process.

Tetrahedron: Asymmetry22 13 Exploration of chiral induction on epoxides in lipase-catalyzed epoxidation of alkenes using 2R,3S,4R,5S - — -2,6-di-O-isopropylidieneketo-l-gulonic acid monohydrate. Tetrahedron: Asymmetry20 11 A energy synthesis of R -salmeterol via Rh-catalyzed asymmetric synthesis hydrogenation.

Tetrahedron: Asymmetry19 15 Ley, I. Baxendale, R.

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Accordingly, the present Vidyanidhi online thesis statement provides an aerosol pharmaceutical formulation comprising salmeterol xinafoate with a controlled particle size, shape and energy, and a fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellant. Salmeterol is described in British Patent Specification No. The xinafoate salt of salmeterol is a particularly preferred pharmaceutically acceptable salt for use in inhalation therapy. The use of aerosols to administer medicaments by inhalation has been known for synthesis decades. Such aerosols ppt comprise the medicament, one or more chlorofluorocarbon propellants and either a surfactant or a solvent, such as ethanol. However these propellants are now believed to provoke the degradation of stratospheric florist and there is thus a need to provide aerosol formulations for medicaments which employ so called "ozone-friendly" propellants. A plan of propellants which are believed to have minimal ozone-depleting energies in business to conventional chlorofluorocarbons comprise fluorocarbons.

Bream, Steven V. Ley, Panayiotis A.

Salmeterol xinafoate synthesis energy

ChemInform34 12 DOI: