Dimethyl sulfoxide

Absorption

Readily and rapidly absorbed following administration by all routes and distributed throughout the body.

Toxicity

The oral LD50 of dimethyl sulfoxide in the dog is greater than 10 gm/kg. It is improbable that this dosage level could be obtained with intravesical instillation of dimethyl sulfoxide in the patient.

Description

Dimethyl sulfoxide (DMSO) is a widely used solvent that is miscible with water and a wide range of organic solvents. It goes by several names, including methyl sulfoxide, sulfinylbismethane, and dozens of trade names. DMSO was first discovered in the late 19th century as a byproduct of the kraft process for making paper from wood pulp. About the same time, Russian chemist Alexander Zaytsev synthesized it by oxidizing dimethyl sulfide, another kraft process byproduct. Zaytsev’s synthesis is the basis for the manufacturing process still used today.

Description

First synthesized in 1866 by Alexander Zaytsev in the Russian Empire, dimethyl sulfoxide is an organosulfur compound. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water.

Chemical properties

Dimethyl sulfoxide occurs as a colorless, viscous liquid, or as colorless crystals that are miscible with water, alcohol, and ether. The material hasa slightly bitter taste with a sweet aftertaste, and is odorless, or has a slight odor characteristic of dimethyl sulfoxide.Dimethyl sulfoxide is extremely hygroscopic, absorbing up to 70% of its own weight in water with evolution of heat.

Originator

Rimso,Research,US,1978

Occurrence

Reported found in apple, raspberry, cabbage, cucumber, onion, tomato, peppermint and spearmint oils, milk, pork liver, beer, rum, cocoa, coffee, black tea, oatmeal, soybean, beetroot, parsnip root, watercress, sweet corn, malt, cooked shrimp and oysters

The Uses of Dimethyl sulfoxide

Dimethyl sulfoxide (DMSO) is a polar aprotic solvent that can dissolve a wide range of organic compounds. It is a laboratory and industrial solvent for many gases, synthetic fibers, paint, hydrocarbons, salts, and natural products. Because it is aprotic, relatively inert, nontoxic, and stable at high temperatures, it is a frequently used solvent for chemical reactions. Its deuterated form is an ideal solvent for NMR spectroscopy.

The Uses of Dimethyl sulfoxide

DMSO is a polar aprotic solvent used in chemical reactions, in polymerase chain reactions (PCR) and as a cryoprotectant vitrification agent for the preservation of cells, tissues and organs. DMSO is used in cell freezing media to protect cells from ice crystal induced mechanical injury. It is used for frozen storage of primary, sub-cultured, and recombinant heteroploid and hybridoma cell lines; embryonic stem cells (ESC), and hematopoietic stem cells. DMSO is frequently used in the combinations with BSA or fetal bovine serum (FBS).

The Uses of Dimethyl sulfoxide

Human and animal cell lines grown in culture are generally stored frozen. Freezing protects the cell line from changes due to genetic drift and minimizes risk of contamination. Liquid nitrogen used in conjunction with a cryoprotective agent such as DMSO is a widely used method for preserving cells. Without the presence of a cryoprotective agent, freezing is lethal to most mammalian cells. Damage is caused by mechanical injury by ice crystals, concentration of electrolytes, pH changes, and denaturation of proteins. These lethal effects are minimized by adding a cryoprotective agent which lowers

The Uses of Dimethyl sulfoxide

Dimethyl sulfoxide (1-10%) has been shown to accelerate strand renaturation and is believed to give the nucleic acid thermal stability against depurination. As a PCR cosolvent, DMSO may help improve yields, especially in long PCR.

The Uses of Dimethyl sulfoxide

A polar aprotic solvent used in polymerase chain reactions (PCR) and as a cryoprotectant vitrification agent for the preservation of cells, tissues and organs.

The Uses of Dimethyl sulfoxide

Suitable for HPLC, spectrophotometry, environmental testing

The Uses of Dimethyl sulfoxide

Solvent for many organic Compounds including fats, carbohydrates, dyes, resins, and polymers. In organic reactions. As antifreeze or hydraulic fluid when mixed with water. To cryopreserve and store cultured cells. Dimethyl Sulfoxide is a common aprotic organic solvent used to dissolve both polar and nonpolar compounds. Used primarily for NMR study in its deuterated form DMSO-d6 (D479382) due to its ability to dissolve most analytes as well as its easily identifiable NMR spectrum.

Background

A highly polar organic liquid, that is used widely as a chemical solvent. Because of its ability to penetrate biological membranes, it is used as a vehicle for topical application of pharmaceuticals. It is also used to protect tissue during cryopreservation. Dimethyl sulfoxide shows a range of pharmacological activity including analgesia and anti-inflammation.

Indications

For the symptomatic relief of patients with interstitial cystitis.

Definition

ChEBI: A 2-carbon sulfoxide in which the sulfur atom has two methyl substituents.

Production Methods

Dimethyl sulfoxide is prepared by air oxidation of dimethyl sulfide in the presence of nitrogen oxides. It can also be obtained as a by product of wood pulp manufacture for the paper and allied industries.

Manufacturing Process

A current of oxygen at the rate of 370 ml/min was bubbled through a 30-cm layer of dimethyl sulfide maintained at 26.5°C, thereby producing a gaseous mixture containing the stoichiometric amount of oxygen required for the oxidation of the sulfide to sulfoxide. Nitric oxide at the rate of 30 ml/min was added to the gaseous mixture as it passed into the first of a series of four reaction chambers, each consisting of a glass tube 4.3 cm in diameter and 100 cm in length. The reaction started immediately, the temperature of the reaction mixture reached a maximum of about 75°C in the first two tubes where most of the reaction occurred, and the reaction slowed down in the last two tubes. The crude, yellow product, which dropped from the tubes, contained about 10% dimethyl sulfide, about 2% dissolved nitrogen dioxide, about 2% methane sulfonic acid, and some water. The crude product was refluxed at 100°C for 30 minutes and the escaping gas was passed into the first reaction chamber. The dimethyl sulfide was removed by then heating the product to 150°C, the methane sulfonic acid was neutralized by adding slaked lime, and the dimethyl sulfoxide was distilled in vacuum. The yield of pure dimethyl sulfoxide (BP 63°C at 6 mm Hg) was 85% of the theoretical yield from the evaporated dimethyl sulfide.

brand name

Rimso-50 (Bioniche).

Therapeutic Function

Topical antiinflammatory

Aroma threshold values

Aroma characteristics at 100%: fatty, oily, cheesy, over-cooked stir-fry, salty and garlic, mushroom, garlic with a cracker and soy nuance

Taste threshold values

Taste characteristics at 40 ppm: fatty, salty, garlic and cream corn

General Description

A clear liquid, essentially odorless. Closed cup flash point 192°F. Vapors are heavier than air. Contact with the skin may cause stinging and burning and lead to an odor of garlic on the breath. An excellent solvent that can transport toxic solutes through the skin. High vapor concentrations may cause headache, dizziness, and sedation.

Air & Water Reactions

Denser than water and miscible in water.

Reactivity Profile

Dimethyl sulfoxide decomposes violently on contact with many acyl halides, aryl halides and related compounds such as phenyl and tolyl chloride, acetyl chloride, benzenesulfonyl chloride, benzoyl chloride, cyanuric chloride, phosphorus chloride, phosphorus oxychloride, and thionyl chloride [Chem. Eng. News 35(9):87 (1957)]. Reacts, possibly violently, with iodine pentafluoride [Chem. Eng. News 47(12):, 109(1969)]. Vacuum distillation from anhydrous magnesium perchlorate led to an explosion [MCA Case History 1187(1966)]. Violently reactive with fluorinating agents such as silver fluoride [Chem. Eng. News 44(24):7(1956)]. Can explode with sodium hydride [Chem. Eng. News 44(24):7(1966)]. Mixture with methyl bromide resulted in an explosion that shattered the apparatus [NFPA 491M, 1991]. Forms salts with perchloric acid that are explosive when dry [Chem. Abst. 44:p3935d (1950)]. Decomposes when heated above normal boiling point.

Health Hazard

The acute toxicity of DMSO by all routes of exposure is very low. Inhalation of DMSO vapor can cause irritation of the respiratory tract, and at higher concentrations may cause vomiting, chills, headache, and dizziness. The material is only slightly toxic by ingestion and may cause vomiting, abdominal pain, and lethargy. Dimethyl sulfoxide is relatively nontoxic by skin absorption, but can cause itching, scaling, and a transient burning sensation. Dimethyl sulfoxide can increase the tendency for other chemicals to penetrate the skin and so increase their toxic effects. Contact of DMSO liquid with the eyes may cause irritation with redness, pain, and blurred vision. Chronic exposure to dimethyl sulfoxide can cause damage to the cornea of the eye. Dimethyl sulfoxide has not been found to be carcinogenic or to show reproductive or developmental toxicity in humans

Flammability and Explosibility

Combustible when exposed to heat or flame (NFPA rating = 1). Carbon dioxide or dry chemical extinguishers should be used to fight DMSO fires.

Chemical Reactivity

Reactivity with Water No reaction; Reactivity with Common Materials: No reaction; Stability During Transport: Stable; Neutralizing Agents for Acids and Caustics: Not pertinent; Polymerization: Not pertinent; Inhibitor of Polymerization: Not pertinent.

Pharmaceutical Applications

Dimethyl sulfoxide is a highly polar substance that is aprotic, therefore lacking acidic and basic properties. It has exceptional solvent properties for both organic and inorganic components, which are derived from its capacity to associate with both ionic species and neutral molecules that are either polar or polarizable. Dimethyl sulfoxide enhances the topical penetration of drug sowing to its ability to displace bound water from the stratumcorneum;this is accompanied by the extraction of lipids and configurational changes of proteins.
the solvent is diluted. Increases in drug penetration have been reported with dimethyl sulfoxide concentrations as low as 15%,but significant increases in permeability generally require concentrations higher than 60–80%. Furthermore, while low molecular weight substances can penetrate quickly into the deep layers of the skin, the appreciable transport of molecules with a molecular weight of more than 3000 is difficult.
Dimethyl sulfoxide is now incorporated into a number of regulated products for healthcare and drug delivery applications, including stabilizing product formulations, sustained-release applications, and for the delivery of medical polymers.
The use of dimethyl sulfoxide to improve transdermal delivery has been reported for diclofenac, ciclosporin, timolol, and a wide range of other drugs. Dimethyl sulfoxide has also been used in the formulation of an injection containing allopurinol. It has also been investigated for use in an experimental parenteral preparation for the treatment of liver tumors.
In paint formulations of idoxuridine, dimethyl sulfoxide acts both as a solvent to increase drug solubility and a means of enabling penetration of the antiviral agent to the deeper levels of the epidermis.
Dimethyl sulfoxide has also been investigated as a potential therapeutic agent in conditions such as scleroderma, interstitial cystitis,(12) rheumatoid arthritis, and acute musculoskeletal injuries, and as an analgesic.(13–17) It has also been recommended for the treatment of anthracycline extravasation(18–21) and has been investigated as a potential cryoprotectant.

Industrial uses

Dimethyl sulfoxide, a product of an oxidation reaction on dimethyl sulfide, contains a very polar sulfoxide functional group. This highly polar functional group enables DMSO to form complexes with many metal ions, to act as a reaction medium for synthetic reactions, and to dissolve a large number of organic resins and polymers.
Dimethyl sulfoxide is more viscous than many organic solvents and has a rather high surface tension value of 42.3 dynes/cm. The most outstanding property of DMSO is its very high polarity character.
Dimethyl sulfoxide is used as a reaction solvent in the polymerization of acrylonitrile with a vinyl monomer (e.g., styrene). Reaction of diisocyanates and polyols or polyamines dissolved in DMSO yield solutions of the polyurethanes. Mixtures of DMSO and water are used as a spinning solvent for polymer fibers. Polyaryl ether polymers are formed from DMSO solutions containing the reactants bis(4,4-chlorophenyl sulfone) and the disodium salt of dihydroxyphenol.
Dimethyl sulfoxide is a favored solvent for displacement reactions in synthetic chemistry. The rates of reaction in DMSO are many times faster than in an alcohol or aqueous medium. Dimethyl sulfoxide is the solvent of choice in reactions where proton (hydrogen atom) removal is the rate determining step. Reactions of this type include olefin isomerizations and reactions where an elimination process produces an olefin. Another application that uses DMSO is its use as an extraction solvent to separate olefins from saturated paraffins. Several binary and ternary solvent systems containing DMSO and an amine (e.g., methylamine), sulfur trioxide, carbon disulfide/amine, or sulfur trioxide/ammonia are used to dissolve cellulose, and act as spinning baths for the production of cellulose fibers. Organic fungicides, insecticides, and herbicides are readily soluble in DMSO. Dimethyl sulfoxide is used to remove polymer residues from polymerization reactors.

Biological Activity

Solvent with wide ranging applications in biological research.

Biochem/physiol Actions

Dimethyl sulfoxide (DMSO) is a low molecular weight, less hydrophilic and a freely permeable cryoprotectant. It is a polar aprotic solvent used in polymerase chain reactions (PCR) and as a cryoprotectant and vitrification agent for the preservation of cells, tissues and organs.

Pharmacokinetics

Dimethyl Sulfoxide may have anti-inflammatory, antioxidant and analgesic activities. Dimethyl Sulfoxide also readily penetrates cellular membranes. The membrane-penetrating ability of dimethyl sulfoxide may enhance diffusion of other substances through the skin. For this reason, mixtures of idoxuridine and dimethyl sulfoxide have been used for topical treatment of herpes zoster in the United Kingdom.

Safety Profile

Slightly toxic by ingestion. Moderately toxic by intravenous and intraperitoneal routes. Human systemic effects by intravenous route: nausea or vomiting and jaundice. Experimental teratogenic and reproductive effects. A skin and eye irritant. Questionable carcinogen with experimental tumorigenic data. Human mutation data reported. Can cause an anaphylactic reaction. Corneal opacity reported only in rabbits, dogs, and pigs. It freely penetrates the skin and may carry dissolved chemicals with it into the body. Combustible when exposed to heat or flame; can react with oxidizing materials. To fight fire, use water, foam, alcohol foam, CO2, dry chemical. Violent or explosive reaction with many acyl, aryl, and nonmetal halides (e.g., acetyl chloride, benzenesulfonyl chloride, bromobenzoyl acetadde, cyanuric chloride, iodine pentafluoride, Mg(ClO4)2, CH3Br, NI04, oxalyl chloride, P203, phosphorus trichloride, phosphoryl chloride, silver fluoride, silver difluoride, sodium hydride, sulfur dichloride, disulfur dichloride, sulfuryl chloride, tetrachlorosilane, thionyl chloride). Violent or explosive reaction with boron compounds (e.g., borane, nonahydrononaborate(2-) ion), 4(4' bromobenzoyl)acetanilide, carbonyl dhsohocyanate, dinitrogen tetraoxide, hexachlorocyclotriphosphazine, copper + trichloroacetic acid, metal alkoxides (e.g., potassium tert-butoxide, sodium isopropoxide), trifluoroacetic acid anhydride. Incompatible with magnesium perchlorate, metal oxosalts, perchloric acid, periodc acid, sulfur trioxide. Forms powerfully explosive mixtures with metal salts of oxoacids (e.g., aluminum perchlorate, sodrum perchlorate, iron(IⅡ) nitrate). When heated to decomposition it emits toxic fumes of SOx

Safety

Dimethyl sulfoxide has low systemic toxicity but causes local toxic effects. It is readily absorbed after injection or after oral or percutaneous administration and is widely distributed throughout the body. Dimethyl sulfoxide acts as a primary irritant on skin, causing redness, burning, itching, and scaling; it also causes urticaria. Systemic symptoms include nausea, vomiting, chills, cramps, andlethargy;dimethyl sulfoxidecanalsocauseincreases in intraocular pressure. Administration of dimethyl sulfoxide by any route is followed by a garlic-like odor on the breath.
Intravascular hemolysis and biochemical changes and reversible neurological deterioration have been reported following intravenous administration; however, it has been questioned whether these findings were directly attributable to dimethyl sulfoxide rather than to concomitant drug therapy or contaminants. One report describes massive intracranial hemorrhage associated with ingestion of dimethyl sulfoxide. Recently, a hypersensitivity reaction attributed to dimethyl sulfoxide has been reported.
In 1965, the FDA banned investigation in humans of dimethyl sulfoxide owing to the appearance of changes in the refractive index of the lens of the eye in experimental animals.However,in1966,the FDA allowed the study of dimethyl sulfoxide in serious conditions suchasscleroderma,persistent herpes zoster,and severe rheumatoid arthritis, and in 1968 permitted studies using short-term topical application of the solvent. By 1980, the FDA no longer specifically regulated investigations of dimethyl sulfoxide.
Dimethyl sulfoxide enhances the skin penetration of several drugs, which may result in producing the adverse effects associated with those drugs.
LD50 (dog, IV): 2.5g/kg
LD50 (rat, IP): 8.2g/kg
LD50 (rat, IV): 5.3g/kg
LD50 (rat, oral): 14.5g/kg
LD50 (rat, SC): 12g/kg
LD50 (mouse, IP): 2.5g/kg
LD50 (mouse, IV): 3.8g/kg
LD50 (mouse, oral): 7.9g/kg

Veterinary Drugs and Treatments

Purported uses for DMSO are rampant, but the only FDA-approved veterinary indication for DMSO is: “…as a topical application to reduce acute swelling due to trauma” (Package Insert; Domoso?— Syntex). Other possible indications for DMSO include: adjunctive treatment in transient ischemic conditions, CNS trauma and cerebral edema, skin ulcers/wounds/burns, adjunctive therapy in intestinal surgeries, and analgesia for post-operative or intractable pain, amyloidosis in dogs, reduction of mammary engorgement in the nursing bitch, enhancement of antibiotic penetration in mastitis in cattle, and limitation of tissue damage following extravasation injuries secondary to chemotherapeutic agents.
DMSO’s effect on alcohol dehydrogenase, may make it useful in the treatment of ethylene glycol poisoning, but this has not been sufficiently studied as of yet. DMSO’s attributes as a potential carrier of therapeutic agents across the skin and into the systemic circulation and its synergistic effects with other agents are potentially exciting, but require much more study before they can be routinely recommended.
While the potential indications for DMSO are many, unfortunately, the lack of well-controlled studies leaves many more questions than answers regarding this drug.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts theskin, remove contaminated clothing and wash immediatelywith soap and water. Seek medical attention immediately. Ifthis chemical has been inhaled, remove from exposure,begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR ifheart action has stopped. Transfer promptly to a medicalfacility. When this chemical has been swallowed, get medical attention. Give large quantities of water and inducevomiting. Do not make an unconscious person vomit

Environmental Fate

Most physiological properties of DMSO appear to be related to its penetration properties, its potential to inhibit or stimulate enzymes and to act as a free radical scavenger, and its ability to cause histamine release from mast cells. These properties are largely based on DMSO’s chemical characteristics, including its hydrogen bonding behavior, water affinity, ability to interchange with water in membranes, and ability to react with organic molecules.

Metabolism

Dimethyl sulfoxide is metabolized in man by oxidation to dimethyl sulfone or by reduction in dimethyl sulfide. Dimethyl sulfoxide and dimethyl sulfone are excreted in the urine and feces.

storage

Dimethyl sulfoxide is reasonably stable to heat,but upon prolonged reflux it decomposes slightly to methyl mercaptan and bismethylthiomethane. This decomposition is aided by acids, and is retarded by many bases. When heated to decomposition, toxic fumes are emitted.
At temperatures between 40 and 60°C, it has been reported that dimethyl sulfoxide suffers a partial breakdown, which is indicated by changes in physical properties such as refractive index, density, and viscosity.
Dimethyl sulfoxide should be stored in airtight, light-resistant containers. The PhEur 6.0 states that glass containers should be used. Contact with plastics should be avoided.

Shipping

DMSO is not specifically cited in DOT’sPerformance-Oriented Packaging Standards.

Purification Methods

This colourless, odourless, very hygroscopic liquid, is synthesised from dimethyl sulfide. The main impurity is water, with a trace of dimethyl sulfone. The Karl-Fischer test is applicable. It is dried with Linde types 4A or 13X molecular sieves, by prolonged contact and passage through a column of the material, then distilled under reduced pressure. Other drying agents include CaH2, CaO, BaO and CaSO4. It can also be fractionally crystallised by partial freezing. More extensive purification is achieved by standing overnight with freshly heated and cooled chromatographic grade alumina. It is then refluxed for 4hours over CaO, dried over CaH2, and fractionally distilled at low pressure. For efficiency of desiccants in drying dimethyl sulfoxide see Burfield and Smithers [J Org Chem 43 3966 1978, Sato et al. J Chem Soc, Dalton Trans 1949 1986]. [Reddy Pure Appl Chem 25 459 1969, Beilstein 1 IV 1277.] Rapid purification: Stand over freshly activated alumina, BaO or CaSO4 overnight. Filter and distil it over CaH2 under reduced pressure (~ 12 mm Hg). Store it over 4A molecular sieves.

Toxicity evaluation

DMSO is naturally released in the environment, primarily by the oxidation of dimethyl sulfide that is biologically produced in soil, water, and vegetation. It is produced by phytoplankton, and may be released during its production, transport, disposal, and use as a solvent, medicinal analgesic, and other uses.
If released in water, it should disproportionate to dimethyl sulfide and dimethyl sulfone, and may be reduced by reducing agents that may occur in natural waters. In soil, DMSO is rapidly reduced to dimethyl sulfide. In the atmosphere, DMSO will exist primarily in the vapor phase, and will react with photochemically produced hydroxyl radicals with a half-life of w7 h. It also may be released during its production, transport, disposal, and use as a solvent and medical analgesic.
A bioconcentration factor (BCF) of <1 was observed for dimethyl sulfoxide, using orange-red killifish (Oryzias latipes) which were exposed over an 8-week period. According to a classification scheme, this BCF suggests that bioconcentration in aquatic organisms is low.

Incompatibilities

DMSO reacts violently with strong oxidizers, many acyl halides, boron hydrides, and alkali metals. DMSO can form explosive mixtures with metal salts of oxoacids (sodium perchlorate, iron(III) nitrate).

Waste Disposal

Excess dimethyl sulfoxide and waste material containing this substance should be placed in an appropriate container, clearly labeled, and handled according to your institution's waste disposal guidelines.

Regulatory Status

Included in the FDA Inactive Ingredients Database(IVinfusions,SC implants, and topical preparations). Available in the USA as a 50% solution for irrigation in the treatment of interstitial cystitis. Also available in Canada as a 70% solution for use as a topical antifibrotic, and in Germany as a topical gel containing 10% dimethyl sulfoxide for the treatment of musculoskeletal and joint disorders. Included in topical formulations of idoxuridine and diclofenac licensed in the UK.