Robert Strub is director of business development at Gaylord Chemical Company LLC.

Robert Strub

Dimethyl sulfoxide (DMSO) has long been appreciated as a versatile reaction solvent for the production of active pharmaceutical ingredients. It is also established as an important material in medicinal chemistry and as a compound storage medium. The most significant use trend for DMSO in the past 10 years has, however, been its increased adoption in finished pharmaceutical dosage forms and medical devices. 
	In these applications, DMSO is directly administered to humans and animals as a component of regulated pharmaceutical formulations.

	This article updates an earlier review (1) on this subject to include developments from the years 2007-2014, in particular, new drug formulation approvals and changes in the regulatory affairs associated with the use of Dimethyl Sulfoxide 

 The November 2009 launch of Pennsaid (diclofenac sodium topical 1.5%) was notable in that it was the first DMSO-containing topical formulation to obtain FDA marketing approval. The product is manufactured in Canada by its originator company, Nuvo Research (formerly Dimethaid Research). The US approval followed earlier approvals in other parts of the world.

	Penn said is a nonsteroidal anti-inflammatory formulation indicated for treatment of osteoarthritis of the knee. The active ingredient in Pennsaid is diclofenac sodium; Dimethyl Sulfoxide USP, Ph.Eur. is included as an excipient in the formulation at the significant concentration of 45.5% w/v.

	The formulation includes other inactive ingredients (alcohol, propylene glycol, type H hydroxypropyl cellulose, and water). Pennsaid is packaged as a dropping dispenser with patient instructions to apply 40 drops by hand or directly to the knee, four times per day.

	In 2011, the original intellectual property protection surrounding the Penn said formulation expired. Generic competition to produce bioequivalent products immediately emerged. Nuvo initiated litigation against the generic entrants based on a newly issued patent (US 8,217,078) (2). This patent discloses safe and effective methods to use the Pennsaid formulation and is among related patents listed in FDA’s list of Approved Drug Products with Therapeutic Equivalence Evaluations (The Orange Book) (3). A settlement agreement reached in January 2013 allowedApotex to launch its generic version of the Pennsaid product in May of 2014, after Nuvo’s commercial delivery of its next generation Pennsaid product. Verresfield (UK) Ltd. also sells a dichlofenac sodium 1.5% w/w formulation that contains DMSO; apparently this product (Inflaforte) is only marketed in Greece.

	Nuvo received FDA approval for its Pennsaid 2% (diclofenac sodium topical solution) 2% w/v in 2014. Advantages for this product relative to the original include a metered dose pump bottle, simplified dosing regimen (two versus four applications per day) and increased viscosity. Pennsaid 2% is also composed of 45.5% w/v Dimethyl Sulfoxide USP. The company continues to innovate beyond its original DMSO-based platform. Nuvo has developed a novel DMSO foam product (Ibufoam) designed for the topical application of ibuprofen. At the time of writing, the Ibufoam product is in preclinical trials (4).

	Topical 5% idoxuridine in DMSO for the treatment of Herpes Zoster has been marketed in the United Kingdom (Herpid, Astellas Pharma) and elsewhere (5). An ophthalmic idoxuridine product (Antizona) was sold by Sanofi-Aventis.

	There are other topicals, which include DMSO as an excipient, that have been approved outside of the US. In eastern Europe and Russia, there is a healthy market for DMSO-based over-the-counter (OTC) topical “sports medicine” products, containing popular pain-relief ingredients (i.e., capsicum, heparin, menthol, and methyl salicylate) (5). These products include Espol (Nitzpharm), Chondroxide (Nitzpharm), Assan Rem (Permamed), Onychofissan (GlaxoSmithKline), Roll-Bene (Mepha), Venugel (Permamed, Lubapharm), and Neo-Liniment (Neomed). These products have been marketed in Europe and the former Central and Eastern European (CEE) and the Commonwealth of Independent States (CIS) countries for many years.

	The Pharmacircle database (6) discloses the use of DMSO in Actikerall and Verrucare, for the treatment of actinic keratosis (grade I/II) in adult patients. These products are fluorouracil/salicyclic acid formulations and are marketed by Almirall Hermal GmbH and Laboratório Medinfar, respectively. Dendracin Neurodendracin (Physicians Science & Nature Inc.) is a DMSO-containing OTC “sports medicine” formulation sold in the US. It lists capsaicin, methyl salicylate, and menthol USP as active ingredients. Related products have been marketed in Europe and the former CEE countries for many years.

 The adoption of DMSO as an ingredient in injectable drugs and medical devices is maturing. Some roles for DMSO in injectable products include as a vehicle for the delivery of medical polymers--viz. poly(lactic-co-glycolic acid) (PLGA) and polylactic acid (PLA)--and as a preservation media in stem-cell therapeutics. Prochymal (Osiris Therapeutics, Inc.) is a stem-cell suspension for IV infusion that contains 10% DMSO; the product was approved in Canada and New Zealand in 2012 (7).

DMSO has not been formulated into approved oral delivery systems to this point. DMSO may participate as a component of an active drug substance, either as ligand in a metal complex or as a solvate molecule. There is recent evidence that the use of DMSO as a laboratory solvent for platin chemotherapy drugs is problematic, due to ligand displacement by DMSO (8). In 2013, GlaxoSmithKline received approval to market Mekinist (trametanib dimethyl sulfoxide) as a melanoma treatment. Mekinist is administered once daily and delivers 2 mg equivalent basis of the (non-solvated) active substance trametanib. As such, the concentration of DMSO in the dose is quite low. 

 summarizes the pharmaceutical formulations that incorporate DMSO as an active ingredient or as an excipient (9).

	The Pharmacircle database shows that there have been a total of seven US drug master files (DMF) for DMSO dating back to 1964. Only one of these is still active: a type II DMF originally submitted in 1997. This DMF is maintained by Gaylord Chemical Company, which manufactures the product in compliance with International Council for Harmonization (ICH) Q7 Good Manufacturing Practices (GMPs). The company uses dedicated manufacturing equipment to produce Procipient (Dimethyl Sulfoxide USP, Ph.Eur.) in its production facility located in Tuscaloosa, Alabama, USA. The Tuscaloosa facility went into service in late 2010 and has been inspected by FDA. No form 483s have been issued.

	In March of 2014, a certificate of suitability to the European Pharmacopeia Monographs (CEP) was granted for DMSO by the European Directorate for the Quality of Medicines and Healthcare (EDQM). A CEP certificate serves several purposes. It provides a mechanism to certify the suitability of a substance’s 

 monograph to control its chemical and microbiological quality. It also certifies GMP compliance at relevant manufacturing and distribution facilities. A CEP monograph plays many of the same roles of the US DMF for countries of the European Union. It facilitates a relationship between regulatory authorities and industry by assessing the chemistry, manufacturing, and controls (CMC) associated with the production of an active substance or excipient. The drug application process is simplified as the CEP for an ingredient may be used in the quality section of a drug’s marketing authorization application. The CEP monograph number for DMSO is 00763; Gaylord Chemical Company is the holder of the CEP certificate.

	As DMSO has found use in generic-drug products and has applications as an API, it is subject to the Generic Drug User Fees Amendments of 2012 (GDUFA) in the US. GDUFA requires API (DMF Type II holders) and finished dosage form manufacturers to “self-identify” and pay an annual fee. These funds are intended to address the rising cost of generic-drug applications and reduce the backlog of applications under review. FDA publishes a complete list of GDUFA paid facilities (10).

	Since the initial version of this review was published in 2008, a significant regulatory framework has been implemented in the EU: The Registration, Evaluation, Authorization, and Restriction of Chemicals legislation known commonly as REACH. As a requirement to market chemical substances in the EU, a manufacturer must assess and control risks to human health and environmental quality. Compliance with REACH is most often associated with the trade of commodity chemicals; the fee structure and regulatory requirements are tiered based on sales volume. DMSO was successfully registered under REACH by a consortium of producers (registration number 01-2119431362-50-0001). The regulated pharmaceutical DMSO product, Procipient, is not controlled under REACH.

	The history of abuse of DMSO in the hands of the public during the 1960s and 1970s is well documented elsewhere (11). In recent years, however, DMSO has matured as a useful and recognized excipient in regulated and some lightly controlled pharmaceutical applications. In 2011, Health Canada added DMSO to its Natural Health Products Ingredient Database (NHPID). NHPID-listed materials can be freely used in natural health products without a prescription. These are products “used in traditional medicine and in Western natural health product formulations to maintain and improve health” (12). There has been notable movement against purveyors of unregulated DMSO-based therapies by FDA in recent years; one envisions that this enforcement activity will continue. A modern review of all manner of DMSO therapies was published in 2015, coauthored by the late Dr. Stanley Jacob (13). The passing of Dr. Jacob--perhaps the earliest and most devoted champion of the pharmaceutical development of DMSO--in 2015 was a noteworthy event in the history of this unusual substance. 

 summarizes the various regulatory filings associated with DMSO.

 Historically, DMSO products have suffered from malodor and color problems. Interestingly, DMSO is essentially odorless in a highly purified state. Odor and color problems are largely attributable to trace levels of thiochemical impurities, which can include dimethyl sulfide, dimethyl disulfide, and bis-(methylthio)methane. The human nose is extremely sensitive to these substances, which have odor thresholds in the single-digit, part per billion range (14).

	A patented process used to manufacture Dimethyl Sulfoxide USP, Ph.Eur. produces a liquid that is odorless and water-white. These attributes are desirable features for topical dosage forms. Although odor is a subjective measure and the perception of odor varies between individuals, modern organoleptic analytical methods demonstrate clear differences between the odor profile of non-GMP produced DMSO products and a product suitable for use in finished dosage forms. 

 provides principal component analysis data generated by Alpha M.O.S. using their α-Fox “e-nose” instrument. Compared were a Procipient (DMSO USP Ph.Eur.) sample--labeled ‘

 grade’--and a series of technical grade DMSO products that had been purged for various times to remove traces of odorous impurities. The method was capable of measuring odor quality differences between the Procipient sample and the technical DMSO samples, as shown by the areas and location of the sample data on the principal components analysis (PCA) representation map. The data further support the idea that volatile, low molecular weight impurities are the principle source of malodor associated with inferior DMSO products: purge treatment caused the odor profile of the technical grade DMSO product to approach that of the Procipient sample. It is worthwhile to note that these odor differences are apparent despite the fact that the nominal purity of the technical grade DMSO samples was quite high--approximately 99.98 % by gas chromatography-flame ionization detector (GC-FID).

Figure 1: Odor profile comparison: industrial-grade dimethyl sulfoxide (DMSO) product samples to Dimethyl Sulfoxide USP, Ph.Eur. sample (manufactured by Gaylord Chemical Company) (15).

 As growth in injectable and other parenteral dosages develops, appropriate sterilization methods for DMSO are needed. The manufacturer of Procipient (Dimethyl Sulfoxide USP, Ph.Eur.) makes no claims regarding product sterility but does support the product with representative biological endotoxin testing (BET) and bioburden assay data as a courtesy. DMSO is not amenable to heat sterilization as some product decomposition occurs. Chemical sterilization using ethylene oxide (EO) and other oxidizing agents is also not practical as DMSO itself is susceptible to oxidation. Radiation sterilization methods (X-ray, E-beam, γ-ray) are not well developed for DMSO and apparently also lead to decomposition.

	The preferred sterilization for DMSO method has become sterile filtration using 0.22 μ filters and, importantly, in DMSO compatible housings. A difficulty arises during the sterilization of viscous DMSO formulations, such as devices based on solutions of medical polymers. This issue may require the manufacturer to compound separately sterilized components (i.e., DMSO and polymer powder), which are aseptically filled into a sterile container. Vendors who provide filtration media that they recommend for use with DMSO include EMD Millipore and Pall. The use of DMSO as a cryoprotectant for cells and living tissue has grown steadily over time. Supplies of Dimethyl Sulfoxide 

. have been sterilized and repackaged into smaller volumes. Smaller packages better suit the needs of cord blood banks and researchers; such products are available from cell media companies.

	A literature search for the period from 2007 to January 2014 produced many hundreds of relevant papers. A few highlights from this search, categorized by dosage form type, are discussed in the following.

It has been long recognized that DMSO is amenable to gel preparation using established thickening excipients, such as carbomer or methylcellulose. An exciting topical drug-delivery system capable of producing DMSO-based pharmaceutical foam formulations has been developed by Foamix Pharmaceuticals (Rehovat, Israel). Foam-based delivery systems offer advantages over semi-solids (ointments, gels, and creams), including a more appealing residual feel after product use (16).

 Stable DMSO formulations have been developed for the parenteral injection of peptide drugs (17). Options for nonaqueous storage and delivery of hydrolytically sensitive active ingredients are a valuable aspect of such inventions.

 Patented uses for DMSO as a safe vehicle for medical polymers have proliferated. Polymers such as ethylene-vinyl alcohol (EVOH) copolymer or PLGA form in-situ implant devices, which can provide structural benefits. BIOS2 Medical reported an EVOH composition that cures when applied to bone, thereby improving load-bearing capacity (18).

	A polymer-drug mixture so implanted may also be designed to deliver an active ingredient in a controlled manner. A sustained-release implant that releases a breast cancer drug has been invented. The innovators describe the use of DMSO to deliver the polymer/drug formulation into the body (19).

	Use as a processing aid. DMSO has been reported as a processing solvent for polymer/drug compositions applied to implantable medical devices. A recent example discloses its use as a purifying agent to remove impurities from EVOH copolymer. This purification step is intended to produce polymer suitable for use in drug-eluting stents (20).

	Since the last published review on this subject, significant new registrations have occurred for DMSO-based pharmaceutical products. The use of DMSO as an excipient is diversifying to include examples in both topical and parenteral products. Regulatory acceptance of DMSO products manufactured under GMPs has broadened to the EU, with the establishment of a CEP in 2014. These advances, in combination with a growing appreciation of the performance properties of DMSO, suggest that interest in this substance persists.

	The authors would like to gratefully acknowledge the special contribution of Thomas C. DePaul (Pharmacircle). Analysis from the Pharmacircle drug delivery database was useful in the development of this review paper.

. 32 (5) 74-85 (2008). 
	2. Mallinckrodt et al. v. Apotex Inc. et al., Delaware case number 1:12-cv-01087 RGA (2012).
	3. United States Food and Drug Administration (2016) 

Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations

, accessed July 20, 2016.
	4. Nuvo Research website, www.nuvoresearch.com/products/pipeline/, accessed Jan. 21, 2016.
	5. Drugs-about.com website, entry “dimethyl sulfoxide,” referenced Feb. 5, 2016. 
	6. A database product of Pharmacircle (www.pharmacircle.com)--Search results are from January 2015.
	7. A. Pollack “A Stem Cell Based Drug Gets Approval in Canada” 

. 74 (14) 3913-3922 (2014). 
	9. Approval year and DMSO dose content collected from product package inserts. For a review of the withdrawn Tegress product, see R. Dmochowski Rev. Urol. 7 (1) S22-S26 (2005).
	10.

, accessed Jan. 5, 2016.
	11. P.W. Davis, 

Health Canada Natural Health Products Ingredient Database

, accessed July 8, 2016.
	13. S. Jacob and J. De La Torre,

 Dimethyl Sulfoxide (DMSO) in Trauma and Disease

, CRC Press; Boca Raton, FL. (2015).
	14. S. Schiffman, J. L. Bennett, and J. H. Raymer, 

, 108, 213-240 (2001).
	15. J.C. Mifsud, unpublished data courtesy of Alpha MOS Corporation (20 avenue Didier Daurat, 31400 Toulouse,France)
	16. D. Tamarkin 

Formulating Topical Applications--A Practical Guide

, N. Dayan Ed., Carol Stream, IL p. 233-260 (2013).
	17. S. Prestrelski and J. Kinzell, “Stable formulations for parenteral injection of peptide drugs,” WO2012122535, Nov. 2012.
	18. J. D’Agostino et al., “Implantable polymer for bone and vascular lesions,” US20120263797, Oct. 2012.
	19. R. Franco and A. Gutierro, “Injectable compositions comprising letrozole or anastrozole,” WO2014019972A1, Feb. 2014.
	20. J. Pathak and F. Tang, “Method and system of purifying 
	polymers for use with implantable medical devices,” US 7645474 B1, Jan. 2010. 

 Supplement
	September 2016
	Pages: s30-–s35

	When referring to this article, please cite it as A. McKim and R. Strub, "Advances in the Regulated Pharmaceutical Use of Dimethyl Sulfoxide 

Articles

The authors review the regulatory changes associated with the use of dimethyl sulfoxide in finished pharmaceutical dosage forms.

Advances in the Regulated Pharmaceutical Use of Dimethyl Sulfoxide USP, Ph.Eur.

Dimethyl sulfoxide (DMSO) has long been recognized as an important reaction solvent for the synthesis of drug compounds and is becoming increasingly important as an excipient in finished pharmaceutical dosage forms. The powerful solvating properties of DMSO, coupled with a favorable and well-documented toxicological profile, have encouraged formulation scientists to develop applications in topical, transdermal, and other parenteral drug delivery technologies. DMSO is currently approved as an active pharmaceutical ingredient (API) and is being evaluated as an API in several orphan-status drugs worldwide. 

Many pharmaceutical formulators are surprised to learn that a number of regulated products currently available include DMSO as a component of the finished dose. The commercial availability of a DMSO product (Procipient, 

), which is manufactured under current good manufacturing practice (CGMP) protocols to conform to 

 (PhEur) standards, has spurred this developmental activity. 

Dimethyl sulfoxide USP in dosage forms and devices 

Worldwide, there are a number of products that use dimethyl sulfoxide USP, PhEur. The established roles that dimethyl sulfoxide USP, PhEur currently plays in approved pharmaceutical products include:  

Stabilizing product formulations: DMSO may be present in product formulations as a cosolvent intended to keep formulation components in solution.

The delivery of medical polymers: polymers such as polyvinyl alcohol (PVA) and poly(lactic-co-glycolic acid) (PLGA) may be dissolved in DMSO and administered in solution into the body. 

 precipitation of the polymer, followed by dissipation of DMSO, produces an implant than can serve various purposes. Polymer implants may function to provide structural support in the body or as bioerodible depot systems that release impregnated drug substances in a controlled fashion. 

Sustained-release applications: Dimethyl sulfoxide USP, PhEur has been a carrier solvent in subcutaneously implanted delivery systems. Precise delivery of the therapeutic agent is controlled by osmotic technology. 

Transdermal penetration enhancement: Using DMSO in concentrations of 70% or greater has been shown to improve the penetration of agents across the skin. At present, all products approved using this DMSO functionality are approved outside of the United States.

Cryopreservative: When water and DMSO are blended, a eutectic mixture results, which causes a significant depression of the freezing point of water. When mixed at 50% w/w, the solution remains liquid at –80 °C, preventing cellular damage when preserving cells. 

Active pharmaceutical ingredient: There is a long established application wherein DMSO has functionality as an active ingredient in the treatment of interstitial cystitis.

Marketed products containing dimethyl sulfoxide USP

The earliest accounts of DMSO use in therapeutic applications were published in the early 1960s, and great interest in this material as a pharmacologic agent occurred throughout that decade. Although investigational new drug (IND) status was granted for DMSO in 1963, concerns about its safety temporarily resulted in a FDA ban on studies using human subjects in 1965 (1, 2) 

During the following 15 years, FDA relaxed its policies concerning human investigations with DMSO. This process culminated in an abandonment of its policy to regulate DMSO research in 1980 (3) and the first preparation containing DMSO was approved for marketing in the US in 1978.  

 The earliest product approved in the US was RIMSO-50 (recently acquired by 

). The product is indicated for the symptomatic relief of patients with interstitial cystitis, a condition involving inflammation of the bladder wall (4). It is a sterile, nonpyrogenic aqueous DMSO formulation (50% w/w DMSO aqueous solution) supplied in 50-mL bottles. RIMSO-50 is instilled directly into a patient's bladder using an aseptic syringe or a catheter and is allowed to remain in the bladder for 15 min before discharge. 

 (Leverkusen, Germany) has released Viadur, a subcutaneously implanted device that uses DMSO as a solubilizing excipient, for the treatment of prostate cancer (5).  The device is implanted in the upper arm and must be removed when a 12-month treatment course has completed. Alza's Duros technology is used to administer leuprolide acetate in a sustained fashion over 12 months. This device contains a solution of dimethyl sulfoxide USP (104 mg) and leuprolide acetate (72 mg) and represents an alternative to other implanted depot delivery systems. 

With regard to injectable products, there is currently one application listed in  

 FDA's Center for Drug Evaluation and Research

 (CDER) inactive ingredient database (6). The product is intended for administration by intravenous infusion.  The dosage form of this product is described as "powder, for injection suspension, lyophilized." The amount of DMSO in this product is not described. 

There are two device applications referenced by 

 FDA's Center for Devices and Radiological Health

 (CDRH). These applications are similar in that they use DMSO as a solubilizing excipient to deliver a medical polymer (ethyl vinyl alcohol copolymer, EVOH) into the body to provide a structural benefit. The first of these device products (Onyx, EV3 Inc.) is a liquid embolic system intended for use in the brain as a treatment of brain arteriovenous malformations (7). The medical polymer is injected as a DMSO solution, containing either 6 or 8% EVOH copolymer, at a controlled rate into the bloodstream. As the DMSO dissolves in the bloodstream, a polymeric embolus forms that contains a micronized contrast agent. The other device Tegress (C.R. Bard) serves as bulking agent in the urethra. The action is similar to the Onyx product by means of 

 precipitation of injected DMSO-EVOH copolymer solution in the body (8) . 

One product referenced for topical application is listed in the CDER inactive ingredients database and is described as a topical dressing (6). The maximum potency of DMSO is 16.5 mg. A number of other topical or transdermal products that include DMSO are under FDA review for approval at the time of this writing. 

 No approved applications have been developed in the US that incorporate DMSO as a component of an orally administered product. DMSO is essentially nontoxic when ingested, having an oral single-dose LD-50 value of 17.4–28.3 g/kg (rat) (9). The low chronic and acute oral toxicity may offer pharmaceutical formulators a delivery option for difficult-to-dissolve medications.  

Products for animal health approved in the US.

 Currently there are two products approved for veterinary use in the US. Domoso is indicated for use in horses for acute swelling and is prepared both as a liquid and gel formulation (10). Domoso  is 90% DMSO. Synotic contains 60% DMSO and 0.01% fluocinolone acetonide and is approved for otic treatment in canines (10). 

 Dimethyl sulfoxide USP, Ph Eur has long been appreciated as a media for the cryopreservation of bone marrow and blood components. DMSO is an example of a substance "that would be generally acceptable" as a cryoprotectant for use in human cells, tissues, and cellular and tissue-based products (HCT/Ps), as defined by FDA (11). HCT/Ps intended for use in human recipients are regulated by the 

 Center for Biologics Evaluation and Research (CBER)

. Among the applications  referenced by CBER is an HIV test kit (Nuclisense HIV-1QT) (12). Dimethyl sulfoxide USP is widely used in United States for the cryopreservation of hematopoietic stem cells supplied from umbilical cord blood at childbirth. Cord blood can be used to treat certain genetic disorders (i.e., acute lymphoblastic leukemia) that affect the blood and immune system by means of allogenetic or autologous injection. 

DMSO-containing products marketed outside the US.

 In Europe, there are several topical products in which DMSO acts as an excipient. One of these uses an antiviral (idoxuridine) in the treatment of herpes zoster (13). A second product is approved for use in Canada and in the European Union for the topical treatment of certain types of joint pain.  

In Germany, DMSO was approved on an over-the-counter basis for sports-related injuries as Dolicur (Schering AG) and provisions exist in the Russian republics that allow for DMSO self medication (14). DMSO is widely used in China for self-medicated topical pain relief. 

Solubility of excipients and API compounds.

 Dimethyl sulfoxide USP, PhEur is chemically compatible with many pharmaceutical excipients and APIs. A database providing solubility data for more than 100 drug compounds and 30 excipients is available on-line (15), dimethyl sulfoxide USP is referenced in 

The Handbook of Pharmaceutical Excipients 

(16). Some basic physical properties of DMSO are listed in Table I. 

Table I: Basic physical properties of dimethyl sulfoxide. 

DMSO is completely miscible with water, ethanol, propylene carbonate, and propylene glycol. It is practically insoluble–insoluble in many lipophilic ingredients (e.g., light mineral oil USP, soybean oil NF). Table II provides an overview of solubility data for dimethyl sulfoxide USP, with common solubilizing excipients. 

Table II: Common solubilizing excipient solubilities in dimethyl sulfoxide (solvent).* 

It is worthwhile to note that water has a dramatic effect on the properties of dimethyl sulfoxide USP, PhEur (17). Although this may be a useful means to lower the solvent strength of DMSO in limited applications, water contamination in DMSO products may affect formulation stability in a negative sense if formulation components have a low degree of water solubility. Mixtures that are high in water content take on the general solvent properties of water. DMSO is fully hydrated at 67 wt% strength in water (10). 

 The viscosity of DMSO formulations may be modified using additives that work well in water. Some pharmaceutically acceptable materials that may be used for this purpose include hydroxypropyl cellulose (Klucel, 

), hypromellose USP (Methocel E3 Premium LV, Dow Chemical), carbomers (Carbopol, Noveon Corp.), and methylcellulose USP. Although such materials have low solubility levels in DMSO (see Table III), very low loading levels are capable of producing high-viscosity gels. 

Table III: Common viscosity modifying excipient solubilities in dimethyl sulfoxide.* 

A standard procedure for producing a thickened solution (~10,000 cPs, depending upon the product used) from a DMSO base follows: Dimethyl sulfoxide (100 g) is combined with triethanolamine (0.5 g) and is stirred mechanically. Klucel LF (0.5 g) is sifted into the mixture slowly; hasty addition of Klucel can result in its aggregation into clumps which are difficult to disperse. It can be helpful to sift the Klucel into the mixture by passing it through a screen. The mixture is stirred at room temperature for 30 min., at which point no solids are seen to the naked eye. 

For highly viscous gel products, loading levels of 1.5–2.0 wt% are required, and it may be helpful to warm the product (~50 °C) during the mixing process. Carbomer-type thickening agents (e.g., Carbopol) are especially recommended for use with DMSO for their high clarity and gel stability. Figure 1 provides viscosity data at varying loading levels for Carbopol 941. 

Figure 1: DMSO gel viscosity as a function of polymer loading. (MARTIN POOLE/GETTY IMAGES) 

Carbohydrates and miscellaneous excipients.

 Some carbohydrates are freely soluble in DMSO (e.g., β- and D-lactose, sucrose). Table IV provides solubility data for various polymeric excipient products, carbohydrates, and some miscellaneous materials. 

Table IV: Miscellaneous excipient solubilities in dimethyl sulfoxide.* 

 DMSO interacts physically with many polymeric materials (swelling, dissolution). As such, high-density polyethylene, high-density polypropylene, and polytetrafluoroethylene are the only materials suitable for packaging a product containing high levels of DMSO. Product formulations using DMSO with other cosolvents or ingredients should perform package testing to confirm compatibility. 

 Dimethyl sulfoxide, USP, PhEur is a highly pure pharmaceutical product and does not have the odor that has been associated with some industrial materials. When purified, DMSO is essentially odorless.  

Compendial status and manufacturing aspects.

 that reference DMSO (19). These are dimethyl sulfoxide gel, dimethyl sulfoxide irrigation, and dimethyl sulfoxide topical solution. A monograph is established in the 

Dimethyl sulfoxide USP, PhEur is manufactured in the US under Q7 good manufacturing guidelines established by the International Conference on Harmonization (ICH) for APIs.  These guidelines have been adopted by FDA. The chemistry, manufacturing, and controls (CMC) of DMSO are described in a type II drug master file on file with FDA and 

. Applicants may reference the drug master file through its holder, Gaylord Chemical Co. LLC. Dimethyl sulfoxide USP, PhEur is certified kosher parve. 

Dimethyl sulfoxide USP, PhEur does not hold generally regarded as safe (GRAS) status as defined in sections 201(s) and 409 of the US Federal Food, Drug, and Cosmetic Act. As such, the product is not intended for food use and is subject to premarket review in food applications. DMSO has no existing food applications. 

As provided in its "Q3C Impurities: Residual Solvents" guidelines, ICH further designates DMSO a Class 3 residual solvent when used in the manufacture of pharmaceutical products. Class 3 solvents are those considered to represent a low toxic potential (21). 

 Any discussion of DMSO in pharmaceutical applications would be incomplete without mentioning the "wonder drug" status defined for DMSO in the public and lay press in the 1960s and 1970s (22). As important, the public's fascination with—and in some cases, abuse of—DMSO has undoubtedly influenced the approval process for formulated drug products that contain it.

The emergence of DMSO as a cryopreservation agent to preserve living cells and tissue dates back to the early 1960s (24). Dr. Stanley Jacob (an assistant professor of surgery at Oregon Health & Science University) became aware of this property and approached the Crown Zellerbach Corporation. Crown Zellerbach was considering potential commercial applications for the material, which was readily available from its paper–wood products businesses. Dr. Jacob went on to describe the use of DMSO to treat a number of human ailments, including wound treatment, arthritis, and pain relief. In 1964, Crown Zellerbach received IND status for DMSO and granted licenses to six major pharmaceutical companies in the US to develop pharmaceutical applications for DMSO. Among these were Merck and Co., American Home products, Squibb and Sons, Schering, and the Syntex Corp. (23). 

Rubin's report in 1965 that DMSO could cause lenticular changes in certain laboratory animals caused FDA to temporarily halt clinical trials involving DMSO. FDA relaxed its ban the following year but limited research to certain untreatable conditions (such as scleroderma). Continued research into any ocular effects that DMSO might have on humans suggests that such damage is species dependent and is not seen in human subjects (24–26). 

A groundswell of popular interest in the medicinal properties of DMSO arose in the late 1970s, and an effort to legitimize (and legalize) the use of DMSO in medical applications was pursued. In the early 1980s, the public perception that DMSO was being unfairly persecuted by FDA was aired in the popular press. The CBS television show "60 Minutes" presented a segment favorable to this idea (27) and Senator Edward Kennedy (D-MA) chaired a Senate Subcommittee meeting to examine the treatment of DMSO by FDA (22). 

During the past two decades, it would seem that many concerns surrounding the safety of DMSO have largely subsided. A DMSO product suitable for use in humans and that is manufactured according to FDA requirements is available for regulated applications, and the products described previously are being marketed worldwide.  

In addition, the case for DMSO as a panacea for an array of health problems also may be eroding. Although it is likely that DMSO has functionality in many therapy types, it is clear that much fervor has resulted from subjective evaluation and anecdotal experience. Many DMSO "wonder drug" claims have been evaluated in the M.D. Anderson Cancer Center's CIMER DMSO National Standard Patient Monograph (28). 

The regulatory concerns governing DMSO use in regulated applications may be similarly subsiding. It seems likely that the public's excitement over DMSO had a significant impact on the early development of regulated pharmaceutical products that would benefit from its inclusion. One author makes the interesting point that FDA most strictly regulated DMSO research at the same time as the Kefauver–Harris amendment was being drafted in the US as a response to the Kevadon/thalidomide tragedy in the mid 1960s (22).

The toxicology, pharmacology, and metabolic aspects of DMSO have been studied extensively (10, 29). Perhaps the most complete summary of acute/chronic toxicity data, ecotoxicity, and environmental pathway information is available as part of the high production volume (HPV) chemical filing on behalf of a Dimethyl Sulfoxide Manufacturing Consortium with the US Environmental Protection Agency (30). Based on the wealth of information available, it is a fair statement that DMSO possesses a low degree of toxicity to humans via oral and parenteral routes. DMSO is not carcinogenic and is not a reproductive toxin. It is worthwhile to point out that DMSO is used as the background solvent in biological assays of mutigenicity (Ames test). As such, it is widely recognized that DMSO is not a mutagen. Table V provides a thumbnail overview of toxicological indicators for DMSO. 

Table V: Toxicological overview of dimethyl sulfoxide (10).

Perhaps the most widely held concern around the safety of DMSO is that it "can take everything through the skin." Although it is true that DMSO itself can penetrate skin and does enhance the penetration rates of some chemical compounds (31), no solvent has the universal ability to fully negate the barrier properties of human skin. Indeed, it is not widely recognized that all dipolar aprotic solvents have this ability to some extent, and that N-methylpyrollidone is essentially as effective as DMSO in terms of skin penetration (32). Moreover, when water is present as a cosolvent in the formulation, the penetration kinetics of DMSO are greatly diminished. Unlike other solvents, DMSO itself is largely harmless when applied dermally; the LD-50 dermal value for DMSO is quite high (40 g/kg, rat) (9). The larger issue is its ability to facilitate dermal transport of unwanted materials into the body.   

In a general sense, large molecular-weight entities (e.g., polymers, proteins) are unlikely to undergo penetration enhancement when applied in DMSO solution (32, 33). Likewise, DMSO does not uniquely accelerate the absorption of all small-molecule chemical classes (33). In many cases , some assumptions may be made to chemically analogous materials that have been tested for this effect. For situations in which safety is a concern, appropriate tests (e.g., in vitro Franz Cell evaluations, animal study) should be considered to ascertain whether DMSO plays any role in enhancing unwanted dermal penetration of formulation components.  

Lastly, some have expressed concern about the garlic- or onion-like  taste and odor experienced by patients who have ingested DMSO or have had DMSO applied to their skin. This side effect is attributable to a specific DMSO metabolite: dimethyl sulfide (DMS), a component of natural onion and garlic flavors. The low toxicity level of this compound is further exemplified by its inclusion in the US Food Chemical Codex, and as a synthetic flavoring substance and adjuvant (

 21 section 172.515) in the United States (12). 

Once a medical curiosity, dimethyl sulfoxide (DMSO) is now incorporated into a number of regulated products for healthcare and drug delivery applications. Perhaps the most important features of DMSO as an excipient include its use to stabilize formulated products and its ability to solubilize many difficult-to dissolve materials.  

A GMP-produced compendial product (Procipient dimethyl sulfoxide, PhEur) is now commercially available for pharmaceutical applications. This ensures that a pharmaceutically acceptable product which is suitable for use in human applications is reliably attainable.

Regardless of past history, dimethyl sulfoxide USP, PhEur is a versatile and safe material that has much to offer as an excipient product. The number of regulated pharmaceutical products and delivery systems that contain dimethyl sulfoxide USP, PhEur has increased in recent years, and it appears that the positive trends supporting this product will continue. 

 is director of technology at Gaylord Chemical Company LLC, 209 Industrial Parkway, Bogalusa, LA 70433, tel. 985.732.6308, fax: 985.732.6317. 

 is director of business development at Gaylord Chemical Company LLC

*To whom all correspondence should be addressed. 

*Submitted: Oct. 22, 2007. Accepted: Dec. 5, 2007. 

 1.  J.G Harter, "The Status of Dimethyl Sulfoxide from the Perspective of the Food and Drug Administration," 

 2.  L.F. Rubin and K.C. Barnett, "Ocular Effects of Oral and Dermal Applications of Dimethyl Sulfoxide in Animals," 

Agents Used to Treat Interstitial Cystitis in A.M.A Drug Evaluations 

 (American Medical Association, Chicago, IL 4th ed., 1980), pp. 617–618. 

5.  R.G. Strickley, "Solubilizing Excipients in Oral and Injectable Formulations," 

6.  FDA Center for Drug Evaluation and Research, Inactive Ingredient Database,  

www.accessdata.fda.gov/scripts/cder/iig/index.cfm

 (Sept. 14, 2007), accessed Mar. 14, 2008. 

Onyx Liquid Embolic System: Instructions for Use

8.  R.R. Dmochowski, "Tegress Urethral Implant Phase III Clinical Experience and Product Uniqueness," 

9.  E.R. Smith, Z. Hadidian, and M.M. Mason, "The Single and Repeated Dose Toxicity of Dimethyl Sulfoxide," 

10.  C.F. Brayton, "Dimethyl Sulfoxide (DMSO): A Review," 

 (General Services Administration, Washington, DC, Jan. 19, 2001), Part 1271.10 (a). 

12.  Organon Tenika, NucliSens HIV-1Q (Nov. 13, 2001), 

13.  A. Aliago et al., "A Topical Solution of 40% Idoxuridine in Dimethyl Sulfoxide Compared to Oral Acyclovir in the Treatment of Herpes Zoster. A Double-Blind Multicenter Clinical Trial," 

14.  A. Ely and B. Lockwood "What is the Evidence for the Safety and Efficacy of Dimethyl Sulfoxide and Methylsulfonylmethane in Pain Relief?" 

15.  Gaylord Chemical, Dimethyl Sulfoxide (DMSO) Solubility Data, (Sept. 2, 2007), 

www.gaylordchemical.com/bulletins/Bulletin102B/index.htm

16.  R.C. Rowe, P.J. Sheskey, and S.C. Owen, 

The Handbook of  Pharmaceutical Excipients 

 (Pharmaceutical Press, London, UK, 5th ed., 2006) 

17.  R.Woodford and B.W. Barry "Penetration Enhancers and the Percutaneous Absorption of Drugs: An Update" 

18.  G. Kvakovszky and A.S. McKim, Gaylord Chemical Company LLC, previously unpublished data.  

 23 (United States Pharmacopeial Convention, Inc., Rockville, MD, 2005), pp. 662–664. 

 (Council of Europe, Strasbourg, 2002), p. 1055. 

21.  ICH, Q3C : Impurities: Residual Solvents, 

www.fda.gov/cder/audiences/iact/ICH_Q3C.htm

The authors survey the approved applications of dimethyl sulfoxide USP, PhEur across the healthcare industry and consider the suitability of DMSO from a regulatory and formulation compatibility standpoint.