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Microemulsion (ME) Formulation

How To Develop A Microemulsion (ME) Formulation

Microemulsion are, by definition, optically clear dispersion of one physically incompatible liquid into another. Microemulsions may be defined as oil dispersed in water or water dispersed in oil; where, the oil phase can be either a liquid technical or a solid technical in solution with an appropriate water insoluble organic solvent.

Aside from matching and maintaining equivalent densities of both oil and water phases under all temperature conditions, it is impossible to uniformly disperse two mutually incompatible liquids without the addition of surfactants. Surfactant function to stabilize the oil/water or water/oil interface since, by their composition, they are single molecules with one "end" that is soluble in water and one "end" that is soluble in oil. By changing the molecular structure of the water soluble end and/or the oil soluble end, it is possible control the degree to which the surfactant solubilizes into the water or oil (at the expense of the other phase). This is referred to as "partitioning" between the water and oil phases. In order to delineate the partitioning effect of a surfactant into water and oil, an arbitrary numerical system has been established which considers the ratio of the water soluble to oil soluble components of a surfactant molecule. This calculated number is referred to as the Hydrophilic-Lipophilic Balance (or, HLB); where, the smaller the HLB value, the more oil soluble the surfactant.

There are three (3) factors that determine whether water or oil is the continuous phase of a microemulsion:

  1. surfactant composition

  2. surfactant quantity

  3. temperature change


Surfactant Composition: Traditionally, it has been believed that continuous phase formation has been dictated by the structure of the surfactant used to formulate the microemulsion. In order to form an oil in water microemulsion, a surfactant containing a large hydrophilic end and a small lipophilic end would sterically 'drive' the emulsion in that direction. Conversely, in order to form a water in oil microemulsion, a surfactant containing a small hydrophilic end and a large lipophilic end would sterically 'drive' the emulsion in that direction.

However, current microemulsion technology has been extended to include surfactant classes that do not use steric hindrance as a means to establish interfacial stability. These include Synperonics® 91/2.5, 4, 5, 6, 7, 8, 10, 12 (polyoxyethylene synthetic primary alcohols) and Atlox® MBAs 11/6, 7, 8, 9, 10 (monobranched alcohol alcoxylates).

The advantage to the Synperonic® and Atlox® MBA surfactant classes involves their ability to formulate higher concentration, lower viscosity microemulsions: less space being taken up by the surfactant in the continuous phase, allowing more room for formulated liquid and less opportunity for the surfactant molecules to "bump" into each other.

Surfactant Quantity: Surprising, ANY ethoxylated nonionic can be used to formulate a microemulsion!!! It merely comes down to a question of performance and cost. Here, the determining factors are the ratio of surfactant to organic liquid required, the temperature(s) at which the microemulsion is to be physically stable, and the performance of the microemulsion upon dilution (if not an RTU, or Ready To Use product). With low ethoxylated nonionics, the formulation may require 99%W/W surfactant, 0.5%W/W technical, and 0.5%W/W water to formulate an optically clear microemulsion. However, upon application dilution, the formulation may separate into oil and water phases since the surfactant system is unable to accommodate (partition adequately) the 'new' solvent system: formulation solvent(s) + application volume.

Likewise, highly ethoxylated nonionics, which are solids at room temperature, may find their application in microemulsions formulated to be physically stable at elevated temperatures where they would exist in a liquid state. The obvious limitation to use of solid surfactants at room temperature would be exceeding the solubility limit of the surfactant in the formulation water/ organic solvent solution.

Where the amount of water is kept constant at 10%W/W, microemulsions can be formulated over a range of organic solvent to emulsifier ratios. As the %W/W of organic solvent in the formulation increases, the microemulsion shifts from oil/water to water/oil (as measured by continuous phase conductivity). Microemulsions, formulated in this manner, may range in assay from 10%W/W (low ethoxylation) to 50-60%W/W and demonstrate a range of emulsion performance upon dilution depending upon the surfactant composition being evaluated.

Within each surfactant class (hydrophobe structure), there is a specific degree of ethoxylation that will result in a clear microemulsion at room temperature which requires a 1:1 ratio of organic solvent:surfactant and at least 60%W/W water. Interestingly, this specific surfactant composition may involve blending of two nonionic surfactants of successive moles of ethoxylation that by themselves will not form a microemulsion. This degree of ethoxylation requirement will change as the organic solvent composition changes and as application at temperatures other than room temperature is required. Although the A.I. concentration is relatively low (<20%W/W), there are formulation savings incentives versus traditional Emulsifiable Concentrate (EC) formulations of equivalent concentration. The savings arise from the replacement of organic solvent with water in the formulation. Again, emulsion performance upon dilution may vary; however, in most cases, where the optimum surfactant composition is selected, the microemulsion maintains its optical clarity upon dilution.

Temperature Change: Surfactant partitioning between the water and oil is affected by temperature. As the tem- perature of the oil/water (or water/oil) dispersion increases, the surfactant 'moves' from the water phase to the oil phase. In the absence of oil, as the temperature increases, the surfactant forms larger and larger micelles in the water until it reaches the point where it becomes completely water insoluble. This is called the Cloud Point and is characteristic of the surfactant composition; the higher the degree of ethoxylation, the higher the surfactant Cloud Point.

Where the water content is approximately equivalent to the content of the oil phase of a microemulsion, it is possible to cause an oil/water microemulsion to invert to a water/ oil microemulsion by raising the temperature of the microemulsion above the Cloud Point of the surfactant. This is referred to as the Phase Inversion Temperature (or PIT) and is accomplished in the presence of high agitation.

The physical stability of the phase inverted microemulsion is dependent upon the compo- sition of the surfactant used. Those that are thermodynamically formed, as opposed to their sterically preferred state, will revert back to the most stable form under stress. However, those that are formed using the interfacial 'balance' of hydrophobic and lipophobic components (such as the Synperonic® 91/ series and Atlox® MBA 11/series) demonstrate very good physical stability.

Microemulsion Development:
 To develop a microemulsion involves a series of steps:

  • Establishment of performance criteria

  • Selection of formulation inerts

  • Selection of processing equipment

  • Establishment of test procedures

  • Determination of a development methodology


Establishment of performance criteria:


  • Formulation concentration: dictates formulation composition. At technical con- centrations approaching 30%W/W, the formulation cost of a microemulsion approximates that of an emulsifiable concentrate assuming 1:1 weight ratio of technical:emulsifier (SEE: Technical Bulletin 99-07 Formulation Cost: Emulsifiable Concentrate VS. Microemulsion"). Where the concentration of surfactant is not restricted to a 1:1 weight ratio to the technical (and cost is not a major issue), it is possible to extend the number of 
    acceptable surfactants within a surfactant class considerably.

  • Optical clarity both as a concentrate and upon dilution: is a function of the proper selection and quantity of emulsifier that can maintain small emulsion particle size over a wide range of dilutions in water. Since emulsifiers function at the water/solvent interface, the greater the quantity of emulsi-
    fier, the smaller the particle size.

  • Optical clarity over a temperature range: is an indication that the partitioning of surfactant selected does not change dramatically over the temperature range tested. Microemulsion haziness is an indication of increased 
    particle size due to discontinuous phase agglomeration.

  • Optical clarity over a range of water hardnesses: suggests that the emulsifier system selected can tolerate a known concentration of salts in the water phase before it impacts the surfactant partitioning between phases and, ulti-
    mately, emulsion particle size.

  • No phase separation over a temperature range: can be accomplished either by the addition of more surfactant (low HLB at reduced temperatures; high HLB at elevated temperatures) or by the addition of an organic polar co-solventwhich demonstrates solubilty in both the water and oil phases. Obviously, the greater the solubility in both oil and water, the more effect the cosolvent.

  • Flashpoint: is related to the choice of co-solvent. The more effective the micro- emulsion co-solvent, the lower is its flashpoint. Therefore, it is necessary to either restrict the quantity of co-solvent in the formulation (and compensate by additional surfactant) or select a co-solvent with an acceptable flashpoint.

  • Odor: may be associated with either the technical or choice of co-solvent. When associated with the technical, it may be possible to reduce odor by means of incorporating a chelating agent into the formulation. Where odor is
    associated with the choice of co-solvent, another polar solvent (for example, propylene glycol) may perform acceptably at increased concentrations.
    Alternatively, "masking agents" may be incorporated into the formulation
    to 'hide' the odor.


Selection of formulation inerts: Where governmental regulations/agencies strongly suggest use of specific inert classes in order to expedite product registration, it is best to determine their appropriateness in the new formulation before investigating "new" technologies which do not offer fundamental advantages. In this regard, always obtain from the supplier written documentation that the solicited inert meets all relevant governmental approval requirements.

Assuming that the formulation active ingredient concentration has been established*, inerts must meet the needs for which they were intended in the microemulsion. For example, it is necessary to identify and establish the concentration of an appropriate solvent to maintain a solid technical in solution under the expected storage conditions. How the solubility is determined is critical to the formulation performance.

Since surfactant performance is affected by the solvent composition, it is best to leave the emulsifier choice/concentration till last.

Also, any adjustments to the proposed formula, to account for technical assay variability, should be made with the continuous phase solvent.
[* See Technical Bulletin 99-01: "Calculating an Emulsifiable Concentrate (EC) or Suspension Concentrate (SC) Formula" for assistance in this area.]

Selection of processing equipment: Microemulsion formulations may be processed in the laboratory using a beaker equipped with a propeller-type mixer. In production, this converts to a mixing tank equipped with an in-tank agitator. 

Order of addition is critical to microemulsion performance. It is necessary that organic components be uniformly blended before water is added to the formulation. This includes dissolution of the solid technical, where appropriate, into solvent prior to addition of emulsifier.

 

Correction of low batch assay may prove a bit problematic since addition of technical directly to the microemulsion may not be physically acceptable to the formulation. In this situation, it may be best to add the technical in combination with the emulsifier at the ratios listed in the formula.

Excess shear during processing may result in the formation of foam due to air incorporation. Therefore, the amount of shear placed upon the formulation during processing should be regulated. In addition, it is important to be cognizant of processing equipment batch size limitations, both upper and lower limits, in order that the equipment is used efficiently to properly incorporate formulation components.

Generation of heat during processing, as a result of excess shear, may adversely affect microemulsion performance since emulsifiers partition as a function of temperature.

Determination of a development methodology: There are two approaches that can be taken to expeditiously develop a microemulsion where the active ingredient concentration has been established:

    1. Select an emulsifier and then determine its requirement in the formulation

    2. Establish an emulsifier requirement and then determine which emulsifier meets that requirement


With the first approach, the development methodology becomes one of blending three components where one of the components is the emulsifier of interest, another is the continuous phase solvent, and the last component would be an evaluation of the need to include a "coupling" solvent.

Where the active ingredient concentration has not been established, the development methodology becomes a process of blending four components.

The actual mechanics of blending either three or four components is addressed in Technical Bulletin 99-3: "Experimental Design: Optimizing Surfactant Blends for Emulsification Properties."

With the second approach, the basic microemulsion formula has been established and each emulsifier (or blend of emulsifiers) is substituted directly into the formula.

Whereas the first approach allows for the evaluation of individual component interaction, the second approach does not. However, the first approach may require a significantly greater time/resource commitment due to the number of sample preparations required, the second approach may be accomplished in a relatively short time frame if the "right" emulsifiers are identified upfront.

It is important to realize that an Experimental Design approach does not guarantee the successful development of a microemulsion formulation. It still falls upon the formulation chemist to select the excipients to be evaluated, to determine the impact of the processing equipment upon the formulation, and whether the formulation performance is impacted by the application equipment..

What Experimental Design does do is to provide the formulation chemist with a "road map" to monitor whether the changes in formulation inerts, processing equipment, and application equipment are taking him/her closer to or farther from their ultimate destination: a commercial product.