The recording of our recent webinar, entitled "Commercial Production of Water-Soluble THC & CBD by High-Intensity Ultrasound", featuring Dr. Alexey Peshkovsky as a speaker, is now ready. The webinar, which was held on Wednesday, May 13th, 2020, had over 400 registered participants and generated close to 200 questions. Some of these questions were addressed by Alexey during the webinar, the answers to the rest are provided in this post. If you have any additional questions, please do not hesitate to contact us or leave a comment below.
Webinar Recording:
Webinar Questions & Answers:
1. What potential exists for cbd delivery with ethosomal suspension?
Ethosomes are very promising for topical and, possibly, transdermal CBD delivery. For beverages, these formulations are not likely to be appropriate due to their high ethanol and glycol content.
2. We have another ultrasonic processor, not manufactured by you and we tried to order your emulsifier surfactant but were told we could not buy it unless we purchased your equipment. In the future will you sell the emulsifiers separately to companies like mine?
We currently offer NanoStabilizer® without restrictions. Please keep in mind, however, that it was designed to work in conjunction with our Barbell Horn Ultrasonic Technology-based processors. Since third-party technology cannot be guaranteed to establish the combination of conditions required for the correct performance of this product, our SOPs would not apply. Here is a link to our web store where you can purchase NanoStabilizer®: https://sonomechanics.myshopify.com/products/nanostabilizer
3. Would you please compare Sonomechanics system to other ultrasonic manufacturers?
This question was answered during the webinar. Please see timestamp 0:57:12 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
4. What, in your opinion, is the reason we are not seeing more cannabis beverages on the market?
This is an emerging technology, and most providers and consumers are not familiar with it yet. We believe this will change with time.
5. We have heard that some cannabis beverages packaged in cans in Canada, have reportedly lost their potency quickly, due to some reaction with the can lining. Are you aware of this? Are there issues in packaging choices for nanoemulsions?
This question was answered during the webinar. Please see timestamp 0:52:57 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
6. Do you have reference studies for why MCT oils are not good carriers for CBD nanoemulsions? Why LCT vs. MCT? What makes the long chain oils more effective than medium chain oil for the nanoemulsion? Why are MCTs not a good carrier oil?
This is a good reference on the subject: Qian C, Decker EA, Xiao H, McClements DJ. Nanoemulsion delivery systems: influence of carrier oil on ß-carotene bioaccessibility. Food Chem. 2012 Dec 1;135(3):1440-7. doi: 10.1016/j.foodchem.2012.06.047. Epub 2012 Jun 29.
7. Explain "high-shear" requirements in greater detail. Is this ALWAYS necessary to create nanoemulsion? Can you create good quality nanoemulsion without high shear? Even possibly a comment on theoretically thoughts or lower vs. upper limits?
Nanoemulsions cannot be created without high-shear equipment, however, microemulsions can. This question was answered in detail during the webinar. Please see timestamp 01:01:04 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
8. What is advantage of using NanoStabilizer® vs. Span80+Polisorbat80 composition?
This question was answered during the webinar. Please see timestamp 0:54:38 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
9. We currently use the BSP-1200 sonicator and have been using the same horn for over a year now. We are noticing an increase in the heat production during emulsification. What metrics can we use to determine whether our efficiency has decreased and when we would need to replace the horn?
Ultrasonic horns are a lot like light bulbs - they either work or they don't. The efficiency does not diminish during a horn's lifespan (and if it did, the heat production would go down, not up). When your horn is no longer operational, the generator will report an error, at which point you should to contact us for a replacement.
10. Do full-spectrum distillate boost bio? Yes or no?
It is unclear what you mean by "bio" and "boost". If you'd like your question answered, please make it clear in the comments.
11. I have not seen any good pharmacokinetic evidence to show nanoemulsion is absorbed better. It’s a cool technology and theory, but do you have data that compares the absorption of H2O soluble THC/CBD to regular cannabinoids consumed with fat in average healthy people?
We have qualitative data on this - it was discussed in the webinar in detail. Please see timestamp 00:44:17 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
We are currently conducting a formal quantitative pharmacokinetic study to compare absorption profiles of CBD administered as edibles versus nanoemulsions in fasted and fed states. We expect to have the results available later this year.
12. Can you discuss the relationship between particle size, zeta potential, and steric repulsion. I understand that steric repulsion is more robust for emulsion stability than electrostatic repulsion as measured by zeta potential but steric repulsion is difficult to measure directly. Also, do co-block polymers need to be added to achieve steric repulsion or do some surfactants/mixtures of surfactants provide steric repulsion?
Typically, the greater is the ability of surfactants used in the formulation to create electrostatic or steric repulsion between droplets, the smaller is the resulting droplet size in the nanoemulsion and the better is its stability. Electrostatic repulsion (created by ionic surfactants and quantified by zeta potential) works well in situations where the pH and ionic strength are known and not expected to change, as both of these factors can affect the zeta potential and product stability. Steric repulsion (created by non-ionic surfactants), on the other hand, is mostly independent of the pH and ionic strength, and preferred for nanoemulsions used as beverage additives. It cannot be measured directly but can be quantified through droplet size distribution measurements. Block copolymers can be used to establish steric repulsion, however, there are many small-molecule non-ionic surfactants (e.g., polysorbates) that can create strong steric repulsion as well.
13. How does nano-emulsion impact the stability of the THC/CBD, if at all?
Nano-emulsification does not impact the chemical stability of THC or CBD. This subject was discussed in the webinar, please see timestamp 00:43:05 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
14. At what nm size do cannabinoids start to become so small that they break up and turn into difference substances?
At the sizes of individual molecules - about 1 nm for CBD and THC. In other words, breaking up a molecule (not just reducing the size of a droplet) constitutes a chemical (as opposed to physical) transformation, yielding substances other than the original cannabinoids.
15. Have you guys tried to go higher in concentration for your CBD EMULSION, something like 200mg/ml?
Yes, 200 mg/ml is not difficult to achieve as long as translucency is not required and the Median Droplet Size is permitted to exceed ~ 200 nm.
16. At what temperatures do the nano emulsions break down and become unstable?
This question was answered during the webinar. Please see timestamp 0:48:52 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
17. Are there some flavours/formats that are better than others for beverages (eg. juice vs. tea)?
The following blog article contains information on flavoring nanoemulsions: http://blog.sonomechanics.com/blog/managing-the-bitter-taste-of-cannabis-infused-beverages
18. Regarding shelf life, how long does it take for homogeneity to break down? This would be similar to orange juice where it needs to be shaken to have particles properly dispersed?
This question was answered during the webinar. Please see timestamp 0:49:45 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
19. We have heard rumor that nano-emulsions have some application difficulties with aluminum cans and the liners featured in them. Can you elaborate on application challenges of nano-emulsions sticking to different types of materials and surfaces?
This question was answered during the webinar. Please see timestamp 0:52:58 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
20. How much carrier oil, do you propose in compared to cannabis extract? What ratio do you propose?
About 2:1 carrier oil to cannabis extract or isolate is typically recommended.
21. Does filtration change the mg/ml ratios?
This question was answered during the webinar. Please see timestamp 0:50:52 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
22. I have a 50 watt ultrasonic processor. Will your nanoemulsion work with that unit?
It depends on the maximum amplitude your unit is able to generate. If it can achieve about 80 microns peak-to-peak, then it should be able to process about 10 - 15 ml of nanoemulsion at a time.
23. Saying transmucosal administration is inefficient is not an accurate statement. Studies are showing that THC/CBD taken through sublingual & the buccal route has a much more rapid onset (roughly 15 mins). Do you have data showing that nano emulsified THC/CBD outperforms oil-based THC/CBD? Most of this sounds highly speculative based on the mechanism of action.?
The term "inefficient" was used in reference to transdermal administration, not transmucosal. Please see timestamp 0:06:08 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
Transmucosal absorption is indeed known to be fairly quick. It was discussed earlier in the presentation, see timestamp 0:05:24 of the recording.
Our qualitative data, comparing the effects of THC administered as edibles versus nanoemulsions in fasted and fed states, was discussed in the webinar in detail. Please see timestamp 00:44:17 of the recording.
24. Are there formulation or packaging considerations to take into account when putting into a beverage? For example, does ph or bird affect the solubility and I’ve heard people having inconsistent testing results when using aluminum can packaging?
The behavior of correctly prepared nanoemulsions is pH and ionic strength-independent in a fairly wide range, covering most beverages.
Aluminum can packaging may or may not create an issue. This question was addressed during the webinar. Please see timestamp 0:52:58 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
25. What if any are the differences in making the liquid or the powder? How is the powder nanoemulsion made? What is the process of making nanoemulsion into a powder? What is the required hardware to achieve water soluble powder?
Making a liquid nanoemulsion is the first step in the process of producing a nanoemulsion powder. It is followed by the addition of a suitable binder and, typically, spray drying.
26. What are some natural surfactants?
Quillaja Saponin, Lecithin and Gum Arabic are typically considered the most effective natural surfactants.
27. How exactly does light affect the stability of emulsions? Does the cannabinoid profile or potency brake down under light conditions?
This question was addressed during the webinar. Please see timestamp 00:43:04 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
28. What prevents the excess surfactants from forming micelles with themselves (in microemulsions)?
Nothing prevents this process from occurring when significant excess surfactants are present. Microemulsions, which have high excess surfactant concentrations, typically comprise such micelles in large quantities. Correctly designed nanoemulsions, on the other hand, are made under surfactant-starvation conditions, ensuring complete surfactant absorption to droplet surfaces with no excess remaining for micelle formation.
29. What are the particle size range and concentration of your cannabinoid nanoemulsions?
Generally, our target is 20 - 40 nanometers (d50, volume distribution) for cannabis extract concentrations up to 50 mg/ml.
30. How does Phenoxyethanol alter nanoemulsion stability?
To the best of our knowledge, phenoxyethanol does not affect the stability of nanoemulsions prepared with NanoStabilizer.
31.Can you oversonicate, in terms of time and amplitude? Will it destroy cannabinoids? Can you run the solution too long? Does it degrade the nanoparticle?
This question was answered during the webinar. Please see timestamp 0:55:46 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
32. Are there any other fats that need to be avoided in the formulation of edibles that affect the bioavailability and the absorption of THC/CBD? Any shelf life of these products before they start to lose their stability? Are these product temperature sensitive? Any problems with these products being stuck on the wall of the drink bottles? What is the best bottle material that a company can use to avoid precipitation of these nanoemulsion products for drink products?
Most LCTs work well as carrier oils. Our recommendation, however, is to avoid unsaturated oils, which have the potential to become oxidized.
The subject of stability/shelf life was discussed in the webinar, please see timestamp 00:43:05 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
Correctly prepared nanoemulsions are stable against droplet size increase, flocculation and separation in the temperature range of about 0 - 90 C (32 - 194 F).
The question about the potential of the droplets to stick to container walls and the best material to use was answered during the webinar. Please see timestamp 0:52:58 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
33. Is there a reason not to have amplitude and frequency at the maximum on the runs?
The frequency is not under the operator's control, it is automatically adjusted to the optimal value by the ultrasonic generator.
The amplitude should be sufficiently high (typically, about 80 - 90 microns peak-to-peak) to get the desired effect but should not exceed this level in order to minimize unnecessary equipment wear.
34. Are there different variations of your premix?
This question was answered during the webinar. Please see timestamp 1:02:03 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
35. How pH stability of a given nanoemulsion?
Correctly prepared nanoemulsions are stable in a wide pH window.
36. If making a nano formulation for use in lemonade beverage that would require pasteurization. What would u recommend for carrier oils/ surfactants that will remain stable thru process?
As long as the pasteurization process occurs under about 90 C (194 F), there should be no destabilization of the incorporated nanoemulsions made with NanoStabilizer. As an option, it is typically possible to pasteurize the beverage before the addition of the nanoemulsion, which should be passed through a sterilizing filter (hydrophilic membrane with 220 nm pores).
37. What would be the best delivery method for cannabis additive, steam distillate? Would pressed rosin be acceptable?
Our opinion is that the most efficiently-delivered form of any type of cannabis extract (including steam distillate and pressed rosin) is a nanoemulsion-infused beverage.
38. Have you found a direct correlation between shelf life/stability and pH? Some water soluble formulations are not effective with citrus-based carbonated beverages?
We have not observed this effect with NanoStabilizer-based nanoemulsions. They are stable in citrus-based carbonated beverages, to the best of our knowledge.
39. Does the viscosity of the cannabis oil play a factor in production?
This question was answered during the webinar. Please see timestamp 0:59:16 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
40. What's the maximum loading of CBD in the nanoemulsion?
This question was answered during the webinar. Please see timestamp 01:00:04 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
41. How important is a filtration step following nano-emulsion formation using Sonomechanics' equipment since my understanding is that minor amounts of metal can end up in the emulsion? What filter size is recommended?
Sterile filtration is an important post-processing step of ultrasonic nano-emulsification. Passing a translucent nanoemulsion through a hydrophilic filter membrane with 220 nm pores removes practically all particulate contamination it may contain, including any microorganisms (sterilization), dust, titanium particles shed by the ultrasonic horn, leftover plant matter, etc. For further information on this subject, please see:
http://blog.sonomechanics.com/blog/should-i-filter-my-water-soluble-cannabis-nanoemulsion
42. What was your target HLB for your oil in water emulsions with CBD and does HLB differ for THC and CBD?
The required HLB is typically in the range of 11 - 13, both for CBD and THC.
43. I have made hard candy with the nanoemulsion, heated to 300F and when the hard candy is sucked for a period of time, it has a quick onset, but I found using isolmalt does not allow for a fast onset. I wonder if this is because isomalt does not absorb water as well as sugar so it doesn't allow it to go back to nanostate.
It is likely that the nanoemulsion destabilizes in the candy when heated to this temperature, resulting in a broad droplet size distribution and unreliable onset time. Our recommendation is to measure droplet size distributions after reconstitution in water to verify stability.
44. What is the ideal filter material so as not to adsorb droplets?
We recommend hydrophilic polyvinylidene difluoride (PVDF) or nylon membranes.
45. Can you add other plant oils with the cannabis oils to make products?
Yes, it is typical to add other plant oils (e.g., carriers) with cannabis oils to make nanoemulsions.
46. Have you seen any issues with labs being able to test THC content by volume, after emulsion?
This question was answered during the webinar. Please see time stamp 0:52:07 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
47. Bringing to a practical business perspective (if you have seen any specific trends among your clients), how do cannabis companies MARKET their nanoemulsions & the better quality high / pharmaceutical benefit? Is it simply in the end products themselves being unique (i.e. dissolvable flavored strips, water soluble CBD / THC products, etc.) or do processors market their products as nanoemulsions? I ask because supposedly producers could achieve the same customer / patient benefit & effect with way lower CBD / THC mg/ml concentration, so theoretically BETTER but LESS POTENT products, correct? How do business reconcile making more effective but less potent products?
This market is rapidly evolving and so is the messaging associated with novel products. Our clients report experiencing constant downward pressure on pricing and upward pressure on quality, despite the unfortunate lack of universally-accepted guidelines on how quality should be measured.
We frequently hear the "stronger effect with less CBD/THC" argument. While technically correct, it cannot be truly supported without having pharmacokinetic study results for the associated products, which most companies are unable to provide. Droplet size distributions, on the other hand, are more readily available, and can serve as adequate quality indicators and bioavailability enhancement predictors. Uniqueness, especially when optical clarity is important, is another marketing aspect companies can focus on. Since translucency increases as droplet sizes are reduced, product uniqueness claims can also be supported by droplet size distribution measurements.
48. Does the nano-emulsification process oxidize the CBD?
It does not, to the best of our knowledge.
49. Is lecithin acceptable as a surfactant?
Yes, in most cases it is.
50. The temperature that the request reaches in the sonication process, damages the extract?
No, it does not.
51. Is heat production or heat buildup an issue with nanoemulsion production? You mentioned stability to 90C. Are chillers required?
It is necessary to continuously cool the nanoemulsion, maintaining the temperature of about 50 C (122 F) during processing. Each of our ultrasonic processors includes a reactor chamber with a cooling jacket (LSP-600 and BSP-1200) or a stand-alone heat exchanger (ISP-3000), which can be used to establish precise temperature control. Chillers with appropriate cooling capacities are required.
52. Are certain beverages not recommended to mix with nanoemulsions?
Any beverage can be accommodated, although formulation adjustments may be needed in some cases (e.g., with some red wines).
53. Does the cannabinoid have to be in an isolated form or could a full spectrum oil be used?
Our technology (ultrasonic processors and NanoStabilizer®) can be used to nano-emulsify practically any type of extract as well as other oil-soluble bioactives, including full-spectrum oils, distillates, isolates, vitamins, essential oils, terpenes, nutraceuticals and pharmaceuticals.
54. 1) Does the preservatives affect in the droplets size? 2) What kind of emulsifiers do you use? Synthethic or natural, like proteins, etc? 3) Have you tried any digestion model in order to analyze the behavior of the nanoemulsions in the gastrointestinal process?
1) Typically, they do not.
2) We use both types, depending on the objective. In case your question is about NanoStabilizer® – it comprises food-grade (GRAS) carrier oils, emulsifiers, and preservatives, all tasteless and derived from natural sources.
3) We have qualitative data on this - it was discussed in the webinar in detail. Please see timestamp 00:44:17 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
We are currently also conducting a formal quantitative pharmacokinetic study to compare absorption profiles of CBD administered as an edible versus a nanoemulsion under fasted and fed conditions. We expect to have the results available later this year.
55. Is a nanoemulsions broken when formulating a lotion via a high temp oil in (CBD) water emulsion?
It depends on the temperature. Nanoemulsions prepared with NanoStabilizer® are stable against droplet size increase, flocculation and separation in the temperature range of about 0 - 90 C (32 - 194 F).
56. Which container is the best to hold and maintain beverages with nanoemulsion thc/cbd?
Dark glass is the best option. This question was answered in detail during the webinar. Please see timestamp 0:43:04 of the webinar recording: https://youtu.be/J_WwxbCRSIQ
57. Why are liposomal (lecithin) based nano-emulsion always milky white?
Liposomal nanoemulsions do not exist. Please see the following timestamp 00:17:10 of the webinar for more information: https://youtu.be/J_WwxbCRSIQ
Lecithin-based nanoemulsions are typically milky white when their droplet sizes are larger than 100 nm.
58. Are there certain surfactants that lead to indigestion or diarrhea?
Yes, when taken in excessive quantities (e.g., as part of a microemulsion), many surfactants can lead to such issues.
59. How does nano emulsification affect efficacy and stabilization of a topical vs. traditional methods?
The use of nano-emulgels in topicals has been shown to be very advantageous in terms of bioavailability. This is a good review on the subject:
http://iosrphr.org/papers/v5i10/F0510043047.pdf
60. If the cannabis nanoemulsion is introduced to a beverage, is the stability affected?
Stability will not be affected in most cases.
61. Do you supply the correct times for inline sonication for the quantities processed, 5 liters or 10 etc. also the amplitude to use? I just ordered your bench scale unit.
When producing translucent nanoemulsions with up to 50 mg/ml of a hydrophobic bioactive (full-spectrum oils, distillates, isolates, vitamins, essential oils, terpenes, nutraceuticals, pharmaceuticals), in conjunction with NanoStabilizer®, the productivity rates of our ultrasonic processors are as follows:
LSP-600: approximately 1 L/hr (up to 5,000 doses/hr, 10 mg/dose),
BSP-1200: approximately 5 L/hr (up to 25,000 doses/hr, 10 mg/dose),
ISP-3000: approximately 20 L/hr (up to 100,000 doses/hr, 10 mg/dose).
The recommended ultrasonic amplitude is 80 microns peak-to-peak. NanoStabilizer® comes with detailed processing instructions and makes it unnecessary for our customers to develop their own formulations.
62. What is the highest CBD concentration that can be achieved with your equipment and NanoStabilizer and yield an average nanoparticle size of 100 nm?
About 150 mg/ml, depending on the type of extract. It will not be translucent above approximately 50 mg/ml.
63. Will caffeine effect the dose?
Caffeine will not have any effect on the cannabis extract dose present in a given volume of a nanoemulsion.
64. What would u recommend the best Long chain triglyceride to use in formulating nano-emulsion for beverage would be?
Most LCTs work well. The choice is commonly based on the flavor profile or health-related considerations. Typically, soybean, olive and coconut oils are used, but fish oil and other less common LCTs can be selected as well.
65. Are there any informal or formal studies that demonstrate bioavailability, absorption of nanoemulsified products vs. non-nanoemulsified products?
There are many bioavailability enhancement studies done for nanoemulsions, such as the one mentioned in this webinar. We have not yet seen any quantitative studies done for cannabis nanoemulsions specifically.
66. We’ve talked a lot about THC & CBD… but I am curious of your thoughts on Terpenes and the use of a full spectrum cannabinoid oil. Are there difficulties using a true full spectrum cannabinoid extracts including terpenes?
Not at all, in fact, it is typically easier to work with full- and broad-spectrum extracts, specifically due to the presence of terpenes. It is also possible to make nanoemulsions from isolated or mixed terpenes, essential oils and similar bioactives. The procedure remains the same.
67. How much is your equipment?
For pricing, please contact us via:
https://info.sonomechanics.com/main-contact-us
