Crystallization of Cannabinoids with Sonication
Crystallization is a necessary process step in order to produce crystalline CBD isolate. Ultrasonic nano-crystallization (sono-crystallization) is widely used to prepare crystalline isolates such as CBD isolate from a supersaturated solution. By high-power ultrasound frequency waves, intense agitation promotes the formation of pristine CBD crystals. Ultrasonic crystallization is a precisely controllable, highly efficient, and rapid method for the production of crystalline CDB isolate.
Ultrasonic CBD Crystallization
Crystallization of CBD isolate is a precipitation process in which CBD solids form in a solvent. In order to crystallize CBD, the solute (i.e., distilled CBD oil) must be dissolved in a solvent forming a supersaturated solution. Ultrasonic waves act as an external stimulus that initiates the formation of crystal seeds (nucleation) and helps to promote and control crystal growth.
Typically used solvents: pentane or heptane.
How Does Ultrasonication Promote CBD Crystallization?
Ultrasonication is a highly efficient agitation method that produces a homogeneous supersaturated solution of the CBD extract in a solvent. During the intense ultrasonic stirring of the supersaturated solution, crystal seeds can form which subsequently act as growth points for the CDB crystals. Ultrasonic agitation intensifies the mass transfer between initial crystal seeds and the supersaturated solution so that the crystals grow fast and uniformly. This means sonication is a very efficient technique to promote and control the production of CBD crystals.
What Research Says
“When ultrasound is applied to a solution for crystallization, it can affect the properties of the crystalline products significantly. Ultrasonic irradiation decreases the induction time and metastable zone and increases the nucleation rate. Due to these effects, it generally yields smaller crystals with a narrower size distribution when compared with conventional crystallization. Also, ultrasonic irradiation can cause fragmentation of existing crystals which is caused by crystal collisions or sonofragmentation.” [Kim and Suslick, 2018]
Stirred Crystallization of Cannabinoids
Ultrasonic crystallization (also known as sono-crystallization) is a form of controlled stirred crystallization, which excels conventional precipitation techniques by rapid crystal formation due to intense ultrasonic agitation. The ultrasonic stirring and mixing introduces high kinetic forces into the mixture of CBD extract and solvent. Thereby, a supersaturated solution is produced in which subsequently ultrasonic agitation promotes the mass transfer that accelerate the crystallization rate. Ultrasonic crystallization is a rapid process, which can be precisely controlled. This enables for the growth of uniform crystal size and a continuously high product quality standard. Ultrasonic crystallization allows by adjustment of the sonication parameters for the crystallization of uniform micron- or nano-sized crystals. Grow crystals to tailored size by applying established process parameters. By the application of sono-crystallization, it becomes possible to precipitate nano-sized crystals, which offer superior bioavailability and are valued by customers for higher efficiency and pronounced health benefits. The exact control over the sono-crystallization parameters gives repeatable/reproducible results. Furthermore, ultrasonic crystallization of cannabinoids can be complete linearly scaled to any production volume. As ultrasonic crystallization results in high-quality CBD isolate, downstream processes such as purification are reduced to a minimum.
- Stirred Crystallization
- Anti-solvent crystallization
- Cooling crystallization
- Melt Crystallization
- Reactive crystallization / precipitation
Ultrasonic Crystallizers for CBD Isolate Production
Hielscher Ultrasonics is your long-term experienced partner for high-performance ultrasonic crystallization processes. Hielscher Ultrasonics supplies a wide range of ultrasonic crystallization equipment for batch and continuous inline processing. Hielscher Ultrasonics’ equipment is installed worldwide in food and pharmaceutical processing facilities and fulfils highest quality standards. Suitable for process standardization, continuous high product quality and Good Manufacturing Practices (GMP), Hielscher ultrasonic crystallization systems are in line with your goals of superior production standards.
- Micron- and nano-sized crystals (adjustable)
- High efficiency
- Precisely controlled crystal growth
- Uniform crystal growth
- Pristine shape
- Singe-Pass / One-Pot process
- Repeatable, reproducible outcome
- Easy and safe to operate
High Amplitudes for Sonocrystallization
Sonication with high-amplitude ultrasound waves decreased induction time more than sonication with low-amplitude waves. [Kim and Suslick, 2018] High-power ultrasonication at high amplitudes generates consistently intense micro-turbulences, shear forces, and agitation. These micro- and macro-movement in the supersaturated slurry results in improved mass transfer and subsequent increased crystallization rates. Hielscher Ultrasonics’ industrial ultrasonic processors can deliver very high amplitudes. Amplitudes of up to 200µm can be easily continuously run in 24/7 operation. For even higher amplitudes, customized ultrasonic sonotrodes are available.
All equipment is built for the 24/7/365 use under full load and its robustness and reliability make it the work horse in your sono-crystallization process. This makes Hielscher’s ultrasonic equipment a reliable work tool that fulfils your sono-crystallization requirements.
Precisely Controllable Amplitudes for Superior Crystallization
All Hielscher ultrasonic processors are precisely controllable and thereby reliable work horses in R&D and production. The amplitude is one of the crucial process parameters that influence the efficiency and effectiveness of sono-crystallization. All Hielscher Ultrasonics’ processors allow for the precise setting of the amplitude. Hielscher’s industrial ultrasonic processors can deliver very high amplitudes and deliver the required ultrasonic intensity for demanding applications. Amplitudes of up to 200µm can be easily continuously run in 24/7 operation.
Precise amplitude settings and the permanent monitoring of the ultrasonic process parameters via smart software give you the possibility to influence the sono-crystallization reaction precisely. During every sonication run, all ultrasonic parameters are automatically recorded on a built-in SD-card, so that each run can be evaluated and controlled. Optimal sonication for most efficient sono-crystallization!
Temperature Controlled Sonication
For crystallization processes of cannabinoids, temperature is a crucial process parameter that influences the outcome and quality of CBD crystals. Hielscher sono-crsytallization reators are equipped with a cooling jacket to keep the process temperature in range. Furthermore, our sono-crsytallization systems feature intelligent software that monitors the process temperature via a pluggable temperature sensor. In the user-friendly menu, the user can set an upper and lower temperature limit. As soon as the process temperature exceeds the set temperature range, the ultrasonicator pauses until the temperature is back in the pre-set ∆T. This gives you precise control over the important process crystallization parameter “temperature”.
The MultiPhaseCavitator for Uniform Crystals
The MultiPhaseCavitator MPC48 is a unique flow cell insert featuring 48 cannulas to inject the second phase (i.e., the CBD distillate) directly into the cavitational hot-spot. Thereby, a highly uniform mixture of CBD distillate and solvent forms the supersaturated solution, in which the nuclei of the CBD crystals will form. The exposure in the ultrasonic reactor allows for precisely controllable nucleation and crystal growth. The MultiPhaseCavitator makes crystallization processes highly efficient and allows due to the precise control for process standardization. A highly standardized manufacturing process is part of Good Manufacturing Practices (GMP) and helps to produce continuously products of highest quality.
Highest Quality – Designed and Manufactured in Germany
As a family-owned and family-run business, Hielscher prioritizes highest quality standards for its ultrasonic processors. All ultrasonicators are designed, manufactured and thoroughly tested in our headquarter in Teltow near Berlin, Germany. Robustness and reliability of Hielscher’s ultrasonic equipment make it a work horse in your production. 24/7 operation under full load and in demanding environments is a natural characteristic of Hielscher’s high-performance ultrasonic probes and reactors.
Contact us now and tell us about your sono-crystallization requirements! We will recommend you the most suitable ultrasonic crystallizer and reactor setup!
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Literature / References
- Kim, Hyo Na; Suslick, Kenneth (2018): The Effect of Ultrasound on Crystals – Sonocrystallization and Sonofragmentation. Crystals 2018, 8, 28.
- Gielen, Bjorn; Jordens, Jeroen; Thomassen, Leen C. J.; Braeken, Leen; Van Gerven, Tom (2017): Agglomeration Control during Ultrasonic Crystallization of an Active Pharmaceutical Ingredient. Crystals 7, 40. 2017.
- Antunes, ABD; De Geest, BG; Vervaet, C.; Remon, JP (2013): Solvent-free drug crystal engineering for drug nano- and micro suspensions. European Journal of Pharmaceutical Sciences, 48(1-2), 2013. 121-129.
- R. McKee, E. Frank, J. Heath, D. Owen, R. Przygoda, G. Trimmer, F. Whitman (1998): Toxicology of n-pentane (CAS no. 109-66-0). Journal of Applied Toxicolicology Nov-Dec 1998;18(6):431-42.
Facts Worth Knowing
Pentane as Solvent
n-Pentane (CAS no. 109-6-0) is a hydrocarbon solvent, which is usually applied for the crystallization of cannabinoids such as CBD.
“n-pentane was not acutely toxic by oral or inhalation routes, it was not a skin or eye irritant and did not induce skin sensitization. It did not exhibit cumulative toxicity at levels up to 20000 mg m(-3), which is approximately one-half of the lower explosive limit and the highest level considered safe to test. It did not induce developmental toxicity and was not mutagenic. From this and other existing information, it is concluded that n-pentane does not require classification for potential toxic hazards (as defined by Annex VI of the EU Dangerous Substance Directive, 1993), although the physical properties indicate that it would be appropriate to warn for the potential for aspiration. Further, there is no reason to reduce the current occupational exposure recommendations. Finally, although there are some safety issues relating to the flammability of n-pentane, the absence of any demonstrable toxicity at high treatment levels indicates that the risk of adverse health effects is minimal for all segments of the population.” (McKee et al. 1998)