Endüstriyel kenevirin(Cannabis sativa L.) dişi çiçeği kullanılarak  CBD yağı üretiminin proses tasarım ve simülasyonu
Process design and simulation of CBD oil production using female inflorescences of industrial hemp(Cannabis sativa L.)
Yazar: BERK GÜNYEL
Danışman: PROF. DR. GÜLHAYAT SAYGILI
İstanbul Teknik Üniversitesi / Lisansüstü Eğitim Enstitüsü / Kimya Mühendisliği Ana Bilim Dalı / Kimya Mühendisliği Bilim Dalı
Derece: Yüksek Lisans, 2022
Konu: Kimya Mühendisliği = Chemical Engineering
Dizin: Endüstriyel bitkiler = Industrial plants ; Kannabidiol = Cannabidiol ; Kenevir = Hemp

Özet:
Kannabinoidlerin insan sağlığı açısından faydaları ve kullanım alanları tıp bilimi tarafından bilinip her geçen gün yeni özellikleri keşfedilmektedir. Bu uğurda üretime yönelik adımlar ve yatırımlar gerek ülkelerce gerekse de özel firmalar tarafından atılmaktadır. Ayrıca, yakın tarih boyunca yasak olan kenevir üretimi, endüstriyel kenevir için kalkmakta ve yeni yasalarla beraber kenevir bitkisinin türüne göre düzenlemeler yapılmaktadır. 
Bu yüksek lisans tez çalışmasında ise Türkiye'de üretimi yasallaştırılan ve üretiminin ilerleyen yıllarda ivmelenerek artması planlanan ve artacak olan endüstriyel kenevirin (Cannabis Sativa L.) çiçek kısmı kullanılarak FDA ve GMP regülasyonlarına, limitasyonlarına uygun, ilaç sektöründe hammadde olarak kullanılabilecek, fitoterapik amaçlarla tüketilebilecek CBD yağı üretecek prosesin simülasyonu ve tasarımı yapılmıştır. Proses simülasyonu için ASPEN programı kullanılmıştır. Simülasyon sonucunda ise ekipman tasarımı yapılmıştır. Ekipman tasarımı ve tüm proses tasarımı sonucunda ise ekonomik analiz yapılmış ve sonuçlar irdelenerek Türkiye için kenevir üretimi ve bu üretimle paralel CBD yağı üretimi konusunda öneriler verilmiştir.
Türkiyenin kenevir üretim kapasitesi ve atılımları göz önünde bulundurulduğuna ise kimya mühendisliği tasarımı alanında yapılan bir takım kabullerin dışında kaldığı gözlemlenmiştir. Bu gözlemler ve Türkiye'nin içinde bulunduğu özel durum, tez çalışması boyunca detaylıca irdelenmiştir. Proses, hem dünyada üretilen diğer CBD yağları ile rekabet düzeyi yüksek saflıkta hem de kenevir bitkisinin tüm kısımları kullanılarak üretilebilecek diğer potansiyel sektörel ürünler (kağıt, deri, gıda, enerji...) için gereken proseslerle entegre bir proses şeklinde dizayn edilmiş ve bu çerçevede yaklaşılan dünyadaki ilk ve tek proses olma özelliği taşımaktadır. Bu dizayn ile beraber tüm bu proseslerde işletim maliyetinin minimum düzeye inmesi başarılmış ve en kaliteli CBD yağı en ucuz şekilde üretilmiştir.
Üretilecek CBD yağı için "Entourage Etkisi" dikkate alınmış ve bu etki perspektifinde kannabinoidlerle beraber terpen yapısı da korunarak bir final ürün elde edilmiştir. Simülasyon ve tasarım boyunca final ürünün CBD, ∆9-THC, CBG profilleri analiz edilmiştir ve elde edilen simülasyonda final ürün CBD yağı olarak hata payı olmadan sistem başarılı bir şekilde simüle edilebilmiştir. Proses simülasyonları boyunca FDA ve GMP limitasyonları gereğince proseste kullanılacak olan çözücü n-hekzan ve etanolün de ppm değerleri irdelenmiş ve izin verilen değerlerin altında kalacak şekilde proses dizayn edilmiştir. Simülasyonla beraber üretilecek CBD yağının içeriği %52.9-%52.4 CBD yağı ve n-hekzan, etanol ppm değerleri sırasıyla n-hekzan için kalıntı dahi kalmayacak şekilde ve etanol için %0.0463 olacağı öngörülmüştür.

Abstract:
For the past 20 years , humankind is exploring the world of cannabinoids and cannnabis as a plant. Both worldwide and Turkey's perspective, the plant harvest field area and the industrial production rate is increasing exponentially and furthermore product range is expanding. By that means economy profits and investments are increasing as the demand grows.
In Turkey, industrial cannabis(Cannabis Sativa L.) is legalized in 2019 and in addition to that, this master degree thesis is focused on designing and simulating 50% CBD oil using female inflorescences of industrial hemp. Since the oil is used for phytotherapic means, the process is simulated and designed with following FDA and GMP regulations. Aspen simulation is used during the simulation and afterwards, equipment design and economic analysis is conducted. Since Turkey is not a manufacturer of CBD oil and in addition to that there are 19 cities that can legally harvest hemp after ensuring the necessary conditions, industrial scale conceptual design has been done and the scalability of the process is the best compared to other chemical production pathways. There are only ethanol based industrial scale CBD oil production process worldwide  and in this thesis n-hexane based industrial scale production process in completed in order to have the lowest production cost. The reason that this aim is conducted during the simulation and design is that, increasing the competition rate while maintaining the most effective CBD oil.
Additional approach while designing this process is the potential of other industrial hemp products like seed oil, textile, energy, paper and etc. By that means the CBD oil production using industrial hemp female inflorescence is designed with 0 waste, completely green and the best compatible when all other plant parts are considered. With this approach, this design and simulation is the first and only worldwide process that satisfy and appreciate this opportunity. One of the most common mistakes that manufacturers tend to do is to approach CBD oil production, only thinking cannabinoids. However since the terpene and their effects to build up the entourage effect with the cannabinoids inside, a challenge arises. That is the different chemical structure and properties of terpenes alongside the cannabinoids. This process design and simulation allows no terpene loss during purification steps which will end up providing the best health effect of the CBD oil to its users therefore, the consumer will benefit from the final product at the highest rate and the long-term usage of the oil will be more economical to the consumers.
The design is a continuous process and the flow always continuous throughout the process. The biomass is loaded to grinder for the beginning of the process. Then the countercurrent extraction using n-hexane happens. However due to lack of academical research and chemical engineering wise knowledge is very least amount, excess amount of n-hexane is used. Since the hexane recovery rate is greater than 99%, this decision doesn't end up leading any kind of increasement in production cost. It provides n-hexane to solve the cannabinoids and cannabinoid acids better therefore the yield lose is prevented. After the extraction step, wet biomass is goes through a evaporation step in order to clean the biomass from n-hexane to be a useful product that be consumed as a animal bait. Concrete of solvent and the crude oil is then distilled. Since n-hexane and water forms an azeotrope, a further decantation process is done in order to separate the aqueous phase and the organic phase so that n-hexane can be recycled with the highest rate to eliminate the extraction yield lose due to water accumulation. Both from the evaporator and the distillation, n-hexane is recovered more than 99% which eliminates the cost of n-hexane continuously. When the distillation is done, winterization has to be done. There are approximately 3%-5% wax in the crude oil since using n-hexane as solvent. In order to eliminate these impurities, the crude oil is mixed with ethanol than cooled to sub-zero temperatures to settle for 18 hours. Ethanol can't solve these impurities at sub-zero temperatures so lipids floats as solids. Mechanical separation which is filtration is done, so that wax structure is purified in order to get a purer oil composition. A secondary distillation is done for the ethanol, just like n-hexane it should be purified then recycled back to the process. It also serves as a complement distillation for n-hexane since the FDA and GMP limits is very low for n-hexane. With this 2 stage distillation method, it provides process to produce CBD oil with having n-hexane lower than trace amounts. For the final step of the process, decarboxylation is done in order to convert CBDA to CBD and increase its yield. Additional benefit of decarboxylation is that it increases the digestibility of the oil since human body can't recognize cannabinoids acidic forms. Decarboxylation is under vacuum for 1 hours at 100 ℃ as the last step of the process. Final form of CBD oil is formed, %50 full spectrum CBD oil.
The design and simulation aim is to produce the best CBD oil with the lowest cost, highest impurity and the safest way possible. After the simulation, it is found out that the predicted composition of CBD oil will be 52.9%-52.4% with having less than 1 ppb n-hexane in its structure. The n-hexane amount is far less than the FDA and GMP limits. Also, the process is operated at under-vacuum and the n-hexane line is always kept at less than 40 ℃ due to safety concerns. Therefore the 2 downside of using hydrocarbon extraction is managed to be eliminated leading being the best industrial scale process.
Cannabis industry and economics are very versatile everywhere in the world. Economical analysis has been done however, one of the highest utility cost of CBD oil production is 3rd party laboratory quality check. Since there are no CBD oil production in Turkey, that portion of the economical analysis is very large. n-Hexane has far less utility cost which makes it better in the long term compared to alcohol extraction, however n-hexane pathway has a greater investment cost compared to ethanol pathway.
Conceptual design and simulation of the process is done for 1000 kg/h feed capacity. With this capacity, it estimated that the process gains more than 5 billion USD as net profit. When the other pathways are considered (also including supercritical CO2 extraction), all the worldwide profits are very high and even the start-ups return of investment is calculated as 1-2 months. The special case of Turkey, its economy of hemp is considered more briefly in the economic part of the thesis.
There is only a one waste stream that can be considered while operation, that is being CO2 during decarboxylation step. For only female inflorescences process, it can be handled by a photo-synthetic bioreactor that can convert it to oxygen. The reason of the design of a integrated facility becomes more meaningful for this waste stream. Hemp is also very eligible for both pyrolysis and gasification. If a biomass burning process can be designed alongside with the CBD oil production, waste CO2 both from the pyrolysis or gasification and CBD oil can be handled in a common process step which can convert it to methane(CH4) to use it as a fuel to decrease the production expenses which grants the processes to have the best competitiveness amongst all other processes worldwide .