KR102641482B1 - High-purity cannabidiol refinement and crystallization method - Google Patents
High-purity cannabidiol refinement and crystallization method Download PDFInfo
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- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 title claims abstract description 184
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 title claims abstract description 184
- 229950011318 cannabidiol Drugs 0.000 title claims abstract description 184
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 title claims abstract description 184
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 title claims abstract description 184
- 238000002425 crystallisation Methods 0.000 title claims description 13
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims abstract description 92
- 239000013078 crystal Substances 0.000 claims abstract description 69
- WVOLTBSCXRRQFR-DLBZAZTESA-N cannabidiolic acid Chemical compound OC1=C(C(O)=O)C(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 WVOLTBSCXRRQFR-DLBZAZTESA-N 0.000 claims abstract description 61
- WVOLTBSCXRRQFR-SJORKVTESA-N Cannabidiolic acid Natural products OC1=C(C(O)=O)C(CCCCC)=CC(O)=C1[C@@H]1[C@@H](C(C)=C)CCC(C)=C1 WVOLTBSCXRRQFR-SJORKVTESA-N 0.000 claims abstract description 58
- 238000004519 manufacturing process Methods 0.000 claims abstract description 27
- 244000025254 Cannabis sativa Species 0.000 claims abstract description 26
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 claims abstract description 25
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 claims abstract description 25
- 235000009120 camo Nutrition 0.000 claims abstract description 25
- 235000005607 chanvre indien Nutrition 0.000 claims abstract description 25
- 239000011487 hemp Substances 0.000 claims abstract description 25
- 239000012264 purified product Substances 0.000 claims description 19
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- 239000000047 product Substances 0.000 claims description 16
- 230000008025 crystallization Effects 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 2
- 239000001569 carbon dioxide Substances 0.000 claims description 2
- 238000000194 supercritical-fluid extraction Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- FGNLEIGUMSBZQP-UHFFFAOYSA-N cadaverine dihydrochloride Chemical compound Cl.Cl.NCCCCCN FGNLEIGUMSBZQP-UHFFFAOYSA-N 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 23
- 238000000034 method Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 241000218236 Cannabis Species 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/84—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by crystallisation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/004—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by obtaining phenols from plant material or from animal material
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
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- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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Abstract
본 발명은 대마 추출물에서 고수율로 칸나비디올 결정을 제조하는 방법에 관한 것이다. 본 발명의 제조방법은 대마 추출물 내 칸나비디올(CBD) 뿐만 아니라 칸나비디올산(CBD-A)을 칸나비디올(CBD)로 전환시켜 사용하기 때문에 대마 추출물 대비 수율이 높다. 또한, 본 발명의 제조방법은 용매 온도 차이에 따른 용해도 변화를 이용하여 칸나비디올(CBD) 결정을 제조하는데, 본 발명에서 다양한 용매 중 펜테인을 사용하여 고순도 칸나비디올(CBD) 결정을 고수율로 제조할 수 있음을 확인하였다.The present invention relates to a method for producing cannabidiol crystals from hemp extract in high yield. The production method of the present invention uses not only cannabidiol (CBD) in the hemp extract by converting cannabidiolic acid (CBD-A) into cannabidiol (CBD), so the yield is higher than that of the hemp extract. In addition, the production method of the present invention produces cannabidiol (CBD) crystals using solubility changes according to solvent temperature differences. In the present invention, high purity cannabidiol (CBD) crystals are manufactured using pentane among various solvents. It was confirmed that it could be manufactured with high yield.
Description
본 발명은 대마 추출물에서 고수율로 고순도의 칸나비디올(cannabidiol, CBD)을 정제하고, 결정을 제조하는 방법에 관한 것이다.The present invention relates to a method for purifying high purity cannabidiol (CBD) from hemp extract at high yield and producing crystals.
대마(Cannabis sativa L.)는 대마는 중앙아시아 원산의 삼과 식물로 한해살이풀이다. 우리나라에서도 예전부터 삼베옷의 원료로 이용해 왔다. 대마초는 이 대마의 잎과 꽃에서 얻어지는 물질로서, 400여 종 이상의 화학물질이 들어 있다. Hemp ( Cannabis sativa L.) is a perennial plant native to Central Asia. In Korea, hemp has been used as a raw material for clothes since ancient times. Cannabis is a substance obtained from the leaves and flowers of the hemp plant, and contains more than 400 types of chemicals.
대마초를 피우면 기분이 좋아지고, 긴장이 풀리며 식욕이 증가되는 등의 증상이 나타나게 된다. 반면, 입이 마르고 눈이 충혈되기도 한다. 장기간 대마초에 노출된 경우에는 단기 기억력이 짧아지고, 운동감각이 떨어지는 등의 부작용이 생긴다.Smoking cannabis causes symptoms such as feeling better, feeling more relaxed, and increasing appetite. On the other hand, your mouth may become dry and your eyes may become bloodshot. Long-term exposure to cannabis can cause side effects such as short-term memory and decreased motor skills.
대마초에 들어있는 칸나비노이드 중 향정신성 효과가 가장 큰 물질은 델타나인 테트라하이드로칸나비놀(THC)이다. 따라서 THC를 많이 함유한 대마초일수록 인체에 끼치는 해가 크다고 할 수 있다. THC는 수 백 마이크로그램(㎍) 만으로도 환각 증상을 일으킬 수 있다.Among the cannabinoids in cannabis, the substance with the greatest psychoactive effect is delta nine tetrahydrocannabinol (THC). Therefore, it can be said that the more THC it contains, the greater the harm it causes to the human body. Just a few hundred micrograms (㎍) of THC can cause hallucinations.
그런데, 최근 많은 국가가 의료 목적으로 대마 사용을 허용함에 따라 점점 더 많은 사람이 통증 감소 등을 위해 대마 약물 요법을 사용하고 있다.However, as many countries have recently allowed the use of cannabis for medical purposes, more and more people are using cannabis drug therapy for pain reduction, etc.
칸나비디올(cannabidiol, CBD)은 대마에서 확인되는 카나비노이드 중 하나이며, 정확한 원인은 밝혀지지 않았으나 통증, 기분 및 정신 기능에 영향을 미치는 뇌의 화학 물질 분해를 막아서 뇌에 영향을 미치는 것으로 알려져있다. 또한, 마약성이 없으며, 통증, 난치성 뇌전증, 다발성경화증과 같은 질환을 치료하는데 사용되는 약물이다.Cannabidiol (CBD) is one of the cannabinoids found in cannabis. Although its exact cause is unknown, it is known to affect the brain by preventing the breakdown of chemicals in the brain that affect pain, mood, and mental function. In addition, it has no narcotic properties and is a drug used to treat diseases such as pain, intractable epilepsy, and multiple sclerosis.
본 발명에서는 높은 수율로 고순도 칸나비디올 결정을 제조하는 방법을 제공하고자 한다.The present invention seeks to provide a method for producing high purity cannabidiol crystals in high yield.
본 발명은 대마 추출물을 정제하여 칸나비디올(CBD) 및 칸나비디올산(CBD-A)을 60%(w/w) 이상 포함하는 정제물을 얻는 단계 (a); 상기 단계 (a) 후, 상기 정제물을 90~130℃ 온도로 열처리하여 칸나비디올산(CBD-A)이 칸나비디올(CBD)이 되도록 전환시키는 단계 (b); 상기 단계 (b) 후, 상기 열처리물을 냉각한 후 펜테인(Pentane)을 첨가하고, 온도를 더 떨어뜨려 칸나비디올(CBD)을 용출시키는 단계 (c);를 포함하는 것을 특징으로 하는 칸나비디올 결정 제조방법을 제공한다.The present invention purifies a hemp extract to obtain a purified product containing more than 60% (w/w) of cannabidiol (CBD) and cannabidiolic acid (CBD-A); After step (a), heat treating the purified product at a temperature of 90 to 130° C. to convert cannabidiolic acid (CBD-A) into cannabidiol (CBD) (b); After step (b), cooling the heat-treated product, adding pentane, and further lowering the temperature to elute cannabidiol (CBD) (c). A method for producing nabidiol crystals is provided.
본 발명의 칸나비디올 결정 제조방법에 있어서, 상기 단계 (a)의 정제물은 대마 추출물에 중압 액체 크로마토그래피(Medium pressure liquid chromatography, MPLC)를 실시하여 얻은 칸나비디올(CBD) 또는 칸나비디올산(CBD-A)이 용출되는 구간의 분획물일 수 있다.In the method for producing cannabidiol crystals of the present invention, the purified product of step (a) is cannabidiol (CBD) or cannabidiolic acid obtained by subjecting a hemp extract to medium pressure liquid chromatography (MPLC). It may be a fraction of the section where (CBD-A) is eluted.
본 발명의 칸나비디올 결정 제조방법에 있어서, 상기 단계 (c)의 펜테인은 바람직하게 상기 열처리물:펜테인이 1:0.3~5.0의 무게비율이 되도록 첨가하는 것이 좋다.In the method for producing cannabidiol crystals of the present invention, the pentane in step (c) is preferably added in a weight ratio of the heat-treated product:pentane of 1:0.3 to 5.0.
본 발명의 칸나비디올 결정 제조방법에 있어서, 상기 단계 (c)의 용출은 상기 '펜테인(Pentane)을 첨가한 열처리물'을 -15~-5℃의 냉동고에서 냉각시켜 수행하는 것일 수 있다.In the method for producing cannabidiol crystals of the present invention, the elution in step (c) may be performed by cooling the 'heat-treated product to which pentane has been added' in a freezer at -15 to -5°C. .
본 발명의 칸나비디올 결정 제조방법은 바람직하게 칸나비디올 결정을 여과하여 1차로 '결정화되지 않고 남아있는 액체 분획'을 제거하고, 칸나비디올 결정에 -10~0℃의 펜테인(Pentane)을 처리하여 잔존한 '결정화되지 않고 남아있는 액체 분획'을 2차로 제거한 후, 감압증류하여 펜테인(Pentane)을 제거하는 단계 (d)를 더욱 포함하는 것이 좋다.The method for producing cannabidiol crystals of the present invention preferably filters the cannabidiol crystals to first remove the 'liquid fraction remaining without crystallization', and adds pentane to the cannabidiol crystals at -10 to 0°C. It is better to further include a step (d) of secondly removing the remaining 'liquid fraction that has not been crystallized' through treatment and then removing pentane by distillation under reduced pressure.
본 발명의 제조방법은 대마 추출물 내 칸나비디올(CBD) 뿐만 아니라 칸나비디올산(CBD-A)을 칸나비디올(CBD)로 전환시켜 사용하기 때문에 대마 추출물 대비 수율이 높다. The production method of the present invention uses not only cannabidiol (CBD) in the hemp extract by converting cannabidiolic acid (CBD-A) into cannabidiol (CBD), so the yield is higher than that of the hemp extract.
또한, 본 발명의 제조방법은 용매 온도 차이에 따른 용해도 변화를 이용하여 칸나비디올(CBD) 결정을 제조하는데, 본 발명에서 다양한 용매 중 펜테인을 사용하여 고순도로 칸나비디올(CBD) 결정을 제조할 수 있으며, 결정 전환 비율(결정화율) 또한 높아 고수율로 칸나비디올(CBD) 결정을 제조할 수 있음을 확인하였다. In addition, the production method of the present invention produces cannabidiol (CBD) crystals using solubility changes according to solvent temperature differences. In the present invention, cannabidiol (CBD) crystals are produced with high purity using pentane among various solvents. It was confirmed that cannabidiol (CBD) crystals can be manufactured in high yield and that the crystal conversion rate (crystallization rate) is also high.
또한, 본 발명에서 펜테인의 첨가 비율 및 반응 시간을 조절하여 더욱 고순도의 칸나비디올(CBD) 결정을 고수율로 제조할 수 있음을 확인하였다.In addition, it was confirmed that in the present invention, higher purity cannabidiol (CBD) crystals could be produced in high yield by controlling the addition ratio and reaction time of pentane.
도 1은 대마 추출물을 열처리함에 따라 칸나비디올산(CBD-A)이 칸나비디올(CBD)로 전환되는 것을 확인한 결과이다. 즉, 본 발명 열처리 단계의 처리 조건에 따른 열처리물 내 칸나비디올(CBD)/칸나비디올산(CBD-A)의 비율을 보여준다.
도 2는 본 발명 칸나비디올(CBD) 결정 제조방법의 결정 제조단계에서의 반응 조건을 최적화하기 위해 펜테인(Pentane)을 다양한 비율로 첨가하고, 다양한 시간동안 결정화시킨 후 얻은 결과로 반응표면분석법을 실시한 결과를 보여준다. Figure 1 shows the results confirming that cannabidiolic acid (CBD-A) is converted to cannabidiol (CBD) as hemp extract is heat treated. That is, it shows the ratio of cannabidiol (CBD)/cannabidiolic acid (CBD-A) in the heat-treated product according to the treatment conditions of the heat treatment step of the present invention.
Figure 2 shows the results obtained after adding pentane in various ratios and crystallizing for various times to optimize the reaction conditions in the crystal production step of the cannabidiol (CBD) crystal production method of the present invention, using response surface analysis. It shows the results of carrying out.
본 발명은 대마 추출물을 정제하여 칸나비디올(CBD) 및 칸나비디올산(CBD-A)을 60%(w/w) 이상 포함하는 정제물을 얻는 단계 (a); 상기 단계 (a) 후, 상기 정제물을 90~130℃ 온도로 열처리하여 칸나비디올산(CBD-A)이 칸나비디올(CBD)이 되도록 전환시키는 단계 (b); 상기 단계 (b) 후, 상기 열처리물을 냉각한 후 펜테인(Pentane)을 첨가하고, 온도를 더 떨어뜨려 칸나비디올(CBD)을 용출시키는 단계 (c);를 포함하는 것을 특징으로 하는 칸나비디올 결정 제조방법을 제공한다.The present invention purifies a hemp extract to obtain a purified product containing more than 60% (w/w) of cannabidiol (CBD) and cannabidiolic acid (CBD-A); After step (a), heat treating the purified product at a temperature of 90 to 130° C. to convert cannabidiolic acid (CBD-A) into cannabidiol (CBD) (b); After step (b), cooling the heat-treated product, adding pentane, and further lowering the temperature to elute cannabidiol (CBD) (c). A method for producing nabidiol crystals is provided.
본 발명의 칸나비디올(CBD) 결정 제조방법은 칸나비디올(CBD)을 용매와 혼합시킨 후, 용매를 냉각시켜 용해도가 내려가 과포화상태가 되면, 칸나비디올(CBD) 결정이 용출되는 것을 이용한다.The method for producing cannabidiol (CBD) crystals of the present invention utilizes the process of mixing cannabidiol (CBD) with a solvent, cooling the solvent, lowering the solubility to a supersaturated state, and eluting the cannabidiol (CBD) crystals. .
본 발명자들은 대마 추출물로부터 칸나비디올(CBD) 만을 수득하여 이용하는 것이 아니라, 칸나비디올산(CBD-A)도 수득하여 이용하는데, 즉 칸나비디올 및 칸나비디올산을 모두 포함하는 정제물을 사용하는데, 정제물 내 카나비디올산은 본 발명에서 추가한 열처리 공정에 의해 칸나비디올(CBD)로 전환되어 결정으로 추출된다. 이를 통해 대마 추출물 대비 고수율로 칸나비디올(CBD) 결정을 제조할 수 있는 것이다. The present inventors not only obtain and use cannabidiol (CBD) from hemp extract, but also obtain and use cannabidiolic acid (CBD-A), that is, use a purified product containing both cannabidiol and cannabidiolic acid. , cannabidiolic acid in the purified product is converted to cannabidiol (CBD) by a heat treatment process added in the present invention and extracted as crystals. Through this, cannabidiol (CBD) crystals can be manufactured at a higher yield compared to hemp extract.
그런데, 칸나비디올산(CBD-A)을 수득하여 이용하는 경우, 수율은 높아질지 몰라도, 정제 분획에 더욱 다양한 불순물들이 더욱 포함되어, 칸나비디올(CBD) 만을 정제하여 결정화시키는 것보다 순도가 낮아지는 문제점이 있다. 하지만, 본 발명에서는 여러 용매 중 펜테인(Pentane)을 사용하여 결정화시킴으로써, 고순도의 칸나비디올(CBD) 결정을 제조할 수 있었으며, 제조 시 결정화율 또한 높아 고수율의 칸나비디올(CBD) 결정을 제조할 수 있었다. However, when obtaining and using cannabidiol acid (CBD-A), the yield may be higher, but the purified fraction contains more various impurities, lowering the purity compared to purifying and crystallizing cannabidiol (CBD) alone. There is a problem. However, in the present invention, high purity cannabidiol (CBD) crystals were manufactured by crystallizing them using pentane among various solvents, and the crystallization rate during production was also high, resulting in a high yield of cannabidiol (CBD) crystals. could be manufactured.
이하 본 발명의 칸나비디올(CBD) 결정 제조방법을 단계별로 구분하여 더욱 구체적으로 설명하고자 한다.Hereinafter, the method for producing cannabidiol (CBD) crystals of the present invention will be described in more detail by dividing it into steps.
<단계 (a): 대마 추출물을 정제하여 칸나비디올(CBD) 및 칸나비디올산(CBD-A)을 60%(w/w) 이상 포함하는 정제물 수득><Step (a): Purify the hemp extract to obtain a purified product containing more than 60% (w/w) of cannabidiol (CBD) and cannabidiolic acid (CBD-A)>
본 단계는 대마 추출물을 정제하여 칸나비디올(CBD) 및 칸나비디올산(CBD-A)을 60%(w/w) 이상으로 포함하는 정제물을 얻는 과정이다. This step is the process of purifying the hemp extract to obtain a purified product containing more than 60% (w/w) of cannabidiol (CBD) and cannabidiolic acid (CBD-A).
본 발명의 칸나비디올(CBD) 결정 제조방법은 칸나비디올(CBD)을 용매와 혼합시킨 후, 용매를 냉각시켜 용해도가 내려가 과포화상태가 되면, 칸나비디올(CBD) 결정이 용출되는 것을 이용한다.The method for producing cannabidiol (CBD) crystals of the present invention utilizes the process of mixing cannabidiol (CBD) with a solvent, cooling the solvent, lowering the solubility to a supersaturated state, and eluting the cannabidiol (CBD) crystals. .
따라서, 정제물에 포함된 칸나비디올(CBD)의 농도가 높아야 높은 온도에서부터 칸나비디올(CBD)이 과포화상태가 되기 때문에, 본 단계에서 정제물의 농도는 중요한 기술적 요소가 된다.Therefore, the concentration of cannabidiol (CBD) contained in the purified product must be high so that cannabidiol (CBD) becomes supersaturated at high temperatures, so the concentration of the purified product becomes an important technical factor in this step.
만약 농도를 60%(w/w) 보다 낮게 정제하여 사용한다면, 보다 낮은 농도에서 결정이 용출되기 때문에, 용매의 냉각된 온도 대비 결정화율이 낮아지는 문제가 생기게 된다. If the concentration is purified and used at a concentration lower than 60% (w/w), the crystallization rate is lowered compared to the cooled temperature of the solvent because crystals are eluted at a lower concentration.
또한, 용매의 온도를 더욱 낮추는 방식으로 상기와 같은 문제를 해결하려고 한다면, 온도가 더욱 내려가는 과정에서 불순물들의 용해도 또한 더욱 낮아지며 불순물들이 용출되기 때문에, 결정의 순도가 낮아지는 문제가 생기게 된다.In addition, if an attempt is made to solve the above problem by further lowering the temperature of the solvent, the solubility of impurities will also be lowered and the impurities will be eluted in the process of further lowering the temperature, resulting in a problem of lowering the purity of the crystal.
한편, 본 단계는 대마 추출물에 다양한 정제 방법을 사용하여 정제물을 수득하는 것일 수 있는데, 바람직하게 중압 액체 크로마토그래피(Medium pressure liquid chromatography, MPLC)를 이용하여 정제한 것일 수 있다.Meanwhile, this step may be to obtain a purified product using various purification methods for the hemp extract, preferably purified using medium pressure liquid chromatography (MPLC).
본 단계는 칸나비디올(CBD)과 칸나비디올산(CBD-A)를 모두 포함하는 정제물을 얻는 것에 특징이 있는데, 대마 추출물에 중압 액체 크로마토그래피를 실시하면 칸나비디올(CBD) 및 칸나비디올산(CBD-A)이 모두 용출된 용출물 즉 정제물을 수득하게 된다. This step is characterized by obtaining a purified product containing both cannabidiol (CBD) and cannabidiolic acid (CBD-A). When the hemp extract is subjected to medium pressure liquid chromatography, cannabidiol (CBD) and cannabidiol are obtained. An eluate in which all of the olic acid (CBD-A) has been eluted, that is, a purified product, is obtained.
<단계 (b): 상기 정제물을 열처리하여 칸나비디올산(CBD-A)을 칸나비디올(CBD)로 전환)><Step (b): Heat treat the purified product to convert cannabidiolic acid (CBD-A) into cannabidiol (CBD)>
본 단계는 상기 단계 (a)에서 얻은 정제물을 90~130℃ 온도로 열처리하여 칸나비디올산(CBD-A)이 칸나비디올(CBD)이 되도록 전환시키는 과정이다. This step is a process of converting cannabidiolic acid (CBD-A) into cannabidiol (CBD) by heat treating the purified product obtained in step (a) at a temperature of 90 to 130°C.
칸나비디올산(CBD-A)은 고온에 노출되게 되면 칸나비디올산(CBD-A)의 카르복실기(-COOH)가 제거되며 칸나비디올(CBD)로 전환되는 특징이 있다. 본 단계는 상기와 같은 점을 이용하여 칸나비디올산(CBD-A)을 칸나비디올(CBD)로 전환시키는 단계이다.When cannabidiolic acid (CBD-A) is exposed to high temperatures, the carboxyl group (-COOH) of cannabidiolic acid (CBD-A) is removed and converted to cannabidiol (CBD). This step is a step of converting cannabidiolic acid (CBD-A) to cannabidiol (CBD) using the above points.
한편, 본 단계에서 열처리는 90~130℃ 온도에서 30~180분 동안 처리하는 것일 수 있다. 바람직하게는 대부분의 칸나비디올산(CBDA)이 칸나비디올(CBD)로 전환될 수 있도록 110~130℃ 온도에서 50~125분 동안 처리하는 것이 좋은데, 더욱 바람직하게는 125℃에서 50분 동안 반응시키는 것이 더욱 좋다. 짧은 시간 동안 반응시켜 효율이 우수하면서도, 열처리에 의해 손실되는 양이 적고, 대부분의 칸나비디올산(CBDA)이 칸나비디올(CBD)로 전환되도록 최적화된 온도 및 시간 조건이다.Meanwhile, heat treatment in this step may be performed at a temperature of 90 to 130°C for 30 to 180 minutes. Preferably, the reaction is performed at a temperature of 110 to 130°C for 50 to 125 minutes so that most of the cannabidiolic acid (CBDA) can be converted to cannabidiol (CBD), and more preferably at 125°C for 50 minutes. It is better to do it. The temperature and time conditions are optimized so that the efficiency is excellent by reacting for a short time, the amount lost by heat treatment is small, and most cannabidiolic acid (CBDA) is converted to cannabidiol (CBD).
<단계 (c): 상기 열처리물을 냉각한 후 펜테인(Pentane)을 첨가하고, 온도를 더 떨어뜨려 칸나비디올(CBD)을 용출><Step (c): After cooling the heat-treated product, add pentane, and further lower the temperature to elute cannabidiol (CBD)>
본 단계는 상기 단계 (b)에서 얻은 열처리물을 냉각시킨 후, 펜테인(Pentane)을 첨가하고, 온도를 더 떨어뜨려 칸나비디올(CBD)을 용출시키는 과정이다. This step is a process of cooling the heat-treated product obtained in step (b), adding pentane, and further lowering the temperature to elute cannabidiol (CBD).
본 단계는 먼저 열처리물을 냉각시키는 과정을 거친다. 상기 단계 (b)의 열처리물은 90~130℃의 고온의 상태를 가지게 되는데, 펜테인(Pentane)의 끓는점은 36.1℃이다. 따라서, 펜테인이 기체로 상변이 되는 것을 막기 위해, 열처리물의 온도를 펜테인의 끓는점 이하로 냉각시키는 과정이 필요하다.This step first goes through the process of cooling the heat treated product. The heat-treated product in step (b) has a high temperature of 90 to 130°C, and the boiling point of pentane is 36.1°C. Therefore, in order to prevent pentane from changing into a gas, a process of cooling the temperature of the heat-treated material below the boiling point of pentane is necessary.
이후, 본 단계에서 펜테인(Pentane)을 첨가하고, 온도를 더 떨어뜨리는데, 펜테인의 칸나비디올(CBD)에 대한 용해도가 내려가면서 칸나비디올(CBD) 과포화 상태가 되며 칸나비디올(CBD) 결정이 용출된다.Then, in this step, pentane is added and the temperature is further lowered. As the solubility of pentane in cannabidiol (CBD) decreases, cannabidiol (CBD) becomes supersaturated and cannabidiol ( CBD) crystals are eluted.
한편, 본 단계에서 칸나비디올(CBD) 결정의 용출 과정은 바람직하게 상기 펜테인(Pentane)을 첨가한 열처리물을 -15~-5℃의 냉동고에 넣어 냉각시킴으로써 용출시키는 것일 수 있다. Meanwhile, in this step, the elution process of cannabidiol (CBD) crystals may be preferably carried out by cooling the heat-treated product to which pentane has been added by placing it in a freezer at -15 to -5°C.
한편, 본 단계는 다양한 용매 중 특히 펜테인을 사용하는 것이 특징이 있다. 본 발명의 칸나비디올(CBD) 결정 제조방법은 칸나비디올(CBD) 뿐만 아니라 칸나비디올산(CBD-A)을 이용하기 때문에 정제 과정에서 더욱 많은 불순물들을 포함하게 된다. 그런데, 하기 실시예에서 다양한 용매를 사용하여 실험한 결과 펜테인을 사용하였을 경우에 결정의 순도 및 수율(결정화율)이 특히 높은 것을 확인할 수 있었다. 게다가, 펜테인은 끓는점이 36.1℃로 낮아 이후 용매 제거에도 용이하다.Meanwhile, this step is characterized by the use of various solvents, especially pentane. Since the cannabidiol (CBD) crystal production method of the present invention uses not only cannabidiol (CBD) but also cannabidiolic acid (CBD-A), more impurities are included during the purification process. However, as a result of experiments using various solvents in the following examples, it was confirmed that the purity and yield (crystallization rate) of crystals were particularly high when pentane was used. In addition, pentane has a low boiling point of 36.1°C, making it easy to remove the solvent afterwards.
한편, 본 단계에서 펜테인은 상기 단계 (b)의 열처리물:펜테인을 1:0.3~5.0의 무게 비율이 되도록 첨가하고, 10~60분 동안 반응시켜 결정화시키는 것일 수 있다. 바람직하게는 열처리물:펜테인을 1:0.3~0.6의 무게비율로 첨가하고 30~60분 동안 반응시켜 결정화시키는 것일 수 있으며, 더욱 바람직하게는 열처리물:펜테인을 1:0.5의 무게비율로 첨가하고 48분 동안 반응시켜 결정화시키는 것일 수 있다. 하기 실시예에 따르면, 상기와 같이 결정화시키는 경우 고순도의 칸나비디올(CBD) 결정을 고수율로 제조할 수 있다.Meanwhile, in this step, pentane may be crystallized by adding the heat-treated product of step (b): pentane at a weight ratio of 1:0.3 to 5.0 and reacting for 10 to 60 minutes. Preferably, heat-treated product:pentane may be added at a weight ratio of 1:0.3 to 0.6 and reacted for 30-60 minutes to crystallize. More preferably, heat-treated product:pentane may be added at a weight ratio of 1:0.5. It may be added and reacted for 48 minutes to crystallize. According to the following examples, when crystallizing as above, high purity cannabidiol (CBD) crystals can be produced in high yield.
한편, 본 발명의 칸나비디올(CBD) 결정 제조방법은 칸나비디올(CBD) 결정의 순도를 더욱 높게 하기 위해 하기 단계 (d)를 더욱 포함하는 것이 좋다.Meanwhile, the method for producing cannabidiol (CBD) crystals of the present invention preferably further includes the following step (d) in order to further increase the purity of cannabidiol (CBD) crystals.
<단계 (d): 칸나비디올(CBD) 결정을 여과하여 1차로 제거한 후, 칸나비디올(CBD) 결정에 -10~0℃의 펜테인(Pentane)을 가하여 잔존한 '결정화되지 않고 남아있는 액체 분획'을 2차로 제거하고, 감압증류하여 펜테인(Pentane) 제거><Step (d): After first removing the cannabidiol (CBD) crystals by filtration, Pentane at -10 to 0°C is added to the cannabidiol (CBD) crystals to remove the remaining 'uncrystallized' crystals. The ‘liquid fraction’ is removed secondarily and pentane is removed by distillation under reduced pressure.>
본 단계는 칸나비디올(CBD) 결정을 여과하여 '결정화되지 않고 남아있는 액체 분획'을 1차로 제거한 후, 칸나비디올(CBD) 결정에 차가운 펜테인(Pentane)을 가하여 잔존한 '결정화되지 않고 남아있는 액체 분획'을 2차로 제거하고, 감압증류하여 펜테인(Pentane)을 제거하는 과정이다.In this step, the cannabidiol (CBD) crystals are filtered to first remove the 'liquid fraction that remains without crystallization', and then cold pentane is added to the cannabidiol (CBD) crystals to remove the remaining 'non-crystallized liquid fraction'. This is a process in which the remaining liquid fraction is removed secondarily and pentane is removed through reduced pressure distillation.
상기 단계 (c)를 통해 칸나비디올(CBD)은 결정화가 되지만 대부분의 다른 불순물들은 결정화가 되지 않고 용매 함께 남아있게 된다. 본 단계는 상기와 같은 '결정화되지 않고 남아있는 액체 분획'(Mother liquid)과 용매를 제거시켜 결정의 순도를 높게해주는 단계이다. Through step (c), cannabidiol (CBD) is crystallized, but most other impurities are not crystallized and remain with the solvent. This step is to increase the purity of the crystal by removing the 'liquid fraction remaining without crystallization' (mother liquid) and solvent as described above.
먼저 본 단계는 간단하게 상기 단계 (c)에서 제조한 칸나비디올(CBD) 결정을 여과하여 '결정화되지 않고 남아있는 액체 분획'을 1차로 제거시킨다.First, in this step, the cannabidiol (CBD) crystals prepared in step (c) are filtered to first remove the 'liquid fraction remaining without crystallization'.
여과된 칸나비디올(CBD) 결정에는 모액이 일부 남아있는데, 칸나비디올(CBD) 결정에 차가운 펜테인(Pentane)을 가하여 칸나비디올(CBD) 결정에 붙어있는 '결정화되지 않고 남아있는 액체 분획'을 2차로 제거시킨다. 이때, 펜테인에 의해 칸나비디올(CBD) 결정이 다시 용해되는 것을 방지하기 위해, 펜테인의 온도가 0℃ 이하인 것을 사용한다. There is some mother liquid remaining in the filtered cannabidiol (CBD) crystals. By adding cold pentane to the cannabidiol (CBD) crystals, the remaining liquid fraction that has not crystallized is attached to the cannabidiol (CBD) crystals. ' is removed secondarily. At this time, in order to prevent cannabidiol (CBD) crystals from being dissolved again by pentane, pentane with a temperature of 0°C or lower is used.
이후, 감압증류하여 칸나비디올(CBD) 결정에 남아있는 펜테인(Pentane)을 제거시킨다. 한편, 펜테인(Pentane)의 증발점은 36.1℃로 낮기 때문에, 상온에서 감압시키는 것으로 펜테인(Pentane)의 제거가 가능하다.Afterwards, pentane remaining in the cannabidiol (CBD) crystals is removed through reduced pressure distillation. On the other hand, since the evaporation point of pentane is low at 36.1°C, it is possible to remove pentane by reducing pressure at room temperature.
이하, 본 발명의 내용을 하기 실시예를 통해 더욱 구체적으로 설명하고자 한다. 다만, 본 발명의 권리범위가 하기 실시예에만 한정되는 것은 아니고 그와 등가의 기술적 사상의 변형까지를 포함한다. Hereinafter, the contents of the present invention will be described in more detail through the following examples. However, the scope of the present invention is not limited to the following examples and includes modifications of the technical idea equivalent thereto.
[실시예 1: 대마 초임계 추출물 제조][Example 1: Preparation of cannabis supercritical extract]
체리 와인 헴프(cherry wine Hemp) 품종의 대마의 화서(꽃)를 35℃에서 48시간 동안 열풍건조 후 나이프밀(knife mile)을 이용하여 분쇄하였다.The inflorescences (flowers) of the cherry wine hemp variety were dried with hot air at 35°C for 48 hours and then ground using a knife mill.
상기 분쇄된 건조 시료 1㎏을 이산화탄소 초임계 추출법을 이용하여 추출하였다. 시료 내 칸나비디올(이하 'CBD'로 기재) 및 칸나비디올산(이하 'CBD-A'로 기재)의 최대 추출 수율 조건을 달성하기 위해, 47.27MPa, 60.45℃, 105.45분 조건으로 추출하였다.1 kg of the pulverized dry sample was extracted using a carbon dioxide supercritical extraction method. In order to achieve the maximum extraction yield conditions of cannabidiol (hereinafter referred to as 'CBD') and cannabidiolic acid (hereinafter referred to as 'CBD-A') in the sample, extraction was performed under the conditions of 47.27MPa, 60.45°C, and 105.45 minutes.
[실시예 2: 칸나비디올(CBD) 결정 제조][Example 2: Preparation of cannabidiol (CBD) crystals]
본 실시예에서는 상기 실시예 1의 대마추출물로부터 고수율로 고순도의 CBD 결정을 제조하였다. In this example, high-purity CBD crystals were prepared in high yield from the hemp extract of Example 1.
2-1) 대마 추출물로부터 CBD 및 CBD-A를 포함하는 정제물 수득 2-1) Obtaining purified products containing CBD and CBD-A from hemp extract
상기 실시예 1에서 제조한 대마추출물에 MPLC를 실시하여 CBD 및 CBD-A가 용출되는 구간에서 정제하였다. The hemp extract prepared in Example 1 was subjected to MPLC and purified in the section where CBD and CBD-A were eluted.
2-2) 대마추출물 내 CBD-A의 CBD로의 전환 2-2) Conversion of CBD-A to CBD in hemp extract
정제한 추출물(CBDA, CBD 순도 60% 이상)을 비커에 넣고, 교반기에서 150 RPM으로 교반하며 90~130℃에서 30~180분 동안 반응시키고, 반응 조건에 따른 CBD/CBD-A 비율을 확인하였다 (도 1). The purified extract (CBDA, CBD purity 60% or more) was placed in a beaker, stirred at 150 RPM on a stirrer, and reacted at 90-130°C for 30-180 minutes, and the CBD/CBD-A ratio was confirmed according to the reaction conditions. (Figure 1).
이를 통해, 온도 125℃에서 50분 동안 반응시키는 경우 CBD/CBD-A 비율이 100 이상을 나타내며, 대부분의 CBD-A이 디카르복실화되어 CBD로 전환된 것을 확인할 수 있었다. Through this, it was confirmed that when reacted at a temperature of 125°C for 50 minutes, the CBD/CBD-A ratio was over 100, and most of the CBD-A was decarboxylated and converted to CBD.
2-3) CBD 결정 제조 용매 선택 2-3) Selection of solvent for preparing CBD crystals
93.15% CBD 순도의 시료 10g에 용매(Pentane, Hexane, Heptane, Isopropyl alcohol) 30mL를 30℃로 첨가하여 희석한 후, -10℃의 냉동고에서 교반기를 이용하여 150RPM에서 30분간 반응시켰다. 모액(Mother liquid)를 1차로 제거한 후, 차가운 상태의 용매를 더욱 가하며 남아있는 모액을 더욱 제거시켰다. 이후, 결정을 상온에서 감압 건조시켜 잔류용매를 제거하고, 결정의 무게 및 순도를 측정하였다 (표 1).10 g of a sample with 93.15% CBD purity was diluted by adding 30 mL of solvent (Pentane, Hexane, Heptane, Isopropyl alcohol) at 30°C, and then reacted at 150 RPM for 30 minutes using a stirrer in a -10°C freezer. After the mother liquid was first removed, a cold solvent was further added to further remove the remaining mother liquid. Afterwards, the crystals were dried under reduced pressure at room temperature to remove residual solvent, and the weight and purity of the crystals were measured (Table 1).
(℃)boiling point
(℃)
(g)decision weight
(g)
(%)water
(%)
이를 통해, Pentane을 사용하였을 경우 결정화율이 65.91%로 가장 높으면서도, 순도 또한 가장 높은 것을 확인할 수 있었다. Through this, it was confirmed that when Pentane was used, the crystallization rate was the highest at 65.91% and the purity was also the highest.
2-4) CBD 결정 제조 반응 최적화2-4) CBD crystal manufacturing reaction optimization
오일 형태의 93.15% CBD 순도의 시료 10g에 Pentane을 하기 표 2의 다양한 조건으로 첨가하여 희석한 후, -10℃의 냉동고에서 교반기를 이용하여 150RPM에서 반응시켰다. 모액(Mother liquid)를 1차로 제거한 후, -10~0℃의 Pentane를 더욱 가하며 남아있는 모액을 2차로 제거시켰다. 이후, 결정을 상온에서 감압 건조시켜 잔류용매를 제거하고, 결정의 무게 및 RGB 값을 측정하였다 (표 2).Pentane was added and diluted to 10 g of a sample of 93.15% CBD purity in oil form under various conditions in Table 2 below, and then reacted at 150 RPM using a stirrer in a -10°C freezer. After removing the mother liquid first, Pentane at -10~0℃ was further added and the remaining mother liquid was removed a second time. Afterwards, the crystals were dried under reduced pressure at room temperature to remove residual solvent, and the weight and RGB values of the crystals were measured (Table 2).
(min)reaction time
(min)
(1:X)Sample:solvent weight ratio
(1:X)
(g)decision weight
(g)
(합산)RGB value
(summation)
상기 표 2의 반응 조건에 따른 반응 결과의 상관관계를 나타내어 도 2의 결과를 얻을 수 있었다. 이를 통해, CBD 결정 제조를 최적화한 결과, 반응 시간은 48분, 시료:용매 무게비율은 0.5인 경우에 결정화율이 높으면서도, RGB값이 676으로 흰색 결정을 얻을 수 있을 것으로 계산할 수 있었다. The results shown in Figure 2 were obtained by showing the correlation of reaction results according to the reaction conditions in Table 2 above. Through this, as a result of optimizing the production of CBD crystals, it was calculated that when the reaction time was 48 minutes and the sample:solvent weight ratio was 0.5, white crystals could be obtained with a high crystallization rate and an RGB value of 676.
이후, 상기 최적화한 반응 시간 및 시료:용매 무게비율로 CBD 결정을 제조하여 검증한 결과 상기 최적화를 통해 계산한 결과와 유사한 결정화 비율 및 RGB 값을 얻을 수 있었다 (표 3).Afterwards, as a result of manufacturing and verifying CBD crystals with the optimized reaction time and sample:solvent weight ratio, crystallization ratio and RGB values similar to the results calculated through the optimization were obtained (Table 3).
(min)reaction time
(min)
(1:X)Sample:solvent weight ratio
(1:X)
Claims (5)
상기 단계 (a) 후, 상기 정제물을 온도 125℃에서 50분 동안 열처리하여 칸나비디올산(CBD-A)이 칸나비디올(CBD)이 되도록 전환시켜, CBD/CBD-A비율이 100 이상인 열처리물을 수득하는 단계 (b);
상기 단계 (b) 후, 상기 열처리물을 냉각한 후 펜테인(Pentane)을 열처리물: 펜테인 1: 0.5의 중량비로 첨가하고, 온도를 더 떨어뜨려 48분 동안 반응시켜 흰색 결정의 칸나비디올(CBD)을 용출시키는 단계 (c);를 포함하는 것을 특징으로 하는 칸나비디올 결정 제조방법.
Medium pressure liquid chromatography (MPLC) was performed on the hemp extract obtained using carbon dioxide supercritical extraction to obtain fractions in the section where cannabidiol (CBD) and cannabidiolic acid (CBD-A) were eluted. Step (a) of obtaining a purified product containing more than 60% (w/w) of cannabidiol (CBD) and cannabidiolic acid (CBD-A);
After step (a), the purified product is heat treated at a temperature of 125°C for 50 minutes to convert cannabidiolic acid (CBD-A) to cannabidiol (CBD), so that the CBD/CBD-A ratio is 100 or more. (b) obtaining water;
After step (b), the heat-treated product was cooled, and then pentane was added at a weight ratio of heat-treated product: pentane 1: 0.5, and the temperature was further lowered and reacted for 48 minutes to produce white crystals of cannabidiol. A method for producing cannabidiol crystals, comprising the step (c) of eluting (CBD).
상기 단계 (c)의 용출은,
상기 '펜테인(Pentane)을 첨가한 열처리물'을 -15~-5℃의 냉동고에서 냉각시켜 수행하는 것을 특징으로 하는 칸나비디올 결정 제조방법.
According to paragraph 1,
The elution in step (c) is,
A method for producing cannabidiol crystals, characterized in that it is performed by cooling the 'heat-treated product to which pentane was added' in a freezer at -15 to -5°C.
상기 칸나비디올 결정 제조방법은,
칸나비디올 결정을 여과하여 1차로 '결정화되지 않고 남아있는 액체 분획'을 제거하고,
칸나비디올 결정에 -10~0℃의 펜테인(Pentane)을 처리하여 잔존한 '결정화되지 않고 남아있는 액체 분획'을 2차로 제거한 후,
감압증류하여 펜테인(Pentane)을 제거하는 단계 (d)를 포함하는 것을 특징으로 하는 칸나비디올 결정 제조방법.
According to paragraph 1,
The method for producing cannabidiol crystals is,
The cannabidiol crystals are filtered to first remove the ‘liquid fraction that remains without crystallization’,
After treating the cannabidiol crystals with pentane at -10 to 0°C, the remaining ‘liquid fraction that has not crystallized’ is secondarily removed.
A method for producing cannabidiol crystals, comprising the step (d) of removing pentane by distillation under reduced pressure.
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