CN105732501B - A kind of method that pre- tabletting assisted milling method prepares eutectic - Google Patents
A kind of method that pre- tabletting assisted milling method prepares eutectic Download PDFInfo
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- CN105732501B CN105732501B CN201610080134.8A CN201610080134A CN105732501B CN 105732501 B CN105732501 B CN 105732501B CN 201610080134 A CN201610080134 A CN 201610080134A CN 105732501 B CN105732501 B CN 105732501B
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- eutectic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of methods that pre- tabletting assisted milling method prepares eutectic, it is progress precompressed piece after first mixing eutectic composition, it is ground again after tabletting, carry out tabletting again later, tabletting is combined with grinding, by reasonably adjusting pressure and time, synergistic effect can be generated, improve eutectic efficiency and success rate, it is time saving and energy saving and save raw material.
Description
Technical field
The invention belongs to investigation of materials technical fields, and in particular to a kind of pre- tabletting assisted milling method prepares the side of eutectic
Method.
Technical background
Eutectic refers to that two or more molecules is formed by crystal, eutectic as a kind of functional material, in recent years pharmacy,
The application of electronic material and organic chemical synthesis etc. has received widespread attention.In terms of pharmacy, eutectic process is drug
Active constituent improves its rate of dissolution, thermal stability and mechanical performance provide may, while pharmaceutical co-crystals can also play point
From the effect with purifying active medicine component.
By the excellent properties that eutectic is showed in terms of physical chemistry, the preparation method of eutectic is also ground extensively
Study carefully, currently used eutectic preparation mainly includes that evaporative crystallization, crystallisation by cooling, fusion-crystallization, paste crystallization and solid are ground
Mill method etc..Different preparation methods are often based upon different eutectic formation mechenism processes, and single preparation method often has certain
Therefore limitation develops more preparation methods or householder method means success and prepares the raising of eutectic probability, in addition, passing through
The selection and comparison of more preparation means are conducive to summary and the eutectic mechanism study of eutectic preparation experience.
Solid grinding method is that the mixture that will centainly match passes through mortar craft as preferred eutectic screening technique at present
Grinding or ball mill grinding prepare pharmaceutical co-crystals.Wherein, hand lapping generally requires longer time, and labor intensive is long
Time operation needs certain experiment to protect, and process of lapping be easy to cause local pressure uneven, causes grinding effect bad, real
Test poor repeatability.In addition, grinding duration is difficult to determine for unknown eutectic object system, grinding duration is be easy to cause not enough to drop
The success rate of low eutectic preparation.Then loading and unloading is cumbersome for ball mill grinding, and sample size needed for testing is larger, and cleaning is inconvenient, same right
For unknown eutectic object system, also due to milling time not enough causes preparation to fail.As it can be seen that one kind can be tested rapidly and accurately
The experimental method that unknown material system is demonstrate,proved with the presence or absence of eutectic is significantly to the experimental study of eutectic.In addition, polishing institute
The product of acquisition be powder, form cause structure X-ray powder diffraction test needed for sample size it is larger, this for into
It is to consume very much sample for row high-volume eutectic ligand screening process.Finding one kind can spread out to micro-example progress X-ray
The method for penetrating test is very significant.
Summary of the invention
In order to overcome the shortcomings of present in common grinding mode, the present invention provides when a kind of eutectic success rate height, grinding
Between short, the reproducible pre- tabletting assisted milling method method for preparing eutectic.
The present invention realizes that technical solution used by above-mentioned purpose is to comprise the steps of:
(1) eutectic composition is weighed according to stoichiometric ratio, and carries out physical mixed；
(2) mixture in step 1) is transferred to tablet press machine, adjustment pressure to 10~35MPa, continue tabletting 0.5~
20min obtains flaky mixture；
(3) flaky mixture of step (2) being placed in mortar or ball mill is crushed, grinds, milling time is 1~
10min obtains abrasive flour；
(4) abrasive flour of step (3) being transferred to tablet press machine, adjustment pressure is 10~25MPa, 0.5~2 point of tabletting
Clock obtains lamellar eutectic.
The partial size of above-mentioned eutectic composition is less than 50 μm.
The thickness of above-mentioned lamellar eutectic is 1~3mm.
The method that pre- tabletting assisted milling method of the invention prepares eutectic, be carry out pre- tabletting before the grinding, and
Tabletting again greatly improves the efficiency of grinding using tabletting assisted milling after grinding, and improves the success rate of grinding, pole
It is big to shorten milling time, while manpower is saved, in addition, pressure suffered by sample is stable, uniform, experiment during pre- tabletting
As a result repeatability greatly improves, and the pressure range of tablet press machine is big, can promote the success rate of eutectic preparation by improving pressure,
Gained eutectic of the invention is laminated structure, when it carries out XRD structural analysis, sample size needed for greatly reducing test,
Valable starting materials can be saved for high-volume eutectic ligand screening process, is suitable for laboratory and promotes.
Detailed description of the invention
Fig. 1 is that tabletting assisted milling legal system obtains carbamazepine-succinic acid eutectic X-ray diffracting spectrum in embodiment 1.
Specific embodiment
The following describes the present invention in detail with reference to examples:
Embodiment 1
Now using carbamazepine and succinic acid as eutectic composition, eutectic preparation is realized according to following steps:
(1) carbamazepine 0.156g and succinic acid 0.040g are weighed respectively according to the stoichiometric ratio of 2:1, the two is put in
Medication spoon carries out that 1h is simply mixed in mortar, until being uniformly mixed.
(2) mixture in step 1) poured into the mold of infrared tablet press machine, paved, tablet press machine is transferred to, 25MPa's
Under the conditions of carry out tabletting 0.5 minute, obtain the flaky mixture with a thickness of 1.3mm；
(3) flaky mixture of step (2) is placed in mortar and is ground 1 minute, obtain abrasive flour；
(4) abrasive flour of step (3) is transferred to tablet press machine and continues tabletting 1 minute under 10MPa pressure, obtain thickness
For the lamellar eutectic of 1.5mm.
The lamellar eutectic pressed is carefully taken out, surveys its X-ray diffraction, as shown in the figure.
It as seen from Figure 1, is apparent carbamazepine-succinic acid occur at 5.6 °, 9.6 °, 11.5 ° and 14.3 ° at 2 angles θ
Eutectic diffraction maximum is substantially conformed to the eutectic XRD diffraction pattern of document (Cryst.Eng.Comm.10 (2008) 856-864) report,
Illustrate that grinding efficiency can be improved in tableting processes, grinding can be obtained by eutectic product in a very short period of time, and films test can
To replace powder diffraction, material waste is reduced, saves experimental cost.
Embodiment 2
Now using carbamazepine and succinic acid as eutectic composition, eutectic preparation is realized according to following steps:
(1) same as Example 1.
(2) mixture in step 1) poured into the mold of infrared tablet press machine, paved, tablet press machine is transferred to, 10MPa's
Under the conditions of carry out tabletting 20 minutes, obtain flaky mixture；
(3) flaky mixture of step (2) is placed in mortar and is ground 10 minutes, obtain abrasive flour；
(4) abrasive flour of step (3) is transferred to tablet press machine and continues tabletting 0.5 minute under 10MPa pressure, obtain thickness
Degree is the lamellar eutectic of 3.0mm.
Embodiment 3
Now using carbamazepine and succinic acid as eutectic composition, eutectic preparation is realized according to following steps:
(1) same as Example 1.
(2) mixture in step 1) poured into the mold of infrared tablet press machine, paved, tablet press machine is transferred to, 35MPa's
Under the conditions of carry out tabletting 5 minutes, obtain the flaky mixture with a thickness of 1.2mm；
(3) flaky mixture of step (2) is placed in mortar and is ground 5 minutes, obtain abrasive flour；
(4) abrasive flour of step (3) is transferred to tablet press machine and continues tabletting 2 minutes under 25MPa pressure, obtain thickness
For the lamellar eutectic of 1mm.
Raw material of the invention is not limited only to above-mentioned carbamazepine and succinic acid, applies also for other common eutectic groups
Point, it can also be according to specific raw material appropriate adjustment about pressure and time.
Claims (1)
1. a kind of method that pre- tabletting assisted milling method prepares carbamazepine and succinic acid eutectic, it is characterised in that by following steps
Composition:
(1) carbamazepine 0.156g and succinic acid 0.040g are weighed respectively according to the stoichiometric ratio of 2:1, the two is put in mortar
Middle medication spoon carries out that 1 h is simply mixed, until being uniformly mixed；
(2) mixture in step (1) poured into the mold of infrared tablet press machine, paved, tablet press machine is transferred to, in the item of 25 MPa
It is carried out tabletting 0.5 minute under part, obtains the flaky mixture with a thickness of 1.3mm；
(3) flaky mixture of step (2) is placed in mortar and is ground 1 minute, obtain abrasive flour；
(4) abrasive flour of step (3) is transferred to tablet press machine and continues tabletting 1 minute under 10MPa pressure, obtain with a thickness of
The lamellar eutectic of 1.5mm.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015107017737 | 2015-10-26 | ||
| CN201510701773 | 2015-10-26 |
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| Publication Number | Publication Date |
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| CN105732501A CN105732501A (en) | 2016-07-06 |
| CN105732501B true CN105732501B (en) | 2019-01-15 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004078161A1 (en) * | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazeptine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
| CN102188365A (en) * | 2011-05-11 | 2011-09-21 | 中山大学 | Indissolvable medicament cocrystallizing solid dispersoid and preparation method thereof |
| CN102202753A (en) * | 2008-07-26 | 2011-09-28 | 布拉德福德大学 | Method and product |
-
2016
- 2016-02-04 CN CN201610080134.8A patent/CN105732501B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004078161A1 (en) * | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazeptine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
| CN102202753A (en) * | 2008-07-26 | 2011-09-28 | 布拉德福德大学 | Method and product |
| CN102188365A (en) * | 2011-05-11 | 2011-09-21 | 中山大学 | Indissolvable medicament cocrystallizing solid dispersoid and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 卡马西平-丁二酸共晶热力学研究及溶液络合机理的探索;许慎敏;《天津大学博士论文》;20120903;15-48 |
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| CN105732501A (en) | 2016-07-06 |
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