CN104211604A - Eutectic of ambroxol and p-hydroxybenzoic acid and preparation method thereof - Google Patents
Eutectic of ambroxol and p-hydroxybenzoic acid and preparation method thereof Download PDFInfo
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- CN104211604A CN104211604A CN201410405709.XA CN201410405709A CN104211604A CN 104211604 A CN104211604 A CN 104211604A CN 201410405709 A CN201410405709 A CN 201410405709A CN 104211604 A CN104211604 A CN 104211604A
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Abstract
The invention belongs to the technical field of medicine eutectics, and concretely relates to a novel ambroxol medicine eutectic and a preparation method thereof. The space group of the prepared ambroxol medicine eutectic is a monoclinic system, and an elementary unit of the ambroxol medicine eutectic is formed by combining two ambroxol molecules, two p-hydroxybenzoic acid molecules and one water molecule through hydrogen bonds. The medicine eutectic preparation process employs a mixed solvent of methanol and water as the solvent, the employed method is solvent room-temperature volatility method, and because the employed solvent is relatively low in boiling point, the crystal is precipitated during solvent volatilization. The prepared medicine eutectic inherits the ambroxol characteristics of being capable of promoting removal of viscous secretion in respiratory tracts and reducing delay of mucus and the like, and also is obviously improved in stability.
Description
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, be specifically related to a kind of novel Transbroncho pharmaceutical co-crystals and preparation method thereof.
Background technology
1989, crystal engineering was defined as by G.R.Desiraju: the interphase interaction being understood molecule by packing of molecules, had the novel material of certain physics and chemistry character in order to design.If molecule is that atom is connected by covalent linkage and formed, what so molecule was formed by intermolecular interaction is exactly solid supramolecule (crystal).No matter by which kind of intermolecular forces connected between the chemical type of construction unit and these construction units, crystal engineering has become one and has utilized molecule (ion) interphase interaction to come reasonable design, control crystalline structure to obtain valuable novel material.Coordinate bond and hydrogen bond all have directivity and have certain intensity, have become the two kinds of important means realizing controlling molecular arrangement in crystal engineering.By observing, understanding coordinate bond and hydrogen bond to the synergy of molecular arrangement, contribute to our design and control supramolecular structure.Crystallographer and structurizing scholar are devoted to crystal engineering research for many years, and object is to understand dissimilar molecular interaction better, carry out futuramic crystalline material.
Medicine is related to broad masses of the people's life safety and healthy specialty goods, consider storage, take and the factors such as the convenience of carrying and manufacturing cost, major part medicine is all designed to solid dosage, and in the various solid form of medicine, crystal formation medicine is preferentially selected due to the advantage of the aspects such as stability, circulation ratio and operability.Crystal formation medicine includes the polymorphic hydrate of medicine, solvate and salt.Pharmaceutical activity molecule (API) is usually because having different biological activitys containing various functional group.
Current research finds, these functional groups can utilize hydrogen bond or other non covalent bond effect and generate super molecular compound with other organic molecule by intermolecular recognition reaction, i.e. pharmaceutical co-crystals, thus effectively improve the crystal property of medicine itself, physico-chemical property and drug effect, newly select for one that becomes pharmaceutical solid preparation.The organic molecule be introduced into, also referred to as eutectic reagent, can be auxiliary material, VITAMIN, mineral substance, amino acid and foodstuff additive etc., therefore, for a given medicine, hundreds of pharmaceutical co-crystals may be generated, for dosage form design provides more choices.In addition, new pharmaceutical co-crystals can acquire knowledge property right protection, extends the market cycle of original medicine, has broad application prospects.
The applied research of supramolecular chemistry in drug development is the focus that international academic community and industry member are paid close attention to jointly.Pharmaceutical co-crystals is a kind of new crystal that active constituents of medicine and eutectic reagent are formed by Intermolecular Forces (as hydrogen bond), it can improve physico-chemical property and the bioavailability of active constituents of medicine, so in recent years about the research of pharmaceutical co-crystals has become the large focus of pharmaceutical field one.
The medicinal function of Transbroncho mainly contain following some: dissolve glutinous phlegm, sputum discharge function, antioxygenation and scavenging free radicals, the synthesis of promotion pulmonary surfactant (PS) and release, 1. the ammonia mechanism that wherein bromine rope dissolves sticky phlegm suppress DNA to decompose 2. to impel the lysosome of tracheobronchial mucus cell to discharge, 3. make the acidity in sputum glue egg fibre breakage suppresses the mucinous secretion of trachea-bronchial epithelial cell body of gland 4. to increase respiratory tract serous secretion, and sticky phlegm is diluted.Due to the deficiency of its stability and solubleness aspect, this compound obtains FDA (Food and Drug Adminstration) (FDA) approval with the form of Ambroxol HCl, for abnormal with sputum secretion and expectoration dysfunction acute, chronic respiratory system diseases.We obtain Transbroncho and P-hydroxybenzoic acid eutectic by screening a large amount of acid, and have satisfactory stability.
Summary of the invention
Transbroncho pharmaceutical co-crystals that the object of the present invention is to provide a kind of novel texture and preparation method thereof, and its crystalline structure is tested, its performance is characterized.
The present invention is selected bulk drug Transbroncho, the chemical name of Transbroncho is 4-[(amino-3, the 5-dibromo-benzyls of 2-) are amino] hexalin, and molecular formula is C
13h
18br
2n
2o, its its structural formula is as shown in a; P-hydroxybenzoic acid formula is C
7h
6o
3, its structural formula is shown as b; The molecular formula of water is H
2o, its structural formula as shown by c.
Structural formula
The Transbroncho pharmaceutical co-crystals that the present invention prepares, its crystalline structure simplified summary is as follows: the O(O3 in two p-hydroxybenzoic acids) atom is as the donor of hydrogen bond, the O(O9w of a water molecules) atom as hydrogen bond receptor and form two hydrogen bonds, other two hydrogen bonds are by the O(O9w of a water molecules) atom as the donor of hydrogen bond, the O(O1 in two Transbroncho molecules) as hydrogen bond receptor and formed.
The Transbroncho pharmaceutical co-crystals spacer that the present invention prepares is oblique system, its axial length: a=19.105 ~ 19.505, b=14.771 ~ 15.171, c=15.733 ~ 16.133, α=90, β=110.96 ~ 111.36, γ=90, XRD spectrum signature peak value appears at: 7.58 ~ 7.78 °, 9.72 ~ 9.92 °, 10.64 ~ 10.84 °, 11.04 ~ 11.24 °, 14.88 ~ 15.08 °, 15.28 ~ 15.48 °, 17.90 ~ 18.10 °, 18.34 ~ 18.54 °, 19.24 ~ 19.44 °, 19.6 ~ 19.8 °, 21.34 ~ 21.54 °, 22.32 ~ 22.52 °, 22.52 ~ 22.72 °, 22.84 ~ 23.04 °, 2304 ~ 23.24 °, 23.38 ~ 23.58 °, 23.82 ~ 24.02 °, 2464 ~ 24.84 °, 25.56 ~ 25.76 °, 26.02 ~ 26.22 °, 26.5 ~ 26.7 °, 28.04 ~ 28.24 °, 30.02 ~ 30.22 °, 30.5 ~ 30.7 °, 31.1 ~ 31.3 °, 34.6 ~ 34.8 °.
Transbroncho pharmaceutical co-crystals thermogravimetric curve exists, and 153-156 DEG C starts the first step and decompose, and starts second step and decomposes, weightlessness 81.4% altogether at 297-302 DEG C.Pharmaceutical co-crystals prepared by the present invention to reduce phlegm etc. outside speciality in the treatment inheriting original Ambroxol HCl medicine, and its solvability, stability and bioavailability have obvious change.
The preparation method of invention pharmaceutical co-crystals is solvent room temperature volatilization method, and selected solvent is the mixed solvent of first alcohol and water, because the boiling point of selected organic solvent is relatively low, therefore in the process of solvent evaporates, namely has crystal to separate out.Its step is as follows:
(1) Transbroncho 1 ~ 1.7mmol is put into the mixed solvent beaker that 25 ~ 30ml methyl alcohol and water are housed, 10min ~ 30min is stirred as on agitator, drip 1 ~ 1.7mmol P-hydroxybenzoic acid, then stir 30min ~ 60min, Transbroncho and P-hydroxybenzoic acid are fully reacted:
(2) leave standstill volatilization after 5-7 days, start in container to separate out water white transparency needle-like crystal, i.e. Transbroncho pharmaceutical co-crystals.
The instrument of detection of drugs eutectic structure of the present invention and performance thereof is as follows:
1, eutectic structure is measured by X-ray single crystal diffractometer, and full name is a Rigaku SCXmini diffractometer
2, powder diffractometer is produced by German Bruker company, and model is D8-Discover, Cu-K α (λ=1.54056), tube voltage 40KV, tube current 30mA, sweep velocity 8 °/min.
3, thermogravimetric curve is produced by METTLER TOLEDO company, and model is STARe System, adopts nitrogen atmosphere, temperature rise rate 10 DEG C/min.
The destructive test data of Transbroncho and P-hydroxybenzoic acid are as follows:
Stability experiment conclusion: tested by various influence factor, Transbroncho improves 0.23% with the purity of P-hydroxybenzoic acid than the purity of bulk drug Transbroncho, and simultaneously in various destructive test, the stability of eutectic will apparently higher than Transbroncho itself.
The Acceleration study related data of Transbroncho and P-hydroxybenzoic acid is as follows:
Acceleration study interpretation of result: the eutectic that Transbroncho and P-hydroxybenzoic acid are formed is in Acceleration study process, and indices meets the requirements.
Accompanying drawing explanation
Fig. 1: Transbroncho pharmaceutical co-crystals structural unit schematic diagram:
As shown in the figure, O(O3 in two p-hydroxybenzoic acids) atom is as the donor of hydrogen bond, the O(O9w of a water molecules) atom as hydrogen bond receptor and form two hydrogen bonds, other two hydrogen bonds are by the O(O9w of a water molecules) atom as the donor of hydrogen bond, the O(O1 in two Transbroncho molecules) as hydrogen bond receptor and formed.Its axial length: a=19.105 ~ 19.505, b=14.771 ~ 15.171, c=15.733 ~ 16.133, α=90, β=110.96 ~ 111.36, γ=90.
Fig. 2: the XRD figure spectrum of Transbroncho pharmaceutical co-crystals
As shown in the figure, can find out at 7.68 ° from the X-ray diffraction peak of this eutectic of synthesis, 9.82 °, 10.74 °, 11.14 °, 14.98 °, 15.38 °, 18,18 ° of .44,19 ° of .34 °, 19.7 °, 21.44 °, 22.42 °, 22.62 °, 22.94 °,
23.14 °, 23.48 °, 23.92 °, 24.74 °, 25.66 °, 26.12 °, 26.6 °, 28.14 °, 30.12 °, 30.6 °, 31.2 °, 34.7 ° there is series of features peak.
Fig. 3: the thermogravimetric collection of illustrative plates of Transbroncho pharmaceutical co-crystals
This collection of illustrative plates is under the atmosphere test condition of nitrogen, and Transbroncho pharmaceutical co-crystals I thermogravimetric curve, 153-156 DEG C starts the first step and decompose, and starts second step and decomposes, weightlessness 81.4% altogether at 297-302 DEG C.
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and be only limitted to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement made according to ordinary skill knowledge and customary means or the amendment of change, include within the scope of the invention
.
Embodiment 1: use Transbroncho and P-hydroxybenzoic acid synthesis eutectic
The transparent glass instrument that the present invention uses is external import, and capacity is 50ml.
Weigh:
Transbroncho 328mg feeds intake, and P-hydroxybenzoic acid 137mg accurately takes with analytical balance.
Bulk drug dissolves:
Accurately measure 25ml methyl alcohol and 10ml in 50ml beaker with 25ml transfer pipet, stir 10min, solution becomes clarification, stirs 30min.
Solvent room temperature volatilization method:
After solid dissolves completely, take out stirrer, be filled in a clean 50ml transparent glass bottle with analytical paper, seal bottleneck with preservative film, with the several aperture of pinprick, leave standstill volatilization.After about 6 days, have in bottle and separate out white needles colourless transparent crystal.
Claims (3)
1. a Transbroncho pharmaceutical co-crystals, it is characterized in that: this pharmaceutical co-crystals is using Transbroncho as active constituents of medicine, take P-hydroxybenzoic acid as reactant, the eutectic formed in the mixed system of methanol-water, its spacer is oblique system, two Transbroncho (1) molecules, two P-hydroxybenzoic acid (2) and water molecules (3) consist of the elementary cell of Transbroncho pharmaceutical co-crystals together hydrogen bonded, Sauerstoffatom wherein in two p-hydroxybenzoic acids is as the donor of hydrogen bond, the Sauerstoffatom of a water molecules as hydrogen bond receptor and form two hydrogen bonds, other two hydrogen bonds by the Sauerstoffatom of a water molecules as the donor of hydrogen bond, the oxygen of two Transbroncho molecules as hydrogen bond receptor and formed: its axial length: a=19.105 ~ 19.505, b=14.771 ~ 15.171, c=15.733 ~ 16.133, α=90, β=110.96 ~ 111.36, γ=90, XRD spectrum signature peak value appears at: 7.58 ~ 7.78 °, 9.72 ~ 9.92 °, 10.64 ~ 10.84 °, 11.04 ~ 11.24 °, 14.88 ~ 15.08 °, 15.28 ~ 15.48 °, 17.90 ~ 18.10 °, 18.34 ~ 18.54 °, 19.24 ~ 19.44 °, 19.6 ~ 19.8 °, 21.34 ~ 21.54 °, 22.32 ~ 22.52 °, 22.52 ~ 22.72 °, 22.84 ~ 23.04 °, 2304 ~ 23.24 °, 23.38 ~ 23.58 °, 23.82 ~ 24.02 °, 2464 ~ 24.84 °, 25.56 ~ 25.76 °, 26.02 ~ 26.22 °, 26.5 ~ 26.7 °, 28.04 ~ 28.24 °, 30.02 ~ 30.22 °, 30.5 ~ 30.7 °, 31.1 ~ 31.3 °, 34.6 ~ 34.8 °, as shown in Figure 1.
2. the preparation method of Transbroncho pharmaceutical co-crystals I according to claim 1, its step is as follows:
(1) Transbroncho 1 ~ 1.7mmol is put into the mixed solvent beaker that 25 ~ 30ml methyl alcohol and water are housed, 10min ~ 30min is stirred as on agitator, drip 1 ~ 1.7mmol P-hydroxybenzoic acid, then stir 30min ~ 60min, Transbroncho and P-hydroxybenzoic acid are fully reacted:
(2) leave standstill volatilization after 5-7 days, start in container to separate out water white transparency needle-like crystal, i.e. Transbroncho pharmaceutical co-crystals.
3. the preparation method of Transbroncho pharmaceutical co-crystals according to claim 2, is characterized in that, in step (1), in described methyl alcohol and water mixed solvent, the volume ratio of methyl alcohol and water is 1.5 ~ 2.5:1.
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|---|---|---|---|
| CN201410405709.XA CN104211604B (en) | 2014-08-18 | 2014-08-18 | Eutectic of a kind of ambroxol and P-hydroxybenzoic acid and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292116A (en) * | 2014-09-24 | 2015-01-21 | 江苏正大清江制药有限公司 | Ambroxol pharmaceutical cocrystal and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3536713A (en) * | 1966-05-10 | 1970-10-27 | Boehringer Sohn Ingelheim | N-(hydroxy-cyclohexyl)-aminobenzylamines and the salts thereof |
| US3950393A (en) * | 1973-04-13 | 1976-04-13 | Boehringer Ingelheim Gmbh | Aminobenzyl-amides and salts thereof |
| CN1454888A (en) * | 2002-04-29 | 2003-11-12 | 常州市第四制药厂 | Rapid-dissoved ambroxol salt and preparing method thereof |
| AU2004201457A1 (en) * | 1998-07-28 | 2004-05-06 | Nicox S.A. | Nitric esters and nitrate salts of specific drugs |
| CN103073438A (en) * | 2013-02-05 | 2013-05-01 | 山东罗欣药业股份有限公司 | Ambroxol hydrochloride compound refining method |
-
2014
- 2014-08-18 CN CN201410405709.XA patent/CN104211604B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3536713A (en) * | 1966-05-10 | 1970-10-27 | Boehringer Sohn Ingelheim | N-(hydroxy-cyclohexyl)-aminobenzylamines and the salts thereof |
| US3950393A (en) * | 1973-04-13 | 1976-04-13 | Boehringer Ingelheim Gmbh | Aminobenzyl-amides and salts thereof |
| AU2004201457A1 (en) * | 1998-07-28 | 2004-05-06 | Nicox S.A. | Nitric esters and nitrate salts of specific drugs |
| CN1454888A (en) * | 2002-04-29 | 2003-11-12 | 常州市第四制药厂 | Rapid-dissoved ambroxol salt and preparing method thereof |
| CN103073438A (en) * | 2013-02-05 | 2013-05-01 | 山东罗欣药业股份有限公司 | Ambroxol hydrochloride compound refining method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292116A (en) * | 2014-09-24 | 2015-01-21 | 江苏正大清江制药有限公司 | Ambroxol pharmaceutical cocrystal and preparation method thereof |
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Effective date of registration: 20171130 Address after: 223215 Huaian salty new material industrial park, Huaian, Jiangsu Province, Shi Lian Avenue Patentee after: Jiangsu rewin Pharmaceutical Co. Ltd. Address before: 223005 Huaian North Road, Jiangsu, No. 9 HANKOOK Patentee before: Jiangsu Chiatai Qingjiang Pharmaceutical Co., Ltd. |
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