CN101693669B - Minocycline hydrochloride hydrate crystal forms and preparation method thereof - Google Patents

Minocycline hydrochloride hydrate crystal forms and preparation method thereof Download PDF

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Publication number
CN101693669B
CN101693669B CN2009101527834A CN200910152783A CN101693669B CN 101693669 B CN101693669 B CN 101693669B CN 2009101527834 A CN2009101527834 A CN 2009101527834A CN 200910152783 A CN200910152783 A CN 200910152783A CN 101693669 B CN101693669 B CN 101693669B
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China
Prior art keywords
minocycline hydrochloride
alcohol
crystal forms
hydrochloride hydrate
hydrate crystal
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CN2009101527834A
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Chinese (zh)
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CN101693669A (en
Inventor
胡秀荣
顾建明
陈林深
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浙江大学
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Abstract

The invention relates to minocycline hydrochloride hydrate crystal forms and a preparation method thereof. The invention provides two minocycline hydrochloride hydrate crystal forms, wherein an X-ray diffraction map of the crystal form A shows a characteristic diffraction peak in positions of 2 theta(DEG, +/-0.2)7.2 DEG, 7.8 DEG, 12.5 DEG, 12.8 DEG, 13.9 DEG, 15.5 DEG, 17.0 DEG, 17.5 DEG, 17.9 DEG, 18.8 DEG, 20.0 DEG, 20.8 DEG, 21.9 DEG, 22.3 DEG, 23.3 DEG, 24.3 DEG, 25.0 DEG, 26.8 DEG, 27.3 DEG, 29.5 DEG, 31.4 DEG, and the like; and an X-ray diffraction map of the crystal form B shows a characteristic diffraction peak in positions of 2 theta(DEG, +/-0.2) 7.7 DEG, 8.3 DEG, 9.6 DEG, 10.0 DEG, 12.3 DEG, 13.8 DEG, 14.9 DEG, 15.8 DEG, 16.8 DEG, 18.3 DEG, 20.5 DEG, 20.8 DEG, 21.5 DEG, 22.7 DEG, 23.4 DEG, 24.3 DEG, 26.8 DEG, 27.0 DEG, 28.3 DEG, 28.9 DEG, 29.8 DEG, and the like. The method comprises the following steps: dissolving, crystallizing, filtering and drying minocycline hydrochloride in a certain amount of mixed solvent of alcohol and water to form minocycline hydrochloride hydrate crystals. The preparation process is simple, and the crystal forms have the advantages of high stability, convenient production, transportation and storage, and the like.

Description

Minocycline hydrochloride hydrate crystal forms and preparation method thereof
Technical field
The present invention relates to minocycline hydrochloride.Be specifically related to minocycline hydrochloride hydrate crystal forms and preparation method thereof.
Background technology
Minocycline hydrochloride, chemistry is by name: 4, two (dimethylamino)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-four Oxy-1s, 11-dioxy-2-tetracene carboxamide hydrochloride, molecular formula: C23H27N3O7HCl, its structure is following:
Minocycline HCl (MINOCYCLINE HCL, Minomycin, Minocycline, minocin) is a s-generation tsiklomitsin, is a kind of semi-synthetic tsiklomitsin, is used to treat various light, the grade and moderate infection due to the responsive pathogenic bacteria, and clinical efficacy is better.Because Minocycline HCl has highly lipophilic, and fabulous tissue permeability is arranged, can be distributed widely in each tissue of health and the body fluid, the transformation period also is longer than tsiklomitsin, and Plasma Concentration is high, and sterilizing ability is strong.Simultaneously, this medicine can be almost got rid of from urethra steadily, even decompose, its catabolite is also had an anti-microbial activity, therefore, has efficient, wide spectrum, quick-acting, long-acting, characteristics that oral absorption is fast.It all has certain curative effect at aspects such as dermatosis, urinary system, respiratory tract infection, though certain spinoff is arranged, light than tetracyclines, be a kind of anti-infective that is worthy of popularization.
U.S. Pat 3148212, US3226436, US4948136 have reported the synthetic of Minocycline HCl.Patent WO2008/102161A2 has reported three kinds of crystal formations of Minocycline HCl (alkali) and preparation method thereof.Chinese patent CN02132673.8 has reported freeze-dried minocycline hydrochloride powder injection and preparation method thereof, and CN200710018775.1 has reported minocycline hydrochloride microballoons and preparation method thereof etc.The organic acid salt of Minocycline HCl and Minocycline HCl, inorganic acid salt such as vitriol, trichloroacetate, hydrochloride etc. all can be used as medicinal raw material.Compare with Minocycline HCl (alkali), the hydrochloride of Minocycline HCl, promptly minocycline hydrochloride has better solvability, and what use in present most of preparations such as injection, slow releasing tablet, the dripping pill etc. is minocycline hydrochloride.Therefore good stability is provided, the minocycline hydrochloride of being convenient to produce, transport and store crystal formation helps the use of minocycline hydrochloride.
Summary of the invention
The object of the invention provides minocycline hydrochloride hydrate crystal forms and preparation method thereof, and two kinds minocycline hydrochloride hydrate crystal forms (called after crystal form A and crystal form B) is provided, and has good stability, is convenient to produce, transports and stores.
The present invention provides the hydrate crystal forms A of minocycline hydrochloride, and the X ray diffracting spectrum of said crystal form A is 7.2 ° of 2 θ (°, ± 0.2), 7.8 °, 12.5 °, 12.8 °; 13.9 °, 15.5 °, 17.0 °, 17.5 °, 17.9 °, 18.8 °; 20.0 °, 20.8 °, 21.9 °, 22.3 °, 23.3 °, 24.3 °; 25.0 °, 26.8 °, 27.3 °, 29.5 °, places such as 31.4 ° demonstrate characteristic diffraction peak.Thermogravimetric analysis shows, includes 7.0-8.0% solvent (water) in the said crystal form A, in differential thermal analysis curve, a wide endotherm(ic)peak is arranged about 103 ℃, and 201.9 ℃ have a sharp endotherm(ic)peak.
The crystallography parameter is following:
Crystallographic system: quadrature
Spacer: P212121 (19)
Unit cell parameters:
Z=4。
The present invention provides the hydrate crystal forms B of another kind of minocycline hydrochloride, and the X ray diffracting spectrum of said crystal form B is 7.7 ° of 2 θ (°, ± 0.2), 8.3 °, 9.6 °, 10.0 °; 12.3 °, 13.8 °, 14.9 °, 15.8 °, 16.8 °, 18.3 °; 20.5 °, 20.8 °, 21.5 °, 22.7 °, 23.4 °, 24.3 °; 26.8 °, 27.0 °, 28.3 °, 28.9 °, places such as 29.8 ° demonstrate characteristic diffraction peak.Thermogravimetric analysis shows, includes 15.5-16.5% solvent (water) in the crystal formation, in differential thermal analysis curve, about 110 ℃ and 218 ℃ wide endotherm(ic)peak is arranged.
The crystallography parameter is following:
Crystallographic system: six sides
Spacer: P3121 (152)
Unit cell parameters:
Z=6。
The present invention provides the preparation method of the hydrate crystal forms A of minocycline hydrochloride, is minocycline hydrochloride to be added in the mixed solvent of water with a certain amount of alcohol or alcohol dissolve, and crystallization is filtered, drying, forms a kind of crystal of hydrate A of minocycline hydrochloride.Preparation process is following:
(a) minocycline hydrochloride is joined in alcohol or the alcohol and water, reflux, stirring and dissolving (2-5 hour) forms minocycline hydrochloride solution; The volume ratio of the weight of minocycline hydrochloride and solvent is 1: 10~100 in the said solution;
(b) with the crystallization in 0-5 ℃ ice-water bath of above-mentioned solution;
(c) filtering separation obtains solid, in 35-45 ℃ of following vacuum drying (4-10 hour) drying, gets the minocycline hydrochloride crystalline A.
The present invention provides the preparation method of the crystal form B of another kind of minocycline hydrochloride, be with minocycline hydrochloride with dissolving in a certain amount of alcohol and water, crystallization is filtered, drying, forms a kind of hydrate crystal forms B of minocycline hydrochloride.
Preparation process is following:
(a) minocycline hydrochloride is joined in 10-70% (w/w) alcoholic solution, reflux, stirring and dissolving (2-5 hour) forms minocycline hydrochloride solution; The volume ratio of the weight of minocycline hydrochloride and solvent is 1: 5~80 in the said solution;
(b) with the crystallization in the water-bath of (0-15 ℃) of above-mentioned solution;
(c) filtering separation obtains solid, in 35-45 ℃ of following vacuum drying (4-10 hour) drying, gets minocycline hydrochloride crystallization B.
In the method for preparing the minocycline hydrochloride crystal formation of the present invention, used alcohol is: methyl alcohol, ethanol, propyl alcohol, Ucar 35, Virahol, butanols, butyleneglycol, isopropylcarbinol; Preferably methyl alcohol, ethanol, more preferably methyl alcohol.
Description of drawings
Accompanying drawing 1 is the X-ray powder diffraction collection of illustrative plates (XRD) of minocycline hydrochloride crystal form A;
Accompanying drawing 2 is DTA (DSC) figure of minocycline hydrochloride crystal form A;
Accompanying drawing 3 is thermogravimetric analysis (TGA) figure of minocycline hydrochloride crystal form A;
Accompanying drawing 4 is X-ray powder diffraction collection of illustrative plates (XRD) of minocycline hydrochloride crystal form B;
Accompanying drawing 5 is DTA (DSC) figure of minocycline hydrochloride crystal form B;
Accompanying drawing 6 is thermogravimetric analysis (TGA) figure of minocycline hydrochloride crystal form B;
Embodiment
Embodiment 1:
At room temperature, the 0.5g minocycline hydrochloride is dissolved in 40mL90% (w/w) ethanol reflux; Stirred 2 hours, and treated to dissolve fully clarification and be placed on (0-5 ℃) stirring and crystallizing in the ice-water bath, filter; Vacuum-drying (45 ℃) 8 hours gets minocycline hydrochloride hydrate crystal forms A.
Embodiment 2:
The 10g minocycline hydrochloride is dissolved in 100mL90% (w/w) methyl alcohol, and reflux stirs until dissolving (about 4 hours) fully, and cooling (0-5 ℃) stirring and crystallizing is filtered in the ice-water bath, and vacuum-drying (45 ℃) 8 hours gets minocycline hydrochloride hydrate crystal forms A.
Embodiment 3:
The 1g minocycline hydrochloride is dissolved in 20mL70% (w/w) methyl alcohol, and reflux stirs until dissolving (about 2 hours) fully, slowly cools to 0-5 ℃ of crystallization, filters, and vacuum-drying (40 ℃) 6 hours gets minocycline hydrochloride hydrate crystal forms B.
Embodiment 4:
The 20g minocycline hydrochloride is dissolved in the mixed solvent of 100mL methyl alcohol, 20mL ethanol, 60mL water composition, and reflux stirs; Until dissolving (about 5 hours) fully, be cooled to 10-15 ℃, crystallization; Filter, vacuum-drying (45 ℃) 8 hours gets minocycline hydrochloride hydrate crystal forms B.
Embodiment 5:
The 2g minocycline hydrochloride is dissolved in the mixed solvent of 30mL methyl alcohol, 5mL water composition, and reflux is stirred to dissolving (about 3 hours) fully; Cool off in the 0-5 ℃ of ice-water bath, stirring and crystallizing is filtered; Vacuum-drying (40 ℃) 7 hours gets minocycline hydrochloride hydrate crystal forms A.
Embodiment 6:
The 5g minocycline hydrochloride is dissolved in the mixed solvent of 60mL methyl alcohol, 30mL water composition, and reflux is stirred to solution clarification (about 4 hours); Cooling in the ice-water bath (0-5 ℃), static crystallization filters; Vacuum-drying (45 ℃) 8 hours gets minocycline hydrochloride hydrate crystal forms B.

Claims (4)

1. minocycline hydrochloride hydrate crystal forms A is characterized in that: the X ray diffracting spectrum of said minocycline hydrochloride hydrate crystal forms A, 7.2 ° of 2 θ (°, ± 0.2), 7.8 °, 12.5 °; 12.8 °, 13.9 °, 15.5 °, 17.0 °, 17.5 °, 17.9 °; 18.8 °, 20.0 °, 20.8 °, 21.9 °, 22.3 °, 23.3 °; 24.3 °, 25.0 °, 26.8 °, 27.3 °, 29.5 °; 31.4 ° locate, demonstrate characteristic diffraction peak, include the water of 7.0-8.0% in the crystal formation, in differential thermal analysis curve, a wide endotherm(ic)peak is arranged at 103 ℃, 201.9 ℃ have a sharp endotherm(ic)peak; The crystallography parameter is following:
Crystallographic system: quadrature
Spacer: P212121 (19)
Unit cell parameters: a=7.405; (3) b=22.315; (8) c=14.452; (5)
V=2388.28 Z=4。
2. method for preparing minocycline hydrochloride hydrate crystal forms A is characterized in that: with the mixed solvent dissolving of minocycline hydrochloride with a certain amount of alcohol or alcohol and water, crystallization is filtered, and drying forms minocycline hydrochloride hydrate crystal forms A, and preparation process is following:
(a) minocycline hydrochloride is joined in alcohol or the alcohol and water, reflux, stirring and dissolving forms minocycline hydrochloride solution; The weight g of minocycline hydrochloride is 1: 10~100 with the volume ml ratio of solvent in the said solution;
(b) with the crystallization in 0-5 ℃ ice-water bath of above-mentioned solution;
(c) filtering separation obtains solid, 35-45 ℃ of following vacuum drying 4-8 hour drying, gets the minocycline hydrochloride hydrate crystalline A.
3. according to the preparation method of the said minocycline hydrochloride hydrate crystal forms A of claim 2, it is characterized in that: described alcohol is methyl alcohol, ethanol, propyl alcohol, Ucar 35, Virahol, butanols, butyleneglycol, isopropylcarbinol a kind or 2 kinds.
4. according to the preparation method of the said minocycline hydrochloride hydrate crystal forms A of claim 3, it is characterized in that: described alcohol is methyl alcohol or ethanol.
CN2009101527834A 2009-10-13 2009-10-13 Minocycline hydrochloride hydrate crystal forms and preparation method thereof CN101693669B (en)

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PT106063B (en) * 2011-12-19 2017-05-30 Inst Superior Técnico Thermorresistent crystalline minocycline produced by recrystallation with carbon dioxide
CN107954892A (en) * 2017-12-22 2018-04-24 宁夏启元药业有限公司 A kind of method of solvent residual amount in reduction quadracycline
CN108218738A (en) * 2018-03-21 2018-06-29 宁夏泰瑞制药股份有限公司 A kind of preparation method of minocycline hydrochloride

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