CN116059164B - Doxycycline hydrochloride solution and preparation method thereof - Google Patents
Doxycycline hydrochloride solution and preparation method thereof Download PDFInfo
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Abstract
The application belongs to the field of new materials, and discloses a doxycycline hydrochloride solution which comprises an organic solvent, and a complex and a complexing agent dissolved in the organic solvent; the complex is a complex of doxycycline hydrochloride and metal ions, and the complexing agent does not carry out a complexing reaction with the metal ions in an organic solvent and carries out a complexing reaction with the metal ions after meeting water, so that the doxycycline hydrochloride solution has higher stability in an anhydrous environment, is convenient for long-term storage, long-distance transportation and the like in practical application, is not greatly influenced by temperature factors, has good stability under low temperature, and has higher doxycycline hydrochloride content in the doxycycline hydrochloride solution, thereby being more convenient for preparing the solution at a terminal.
Description
Technical Field
The invention relates to the field of new materials, in particular to a doxycycline hydrochloride solution and a preparation method thereof.
Background
The doxycycline hydrochloride preparation commonly used in veterinary clinical practice comprises injection, tablet, soluble powder, granule, uterus injectant and the like. The injection and the uterus injecta are not suitable for group administration, and repeated administration is easy to cause stress of livestock and poultry; tablets are susceptible to gastrointestinal pH and content; the doxycycline hydrochloride soluble powder which is most widely used at present has certain defects, and the administration modes of the doxycycline hydrochloride soluble powder mainly have two modes, one mode is that the soluble powder is directly added into an administration barrel, and the soluble powder is directly drunk after being dissolved and is connected with a waterline, but is only suitable for small-scale use; the other is that the soluble powder is prepared into high-concentration liquid medicine, and then diluted by a dosing pump according to a certain proportion, when the high-concentration liquid medicine is prepared, the solubility of doxycycline hydrochloride raw material in water is 5%, although the solubility of the soluble powder is improved, the solubility in water is limited, the air temperature is lower in winter in northern areas, the solubility is correspondingly reduced, and when the high-concentration liquid medicine is combined with the dosing pump, the effect of diluting the solution and water according to any proportion can not be achieved; meanwhile, the water-soluble auxiliary materials of the soluble powder are mostly glucose, the water-soluble auxiliary materials are strong in hygroscopicity and easy to agglomerate, the phenomena of precipitation, uneven dissolution and the like are easy to occur when the water-soluble auxiliary materials are dissolved in ultrahigh concentration, and then the water-soluble auxiliary materials are amplified by a dosing pump, so that concentration errors are larger, the terminal dosing concentration is insufficient, the treatment effect is not achieved, drug resistance is easy to occur after long-term use, drug use barriers are caused, bacteria are easy to breed, and nipple, waterline and the dosing pump are blocked to cause further loss. The doxycycline hydrochloride solution is orally administered after being diluted by drinking water, so that the compliance of livestock and poultry is good, the stress response of animals in the administration process is reduced, the administration dosage can be accurately grasped by combining the dilution of an administration pump, the absorption is quick, and an accurate, convenient and stable administration selection is provided for the current intensive culture.
Chinese patent 2015137198. X discloses a doxycycline hydrochloride injection and a preparation process thereof, wherein each 100 ml of the injection comprises: 4.2 to 12.4 portions of magnesium chloride complexing agent, 5 to 15 portions of doxycycline hydrochloride, 20 to 30 portions of alpha-pyrrolidone ml, 10 to 20 portions of dimethylformamide ml, 10 to 20 portions of glycerol formal ml, 0.1 to 0.2 portion of antioxidant g, 5 to 10 portions of cosolvent g and the balance of water for injection.
The complexing agent magnesium chloride used in the scheme mainly plays a role in complexing metal ion magnesium, and the complex is formed by utilizing the complexing characteristic of doxycycline and metal ions so as to improve the solubility and stability of doxycycline hydrochloride.
Chinese patent 201210300975.7 discloses a doxycycline hydrochloride injection for animals and a preparation method thereof, wherein a proper amount of antioxidant and stabilizer are dissolved in water for injection, then the water solution is added into an organic solvent, doxycycline hydrochloride and a complexing agent are added, the pH is regulated, the temperature is kept, then a metal ion chelating agent and partial antioxidant are added, and then the nitrogen is filtered, filled and sterilized to obtain the doxycycline hydrochloride injection for animals.
When the 38 th stage of the specification is observed, in order to ensure the complexing effect of doxycycline hydrochloride, excessive complexing agent is often added, but at the same time, excessive magnesium ions and various trace metal ions brought in by other reagents, solvents or equipment can accelerate the oxidative discoloration of the medicine, so that the chelating agent is used for shielding the excessive magnesium ions and other trace metal ions.
On one hand, the complexing agent in the two schemes is mainly used for complexing superfluous magnesium ions in the medicine or various trace metal ions brought by other reagents, solvents or equipment and the like so as to prevent the magnesium ions and other trace metal ions from accelerating the oxidation of the medicine;
on the other hand, the injection phase is shorter than the peak time of the oral liquid, the effect is quicker, but at the same time, the injection phase is unfavorable for the multiple group administration relative to the oral liquid, in a large-scale livestock farm, the injection phase is in an oral form, although the peak time is prolonged to a certain extent, the mode of carrying out large-scale administration on livestock by a waterline is more convenient, meanwhile, the stress of the livestock can be reduced, the compliance is good, and the cost can be controlled to a certain extent.
Chinese patent 202111242374.0 discloses a doxycycline hydrochloride solution and a preparation method thereof, wherein the solution comprises doxycycline hydrochloride, absolute ethyl alcohol and 1, 2-propylene glycol, the solution isolates water through an organic system consisting of the absolute ethyl alcohol and the 1, 2-propylene glycol, the reaction of dissociation, degradation and the like of the doxycycline hydrochloride in water is avoided, the generation of isomers in the doxycycline hydrochloride solution is also hindered, meanwhile, the solution contains 0.1-1 g complexing agent in every 100 ml in the 16 th section of the specification, and the complexing agent is used for combining with a small amount of metal ions in the doxycycline raw material medicine to increase the stability of the doxycycline hydrochloride solution.
The problem that this scheme needs to solve: how to make doxycycline hydrochloride exist stably in the form of high-concentration solution and can be released stably and quickly when meeting water.
Disclosure of Invention
The invention aims to provide a doxycycline hydrochloride solution, wherein doxycycline hydrochloride in the doxycycline hydrochloride solution is complexed with metal ions to form a complex, the complex is dissolved in an organic solvent, and the organic solvent contains a complexing agent which is not complexed with the metal ions in the organic solvent; when the doxycycline hydrochloride solution meets water, the complexing agent is complexed with metal ions, and doxycycline hydrochloride in the complex is released, so that the doxycycline hydrochloride solution has higher stability in an anhydrous environment, and when the doxycycline hydrochloride solution is used, only the doxycycline hydrochloride solution needs to be diluted by water.
To achieve the above object, the present application discloses a doxycycline hydrochloride solution, comprising an organic solvent, and a complex and a complexing agent dissolved in the organic solvent; the complex is a complex of doxycycline hydrochloride and metal ions, and the complexing agent does not carry out a complexing reaction with the metal ions in an organic solvent and carries out a complexing reaction with the metal ions after meeting water.
Preferably, the concentration of the complex in the organic solvent, calculated as doxycycline, is 10-30wt%.
More preferably, the concentration of the complex in the organic solvent, calculated as doxycycline, is 10wt%, 15wt%, 20wt%, 25wt% or 30wt%.
It should be noted that the upper limit of the concentration of the complex in terms of doxycycline of the present invention may be higher, but it was found in experiments that when it is up to 50% or more, the complexing agent cannot be infinitely dissolved based on the limitation of the solubility of the complexing agent, resulting in the failure of the final doxycycline to be completely released, and thus the present invention selects the range of 10 to 30wt% as the protection range of the present invention.
Preferably, the metal ion is one or more of magnesium ion, calcium ion, zinc ion, aluminum ion and copper ion.
More preferably, the metal ion is one or more of zinc ion, aluminum ion and calcium ion.
Preferably, the complexing agent is at least one of sodium acetate, disodium edetate, sodium ascorbate, sodium tert-butoxide and sodium citrate.
More preferably, the complexing agent is at least one of sodium citrate, sodium acetate and disodium edetate.
Preferably, the mass ratio of doxycycline to complexing agent in the complex is 1:0.1-0.4;
more preferably, the mass ratio of doxycycline to complexing agent in the complex is 1:0.1111-0.361;
more preferably, the mass ratio of complexing agent to doxycycline in the complex includes, but is not limited to, 0.111: 1. 0.161: 1. 0.211: 1. 0.261: 1. 0.311: 1. 0.361:1.
preferably, the organic solvent is selected from one or more of 1, 2-propylene glycol, dimethyl sulfoxide, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, alpha-pyrrolidone, glycerol formal, polyethylene glycol 200, polyethylene glycol 400.
More preferably, the organic solvent is at least one selected from glycerol formal, methanol, 1, 2-propanediol, dimethyl sulfoxide, polyethylene glycol 200, N-dimethylformamide, and α -pyrrolidone.
In addition, the preparation method of the doxycycline hydrochloride solution comprises the following steps:
step 1: preparing a complex, namely mixing doxycycline hydrochloride with a metal ion solution to obtain the complex;
step 2: and (3) preparing the doxycycline hydrochloride solution, namely dissolving the complex and the complexing agent prepared in the step (1) into an organic solvent to obtain the doxycycline hydrochloride solution.
Preferably, the specific operation of step 1 is: in a water bath environment at 0 ℃, doxycycline hydrochloride is dissolved in methanol to obtain a reaction solution A; in the practical operation process, the doxycycline hydrochloride saturated solution is recommended to be prepared;
preparing a metal ion aqueous solution according to the molar ratio of metal ions to doxycycline hydrochloride of 1-1.5:1 to obtain a reaction solution B; because the invention only needs to obtain yellow precipitate, the concentration of the metal ion aqueous solution is not limited, and various concentrations can form precipitate; this is a conventional technique in the art;
adding the reaction solution B into the reaction solution A in a dropwise or batchwise manner, performing the whole reaction in a water bath environment at 0 ℃, stirring while adding, precipitating, filtering, washing, and drying the precipitate to obtain a complex;
the specific operation of the step 2 is as follows: heating organic solvent to 50-65deg.C, adding complex, stirring to dissolve complex, adding complexing agent, and stirring to dissolve completely to obtain doxycycline hydrochloride solution.
In addition, a preparation method of doxycycline hydrochloride is disclosed, and the doxycycline hydrochloride solution and water are mutually dissolved in any ratio for drinking.
Preferably, doxycycline hydrochloride solution is mixed with water at 1:10-2000 mass ratio, and drinking after mutual dissolution;
more preferably, the doxycycline hydrochloride solution is consumed after being mutually dissolved with water in a mass ratio of 1:1000, 1:2000, 1:10, 1:20, 1:50.
The beneficial effects of this application are: the doxycycline hydrochloride in the doxycycline hydrochloride solution is complexed with metal ions to form a complex, the complex is dissolved in an organic solvent, and the organic solvent contains a complexing agent which is not complexed with the metal ions in the organic solvent; when the doxycycline hydrochloride solution meets water, the complexing agent competes with the doxycycline hydrochloride for metal ions, so that the complex is dissociated and restored to doxycycline hydrochloride, the doxycycline hydrochloride solution has higher stability in an anhydrous environment, long-term storage, long-distance transportation and the like are convenient in practical application, meanwhile, the doxycycline hydrochloride solution is not greatly influenced by temperature factors, has good stability under the low-temperature condition, and the doxycycline hydrochloride content in the doxycycline hydrochloride solution is higher, so that the solution is more convenient for terminal preparation.
Drawings
FIG. 1 is a spectrum of doxycycline;
FIG. 2 is a spectrum of doxycycline magnesium complex;
FIG. 3 is a spectrum of doxycycline zinc complex;
FIG. 4 is a 3D spectrum of doxycycline;
FIG. 5 is a 3D spectrum of doxycycline magnesium.
Detailed Description
The present invention will be described more fully hereinafter with reference to the accompanying drawings, in which specific conditions, either conventional or manufacturer-suggested, are not explicitly stated. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
Step 1: preparing a complex, namely dissolving doxycycline hydrochloride in methanol, and carrying out water bath on a NaCl solution at the temperature of 0 ℃ to obtain a reaction solution A;
according to Mg 2+ MgCl is weighed with doxycycline according to the mol ratio of 1.5:1 2 Formulated into MgCl 2 An aqueous solution to obtain a reaction solution B;
dropwise adding a reaction solution B into the reaction solution A, performing the whole reaction in a water bath environment of NaCl solution at 0 ℃, stirring while dropwise adding, filtering until precipitation is separated out, washing the precipitation with ice methanol, and drying after washing to obtain a yellow complex;
step 2: the preparation of doxycycline hydrochloride solution, heating a proper amount of glycerol formal at 50-65 ℃, adding a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex), stirring while adding, dissolving, adding 3 g sodium acetate and 0.11 g disodium ethylenediamine tetraacetate, stirring, dissolving, fixing the volume to 100 ml, cooling, and filtering to obtain the doxycycline hydrochloride solution with the concentration of 10%.
Description: national standard Assembly for veterinary use-local standard for veterinary use, up to the national standard (first book) page 182, doxycycline hydrochloride soluble powder, usage and dosage: calculated as doxycycline;
that is, the weight expression in all examples and comparative examples of the present invention with respect to the complex is not represented as the weight of the complex nor as the weight of doxycycline hydrochloride, but refers to the weight of doxycycline in the complex.
Example 2
Substantially the same as in example 1, except that:
step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, heating a proper amount of glycerol formal at 50-65 ℃, adding a complex formed by doxycycline hydrochloride and magnesium ions (the doxycycline is 20g in the complex), stirring while adding, dissolving, adding 6 g sodium acetate and 0.22 g disodium ethylenediamine tetraacetate, stirring, dissolving, fixing the volume to 100 ml, cooling, and filtering to obtain the doxycycline hydrochloride solution with 20% concentration.
Example 3
Substantially the same as in example 1, except that:
step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, heating a proper amount of glycerol formal at 50-65 ℃, adding a complex formed by doxycycline hydrochloride and magnesium ions (30 g of doxycycline in the complex), stirring while adding, dissolving, adding 9 g sodium acetate and 0.33 g disodium ethylenediamine tetraacetate, stirring, dissolving, fixing the volume to 100 ml, cooling, and filtering to obtain the doxycycline hydrochloride solution with the concentration of 30%.
Example 4
Substantially the same as in example 1, except that:
step 1: preparing a complex, namely dissolving doxycycline hydrochloride in methanol, and carrying out water bath on a NaCl solution at the temperature of 0 ℃ to obtain a reaction solution A;
al is added with 3+ AlCl with doxycycline in a molar ratio of 3:4 3 Formulated into AlCl 3 An aqueous solution to obtain a reaction solution B;
dropwise adding a reaction solution B into the reaction solution A, performing the whole reaction in a water bath environment of NaCl solution at 0 ℃, stirring while dropwise adding, filtering until precipitation is separated out, washing the precipitation with ice methanol, and drying after washing to obtain a yellow brown complex;
step 2: the same as in step 2 of example 1.
Example 5
Substantially the same as in example 1, except that:
step 1: preparing a complex, namely dissolving doxycycline hydrochloride in methanol, and carrying out water bath on a NaCl solution at the temperature of 0 ℃ to obtain a reaction solution A;
cu is added with 2+ CuCl with doxycycline in a molar ratio of 1.5:1 2 Formulated as CuCl 2 Obtaining a reaction solution B;
dropwise adding a reaction solution B into the reaction solution A, performing the whole reaction in a water bath environment of NaCl solution at 0 ℃, stirring while dropwise adding, filtering until precipitation is separated out, washing the precipitation with ice methanol, and drying after washing to obtain a dark green complex;
step 2: the same as in step 2 of example 1.
Example 6
Substantially the same as in example 1, except that:
step 1: preparing a complex, namely dissolving doxycycline hydrochloride in methanol, and carrying out water bath on a NaCl solution at the temperature of 0 ℃ to obtain a reaction solution A;
ca is added with 2+ CaCl with doxycycline in a molar ratio of 1.5:1 2 Is prepared into CaCl 2 Obtaining a reaction solution B;
dropwise adding a reaction solution B into the reaction solution A, performing the whole reaction in a water bath environment of NaCl solution at 0 ℃, stirring while dropwise adding, filtering until precipitation is separated out, washing the precipitation with ice methanol, and drying after washing to obtain a yellow brown complex;
step 2: the same as in step 2 of example 1.
Example 7
Substantially the same as in example 1, except that:
step 1: preparing a complex, namely dissolving doxycycline hydrochloride in methanol, and carrying out water bath on a NaCl solution at the temperature of 0 ℃ to obtain a reaction solution A;
zn is added 2+ With doxycycline in a molar ratio of 3: znCl of 4 2 Preparation into ZnCl 2 Obtaining a reaction solution B;
dropwise adding a reaction solution B into the reaction solution A, performing the whole reaction in a water bath environment of NaCl solution at 0 ℃, stirring while dropwise adding, filtering until precipitation is separated out, washing the precipitation with ice methanol, and drying after washing to obtain a yellow complex;
step 2: the same as in step 2 of example 1.
Example 8
Substantially the same as in example 1, except that:
step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, heating a proper amount of glycerol formal at 50-65 ℃, adding a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex), stirring while adding, dissolving, adding 3.5 g sodium citrate and 0.11 g disodium ethylenediamine tetraacetate, stirring, dissolving, fixing the volume to 100 ml, cooling and filtering to obtain the doxycycline hydrochloride solution.
Example 9
Substantially the same as in example 1, except that:
step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, which is to heat a proper amount of glycerol formal at 50-65 ℃, add a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex), stir while adding, and add the following materials in a mass ratio of 2:1 and sodium citrate of 3.3 g and 0.11 g of disodium edetate are stirred, dissolved and fixed to a volume of 100 ml, cooled and filtered to obtain doxycycline hydrochloride solution.
Example 10
Substantially the same as in example 1, except that:
step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, which is to heat a proper amount of glycerol formal at 50-65 ℃, add a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex), stir while adding, and add the following materials in a mass ratio of 2:1 and sodium citrate 3.3 g and 0.11 g of disodium edetate are stirred, dissolved and fixed to a volume of 100 ml, cooled and filtered to obtain doxycycline hydrochloride solution.
Example 11
Substantially the same as in example 1, except that:
step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, heating a proper amount of glycerol formal at 50-65 ℃, adding a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex), stirring while adding, and adding the solution with a mass ratio of 1:1 and sodium ascorbate 3 g,0.11 g disodium edetate are stirred, dissolved, fixed to volume of 100 ml, cooled and filtered to obtain doxycycline hydrochloride solution.
Example 12
Substantially the same as in example 1, except that:
step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, heating a proper amount of glycerol formal at 50-65 ℃, adding a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex), stirring while adding, dissolving, adding 1 g tertiary sodium butoxide and 0.11 g disodium ethylenediamine tetraacetate, stirring, dissolving, fixing the volume to 100 ml, cooling and filtering to obtain the doxycycline hydrochloride solution.
Example 13
Substantially the same as in example 1, except that the mass ratio of the complexing agent to the complex was 0.4:1.
example 14
Substantially the same as in example 1, except that the mass ratio of the complexing agent to the complex was 0.1:1.
example 15
Step 1: the same as in step 1 of example 1;
step 2: preparation of doxycycline hydrochloride solution glycerin formal and 1, 2-propanediol in 1:2 (v/v)
Mixing to obtain reaction solution C, heating the reaction solution C at 60-65 ℃, adding a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex), stirring while adding, dissolving, adding 3 g sodium acetate and 0.11 g disodium ethylenediamine tetraacetate, stirring, dissolving, fixing the volume to 100 ml by using the reaction solution C, cooling, and filtering to obtain doxycycline hydrochloride solution.
Example 16
Step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, namely uniformly mixing dimethyl sulfoxide and polyethylene glycol 200 according to a ratio of 2:1 (v/v) to obtain a reaction solution D, taking a proper amount of the reaction solution D, heating the reaction solution D at a temperature of between 60 and 65 ℃, adding a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex), stirring the mixture while adding the complex, adding 3 g sodium acetate after dissolving, 0.11 g disodium ethylenediamine tetraacetate, stirring and dissolving, fixing the volume to 100 ml by using the reaction solution D, and cooling and filtering the mixture to obtain the doxycycline hydrochloride solution.
Example 17
Step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, namely uniformly mixing N, N-dimethylformamide and alpha-pyrrolidone 1:1 (v/v) to obtain a reaction solution E, heating a proper amount of the reaction solution E, adding a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex is calculated by doxycycline), stirring while adding, dissolving, adding 3 g sodium acetate and 0.11 g disodium ethylenediamine tetraacetate, stirring, dissolving, fixing the volume to 100 ml by using the reaction solution E, cooling and filtering to obtain a doxycycline hydrochloride solution;
the reaction temperature of the example 17 is slightly lower than that of the example 15 and the example 16, because the N, N-dimethylformamide is heated in the system at a high temperature for a long time, the condition of darker color of the primary raw solution is easy to generate, and the dissolution time is longer when the temperature is too low, and the temperature is controlled at 55-60 ℃ through test verification.
Comparative example 1
Substantially the same as in example 1, except that:
step 1: the same as in step 1 of example 1;
step 2: the preparation of doxycycline hydrochloride solution, heating a proper amount of glycerol formal at 50-65 ℃, adding a complex formed by doxycycline hydrochloride and magnesium ions (10 g of doxycycline in the complex), stirring while adding, after dissolving completely, fixing the volume to 100 ml, cooling and filtering to obtain the doxycycline hydrochloride solution.
The doxycycline hydrochloride solution is diluted with water to generate a large amount of light yellow flocculent precipitate.
Comparative example 2
The preparation of doxycycline hydrochloride solution, heating a proper amount of glycerol formal at 50-65 ℃, adding doxycycline hydrochloride (10 g as doxycycline), stirring while adding, after complete dissolution, fixing the volume to 100 ml, cooling and filtering to obtain the doxycycline hydrochloride solution.
The solution has a darkening color after 48 h storage in a light-proof room temperature closed environment, and has a light-proof soy sauce color after one week, and a small amount of crystals are separated out from the bottom.
As can be seen from comparative example 1, when no complexing agent was added to the doxycycline hydrochloride solution, a large amount of pale yellow flocculent precipitate was formed after the doxycycline hydrochloride was diluted with water. Indicating that doxycycline hydrochloride metal ion complex has poor water solubility, doxycycline hydrochloride cannot be completely dissociated.
As can be seen from comparative example 2, when doxycycline hydrochloride was directly dissolved in an organic solvent and a doxycycline hydrochloride solution was prepared, the doxycycline hydrochloride solution appeared to have a darkened color after 48 h storage in a light-proof room temperature closed environment, and appeared to be light-tight soy color after one week, and a small amount of crystals were precipitated at the bottom. The property and stability of the liquid medicine are not up to the expected requirement.
Stability test after dilution:
according to the actual situation of veterinary clinical application, the doxycycline hydrochloride solution prepared by the scheme is directly diluted with water and then enters a waterline for livestock and poultry to use, and the dilution ratio of the stock solution to the water is 1:1000-2000; the large-scale farms are usually matched with a drug adding device for use, stock solution and water are firstly concentrated to prepare uniform and stable solution, and then the drug adding device is used for diluting the solution according to a certain dilution ratio (1:50-500), and the concentration process is generally carried out with the dilution ratio of 1:10-50. In addition, the waterline drug administration is divided into concentrated drinking water and whole day drinking water, and the concentrated drinking water mode is adopted in which the drugs are mixed with water and then concentrated in a short time to be drunk, generally about 3 hours; the drinking time is generally about 8 hours when drinking water in the whole day, so the solution of doxycycline hydrochloride prepared by the scheme is examined for stability of 4 hours, 8 hours and 12 hours after being diluted with water according to different proportions, and the results are shown in the following table:
table 1: stability test results of doxycycline hydrochloride solution at 10-fold dilution
| Group of | 0h | After 4h of dilution | After dilution for 8h | After dilution for 12h | Difference value |
| Example 1 | 100.50% | 100.20% | 98.40% | 97.80% | 2.70% |
| Example 2 | 99.80% | 99.80% | 99.20% | 97.20% | 2.60% |
| Example 3 | 100.40% | 100.50% | 99.50% | 97.70% | 2.70% |
| Example 4 | 101.00% | 100.90% | 100.00% | 98.50% | 2.50% |
| Example 5 | 100.70% | 100.30% | 99.40% | 97.90% | 2.80% |
| Example 6 | 100.20% | 99.90% | 98.70% | 97.60% | 2.60% |
| Example 7 | 100.40% | 99.90% | 99.20% | 98.10% | 2.30% |
| Example 8 | 100.90% | 100.30% | 99.60% | 98.60% | 2.30% |
| Example 9 | 100.60% | 100.10% | 99.30% | 98.10% | 2.50% |
| Example 10 | 100.20% | 99.60% | 98.90% | 97.80% | 2.40% |
| Example 11 | 101.00% | 100.5% | 99.60% | 98.50% | 2.50% |
| Example 12 | 100.00% | 98.30% | 97.50% | 96.80% | 3.20% |
| Example 13 | 100.80% | 99.90% | 99.00% | 98.30% | 2.50% |
| Example 14 | 100.50% | 99.80% | 98.30% | 97.80% | 2.70% |
| Example 15 | 100.30% | 100.00% | 99.50% | 98.60% | 1.70% |
| Example 16 | 101.10% | 100.30% | 98.90% | 97.30% | 3.80% |
| Example 17 | 100.40% | 98.00% | 97.40% | 96.20% | 4.20% |
Table 2: stability test results of doxycycline hydrochloride at 50-fold dilution
| Group of | 0h | After 4h of dilution | After dilution for 8h | After dilution for 12h | Difference value |
| Example 1 | 101.00% | 100.70% | 99.50% | 98.40% | 2.60% |
| Example 2 | 100.80% | 100.20% | 99.40% | 98.20% | 2.60% |
| Example 3 | 100.50% | 99.90% | 99.10% | 98.00% | 2.50% |
| Example 4 | 101.60% | 101.00% | 100.30% | 99.20% | 2.40% |
| Example 5 | 101.10% | 100.70% | 99.40% | 98.30% | 2.80% |
| Example 6 | 101.90% | 101.20% | 100.00% | 99.40% | 2.50% |
| Example 7 | 100.20% | 99.70% | 99.20% | 97.90% | 2.30% |
| Example 8 | 100.90% | 100.10% | 99.50% | 98.00% | 2.90% |
| Example 9 | 100.00% | 99.30% | 98.80% | 97.50% | 2.50% |
| Example 10 | 100.10% | 99.60% | 99.10% | 97.70% | 2.40% |
| Example 11 | 101.10% | 100.70% | 99.60% | 98.50% | 2.60% |
| Example 12 | 100.60% | 99.70% | 98.30% | 97.50% | 3.10% |
| Example 13 | 101.10% | 100.00% | 98.50% | 98.50% | 2.60% |
| Example 14 | 100.10% | 99.70% | 98.60% | 97.50% | 2.60% |
| Example 15 | 100.60% | 100.10% | 99.60% | 98.10% | 2.50% |
| Example 16 | 101.80% | 100.70% | 99.40% | 98.30% | 3.50% |
| Example 17 | 101.90% | 100.50% | 98.70% | 97.60% | 4.30% |
Table 3: stability test results of doxycycline hydrochloride at a dilution factor of 2000
| Group of | 0h | After 4h of dilution | After dilution for 8h | After dilution for 12h | Difference value |
| Example 1 | 100.70% | 99.90% | 98.40% | 97.70% | 3.00% |
| Example 2 | 101.20% | 100.80% | 100.50% | 98.30% | 2.90% |
| Example 3 | 100.10% | 99.50% | 99.00% | 97.10% | 3.00% |
| Example 4 | 100.90% | 100.30% | 99.60% | 98.30% | 2.60% |
| Example 5 | 101.90% | 100.70% | 99.50% | 98.00% | 3.90% |
| Example 6 | 101.20% | 100.50% | 99.90% | 98.50% | 2.70% |
| Example 7 | 100.40% | 100.00% | 99.70% | 98.50% | 1.90% |
| Example 8 | 100.40% | 99.90% | 99.00% | 97.90% | 2.50% |
| Example 9 | 101.90% | 101.50% | 100.80% | 99.30% | 2.60% |
| Example 10 | 101.00% | 99.90% | 99.00% | 98.50% | 2.50% |
| Example 11 | 100.50% | 99.80% | 98.60% | 97.90% | 2.60% |
| Example 12 | 101.80% | 101.40% | 100.90% | 100.30% | 1.50% |
| Example 13 | 100.40% | 99.90% | 99.20% | 97.90% | 2.80% |
| Example 14 | 100.10% | 99.70% | 98.60% | 97.30% | 2.50% |
| Example 15 | 100.80% | 100.30% | 99.80% | 99.10% | 1.70% |
| Example 16 | 101.40% | 99.90% | 98.60% | 97.80% | 3.60% |
| Example 17 | 100.90% | 99.70% | 98.50% | 96.90% | 4.00% |
The differences shown in tables 1 to 3 refer to the value of 0h minus the value of 12 h.
Analysis of results:
from the analysis of tables 2 and 3 (data representative not strong due to the too high concentrations of table 1), the following conclusions can be drawn:
1. referring to examples 1-3, there was no obvious correlation between stability and stock solution concentration after 12 hours of dilution when doxycycline hydrochloride solution was diluted 50-fold and 2000-fold, and the gap between examples 1-3 was not large.
2. Referring to examples 1, 4-7, example 7 performed best when doxycycline hydrochloride solution was diluted 50-fold, and example 7 performed best when diluted 2000-fold after 12h, indicating that zinc ion complexation was the best choice, both at high and low concentrations.
3. Reference example 1, examples 8-12, which list complexing agents as: sodium acetate: disodium edetate = 3:0.11, sodium citrate: disodium edetate = 3.5:0.11, sodium acetate: sodium citrate: disodium edetate = 2.2:1.1:0.11, sodium ascorbate: sodium citrate: disodium edetate = 2.2:1.1:0.11, sodium acetate: sodium ascorbate: disodium edetate = 1.5:1.5:0.11, sodium tert-butoxide: disodium edetate=1:0.11; example 10 performed best when doxycycline hydrochloride solution was diluted 50-fold, and example 12 performed best when diluted 2000-fold after 12h, it was seen that the formulation of ascorbic acid, sodium citrate and disodium edetate was the best choice when dilution was low and sodium tert-butoxide and disodium edetate was the best choice when dilution was high.
4. Referring to examples 1, 13 and 14, it can be seen that the effect on stability is minor in the case of an excess amount of complexing agent.
5. Referring to examples 1, 15-17, it can be seen that the stability of examples 1, 15 is optimal at high concentrations, but the difference is not to a significant extent, and that example 15 is optimal at low concentrations, that is, it is most preferable to use glycerol formal with 1, 2-propanediol as the organic phase.
In actual production, metal ions, complexing agents and organic solvents can be flexibly prepared according to the guidance of the experimental results so as to adapt to different dilution concentrations.
Performance test:
1. doxycycline hydrochloride and metal ion complex ultraviolet spectroscopy assay: doxycycline hydrochloride and a metal ion complex generated by the doxycycline hydrochloride are dissolved in DMSO to prepare a solution of 25 mug/ml, the solution is put into an ultraviolet spectrophotometer, the wavelength is set to be in a range of 200-400 nm, the ultraviolet absorption spectrum of the doxycycline hydrochloride and the metal ion complex is measured, and a spectrogram is generated (see figures 1-3).
Table 4: ultraviolet absorption wavelength of doxycycline and its metal ion complex
As can be seen from Table 4 and FIGS. 1-5, doxycycline has two absorption peaks at 345 nm and 268 nm, and after binding to metal ions, the ultraviolet absorption peaks of other complexes other than doxycycline zinc complex are red shifted to different degrees to 348-350 nm and 267-268 nm, respectively 3-5 nm and 0-1 nm; while the two absorption peaks of the doxycycline zinc complex were red shifted by 376, nm and 275, nm respectively, 31, nm and 7, nm respectively. The generation of a red shift result may indicate that a reaction between doxycycline and a metal ion has occurred; meanwhile, the 3D spectrogram more intuitively proves the conclusion.
2. Repeated freeze thawing test:
considering that the temperature change range of the invention in the future during transportation, storage or use is below the freezing point, the freezing and thawing test is carried out on the sample of the embodiment, and the specific method is as follows:
the freeze thawing test comprises three cycles, wherein each cycle is carried out by placing 24 h at the temperature of minus 20 to minus 10 ℃ and then placing 24 h at the temperature of 40 ℃, and sampling and detecting.
The content determination method of doxycycline hydrochloride solution comprises the following steps: the content was determined by HPLC.
The chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler (the application range of the pH value is more than 9); acetate buffer solution (0.25 mol/L ammonium acetate solution, 0.1 mol/L disodium ethylenediamine tetraacetate, triethylamine (100:10:1), glacial acetic acid or ammonia water to adjust pH value to 8.8-acetonitrile (85:15) as mobile phase; the column temperature is 35 ℃; the detection wavelength was 280 nm, and the results are shown in table 5:
table 5: freeze thawing test result table
The freeze thawing results show that: the color of all the examples is obviously changed, the phenomenon of low-temperature precipitation does not exist yet, and the content detection result shows that although the content is reduced to 0.4-1.0% through three freeze thawing tests, the freeze thawing stability of the examples is better.
3. High temperature test:
samples of the examples were placed in a 60 ℃ stability test box and sampled at 0, 5 and 10 days, respectively, and the properties and contents of the drugs were measured, and the results are shown in table 6:
table 6: stability test results of high temperature test
The doxycycline hydrochloride is the same as other tetracyclines, hydrolysis, oxidation and other chemical changes are easy to occur when the doxycycline hydrochloride is exposed to heat, and the combination of the properties of the doxycycline hydrochloride and the high-temperature test results shows that the doxycycline hydrochloride has different degrees of color change in the process of being placed at the high temperature of 60 ℃ for 10 days, and the content is not obviously changed (5% different from the initial value) but is degraded to a certain extent as the content results.
4. Acceleration test:
samples of the examples were placed in a stability test box at 40 ℃ ± 2 ℃ and a relative humidity of 75% ± 5%, sampled at 0, 1,2, 3, 6 months, and the properties, content, and results of the drugs were shown in table 7:
table 7: stability test results of acceleration test
The doxycycline hydrochloride is the same as other tetracyclines, hydrolysis, oxidation and other chemical changes are easy to occur when the doxycycline hydrochloride is exposed to heat, and the combination of the properties of the doxycycline hydrochloride and the high-temperature test results shows that the doxycycline hydrochloride solution prepared by the research has good stability as the doxycycline hydrochloride solution has different degrees of color change in the acceleration test and has certain degradation but no obvious change (5% different from the initial value) when the doxycycline hydrochloride is subjected to content results.
Claims (6)
1. The doxycycline hydrochloride solution is characterized by comprising an organic solvent, a complex compound dissolved in the organic solvent and a complexing agent; the complex is a complex of doxycycline hydrochloride and metal ions, the complexing agent does not carry out a complexing reaction with the metal ions in an organic solvent and carries out a complexing reaction with the metal ions after meeting water, and the mass ratio of the doxycycline to the complexing agent in the complex is 1:0.1-0.4;
the complexing agent is used for competing metal ions with doxycycline hydrochloride after the doxycycline hydrochloride solution encounters water, so that the complex is dissociated to recover doxycycline hydrochloride, and the concentration of the complex in the organic solvent calculated by doxycycline is 10-30wt%; the metal ions are one or more of magnesium ions, calcium ions, zinc ions, aluminum ions and copper ions; the complexing agent is at least one of sodium acetate, disodium ethylenediamine tetraacetate, sodium ascorbate, sodium tert-butoxide and sodium citrate.
2. The doxycycline hydrochloride solution according to claim 1, wherein said organic solvent is selected from one or more of 1, 2-propanediol, dimethyl sulfoxide, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, α -pyrrolidone, glycerol formal, polyethylene glycol 200, polyethylene glycol 400.
3. A process for the preparation of doxycycline hydrochloride solutions according to claim 1 or 2, characterized in that it comprises the following steps:
step 1: preparing a complex, namely mixing doxycycline hydrochloride with a metal ion solution to obtain the complex;
step 2: and (3) preparing the doxycycline hydrochloride solution, namely dissolving the complex and the complexing agent prepared in the step (1) into an organic solvent to obtain the doxycycline hydrochloride solution.
4. A method for preparing doxycycline hydrochloride solution according to claim 3, wherein the specific operation of step 1 is: in a water bath environment at 0 ℃, doxycycline hydrochloride is dissolved in methanol to obtain a reaction solution A;
the molar ratio of the metal ion to doxycycline hydrochloride is 1-1.5:1, preparing a metal ion solution to obtain a reaction solution B;
adding the reaction solution B into the reaction solution A in a dropwise or batchwise manner, performing the whole reaction in a water bath environment at 0 ℃, stirring while adding, precipitating, filtering, washing, and drying the precipitate to obtain a complex;
the specific operation of the step 2 is as follows: heating organic solvent to 50-65deg.C, adding complex, stirring to dissolve complex, adding complexing agent, and stirring to dissolve completely to obtain doxycycline hydrochloride solution.
5. A preparation method of doxycycline hydrochloride, which is characterized in that the doxycycline hydrochloride solution as defined in claim 1 or 2 and water are mutually dissolved in any ratio and then are drunk by livestock and poultry.
6. The method of preparing doxycycline hydrochloride according to claim 5, wherein the doxycycline hydrochloride solution is mixed with water in a ratio of 1:10-2000, and is drunk after mutual dissolution.
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