CN104740640B - A kind of crystal modification thing for improving chemical drugs material powder property and preparation method thereof - Google Patents
A kind of crystal modification thing for improving chemical drugs material powder property and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of crystal modification thing for improving chemical drugs material powder property and preparation method thereof, the crystal modification thing is dressing agent to be filled, bind and coalesced the medicine-containing particle being integrated between chemical drugs raw material crystal, and its preparation method is：(1) chemical drugs material crystal is pulverized and sieved；(2) modification agent solution is mixed with chemical drugs material crystal, and makes dressing agent to being filled, binding and gathering into medicine-containing particle chemical drugs raw material crystal；(3) by medicine-containing particle drying, sieving.The present invention can be such that direct tablet compressing technology is further expanded in actual applications, and can improve the stability of medicine.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, and chemical drugs raw material is pre- before being produced in particular to solid pharmaceutical preparation
Treatment technology, more particularly to a kind of crystal modification thing for improving chemical drugs material powder property and preparation method thereof.
Background technology
Chemicals is mostly existing Synthetic Organic Chemistry material in crystalline form.Solid pharmaceutical preparation removes active pharmaceutical ingredient
(active pharmaceutical ingredient, API) outside, usually contains multiple auxiliary materials, such as filler, disintegrant, profit
The chemical substances such as lubrication prescription.Traditional wet granulation technique is using water, ethanol, starch slurry, sugar, dextrin, hydroxypropyl methylcellulose, carboxylic
Wet granular is made as binder, by raw material and filler bonding in the auxiliary materials such as methylcellulose sodium, PVP K30, then through drying, purport
Obtaining homogeneity, mobility and the preferable particle of compressibility.But because preparation process is influenceed by wet, hot, medicine with it is auxiliary
It may occur physically or chemically to change between material, cause raw material crystal formation to change, dissolution rate declines, and content declines and produced harmful
Decomposed substance.Simultaneously as wet granulation is also present, technical process is longer, and energy consumption is big, the defects such as efficiency is low, therefore promotes
Solid pharmaceutical preparation technology gradually develops to the direction of steady quality, low energy consumption, efficient direct powder compression.
However, generally existing polymorphism in chemicals, the dry jet mixing pile of different pharmaceutical crystallization is widely different, more
The defects of mobility is bad or compressibility is poor be present in the crystallization of number insoluble drug；From the raw material of different suppliers,
In the preparation process of tablet, it is also possible to sticking, loose pieces, sliver, content heterogeneity occur because of situations such as crystal formation difference, to life
Production brings the difficulty for being difficult to predict；If more it is appreciated that using direct tablet compressing technique, if there is matter in the tablet prepared
Amount problem, it is difficult to do over again retrieving a loss again.Therefore, direct tablet compressing technology receives a fixed limit in production application
System, especially raw material crystal formation be bad and API in tablets>50% kind, even if the new auxiliary material of vertical compression and equipment change at present
It is good to wait under technical support, still fail break-through skill bottleneck.
Although reducing API ratio by increasing the addition of vertical compression auxiliary material, can improve within the specific limits directly
The tablet quality of tabletting, but it is clearly worthless for the larger kind of content specification, because can so make tablet be made more
Greatly, it is difficult to swallowed by patient, and increase production cost.Therefore, improve the dry jet mixing pile of bulk drug crystallization, be allowed to adapt to directly
Tablet forming technique is connect, is the Main way of the art research.In the prior art, for improving material crystal dry jet mixing pile
Technology and method mainly has following several：
First, use recrystallization technology.Typically example is《Chinese pharmacy information》What the 8th phase of volume 22 in 2006 was introduced
" changing crystal formation improves the research of brufen physicochemical property ".This technology is in additive (gelatin, silica gel and phosphate-buffered
Agent) in the presence of, by solvent evaporate and change solvent brufen is recrystallized, obtained preferable mobility, compared with
High density and the ibuprofen granule of compressibility.
Second, spherocrystal granulating technique (spherical crystalization, SC).Represent the text of SC latest Progress
Offer for《Pharmacy practice magazine》The 1st phase of volume 28 in 2010 introduce " spherocrystal granulating technique prepare it is medicinal can vertical compression particulate grind
Study carefully progress ".The technology is particulate crystal formation is directly translated into sphere aggregates in crystallization or course of reaction, so as to improve particulate
Mobility and compressibility, it is can be used for direct tablet compressing.Its principle is while the medicine is separated out crystallization in the liquid phase, to borrow
Liquid bridging agent and stirring action are helped, the method for being agglomerated into spheric granules.Spherocrystal, which is granulated, to be needed with three kinds of basic solvents, i.e.,：Make
The good solvent of medicine dissolving, makes medicine separate out the poor solvent of crystallization, the liquid bridging agent for coalescing drug crystallization.
Third, use glomerocryst granulation technique (crystal-co-agglomeration, CCA).CCA current research is represented to enter
The document of exhibition is《Chinese Pharmaceutical Journal》" progress of glomerocryst granulation technique " that the l7 phases of volume 49 in 2014 are introduced.With ball
Brilliant granulating technique is similar, and the technology is by liquid bridging agent and stirring action, while the medicine is separated out crystal in the liquid phase, with
The crystal or particulate of another medicine or auxiliary material are agglomerated into spheric granules thing.Its first purpose is to improve medicament powder property,
Vertical compression particle is prepared, extends the application of direct powder compression；The second purpose be by introducing auxiliary material or high polymer material,
Functional particles are prepared, the rate of release of regulating drug, improve bioavilability；Spherocrystal granulating technique is overcome in addition to be only applicable
In the limitation of water-insoluble single medicine, the water solubility or water-insoluble drug of poor compressibility can be prepared into folk prescription or compound ball
It is brilliant.
Technology category raw material production technology category crystallized above, is limited by regulation, is only applied suitable for raw material manufacturing enterprise, nothing
Method is realized in formulation manufacturing processes.In addition, method one be also possible to will with preparation processing need not and with curative effect is incoherent adds
Add agent residual in the feed.Such as acetone, dichloromethane, chloroform, petroleum ether must be used to have in the preparation process of method two, three
Harmful organic solvent, equally it can leave hidden danger because of the residual of solvent for the safe to use of medicine.And three kinds of methods due to operation compared with
For complexity, time-consuming for crystallization process, need to consume a large amount of organic solvents, solvent for use is to the with strong points of kind, and cost is higher, mesh
It is preceding not yet to obtain extensive popularization and application.
The content of the invention
In view of the deficiencies in the prior art, the present invention is repaiied with a kind of pharmaceutically acceptable auxiliary material to bulk drug plane of crystal
Decorations, it is intended in the case of not limited by raw material variety or crystal formation, change the dry jet mixing pile of drug crystallization, provided for preparation production
A kind of applicability technology of chemical drugs pretreatment of raw material.
Therefore, it is an object of the invention to provide it is a kind of improve chemical drugs material powder property crystal modification thing and its
Preparation method.In order to realize the goal of the invention, the present inventor is finally obtained as follows by lot of experiments research and persistent exploration
Technical scheme：
A kind of crystal modification thing for improving chemical drugs material powder property, the crystal modification thing is in chemistry by dressing agent
The medicine-containing particle being integrated is filled, binds and coalesces between medicine raw material crystal.
Preferably, the crystal modification thing of chemical drugs material powder property is improved as described above, dressing agent therein is hydroxyl
Third methylcellulose.
It is further preferred that improve the crystal modification thing of chemical drugs material powder property, modification therein as described above
The viscosity specification of agent hydroxypropyl methylcellulose is 3~10mPas.
The present invention can make to be not suitable with the API of the crystal formation medicine of direct tablet compressing in the formulation and bring up to more than 75%, without by
The limitation of kind.In the most preferably several embodiments of the present invention, the crystallization of above-mentioned improvement chemical drugs material powder property is repaiied
Jewelry, chemical drugs raw material therein are paracetamol, Sulpiride, Amlodipine Besylate Tablet.
A kind of preparation method for the crystal modification thing for improving chemical drugs material powder property, this method include following step
Suddenly：
(1) chemical drugs material crystal is pulverized and sieved；
(2) under mechanical stirring, modification agent solution is mixed with chemical drugs material crystal, and makes dressing agent former to chemical drugs
Medicine-containing particle is filled, binds and gathers between material crystal；
(3) obtained medicine-containing particle is dried；
(4) dried medicine-containing particle is sieved, obtains crystal modification thing.
Preferably, the preparation method of the crystal modification thing of chemical drugs material powder property, step (1) are improved as described above
The granularity of middle chemical drugs material crystal after crushed is 80-150 mesh, preferably 100 mesh.
Preferably, the preparation method of the crystal modification thing of chemical drugs material powder property, step (2) are improved as described above
Described in dressing agent be viscosity specification be 3~10mPas hydroxypropyl methylcellulose.
Preferably, the preparation method of the crystal modification thing of chemical drugs material powder property, step (2) are improved as described above
Described in modification agent solution be mass concentration 0.5%~5.0% hydroxypropyl methylcellulose solution, preferably mass concentration 2%
~4% hydroxypropyl methylcellulose solution.
Preferably, the preparation method of the crystal modification thing of chemical drugs material powder property, step (2) are improved as described above
In to be used to dissolve the solvent of dressing agent be the water with or without ethanol, specifically, the solvent for preparing modification agent solution is to weigh
It is (0~75) to measure ratio:Alcohol-the water of (25~100), preferably weight ratio are (0~50):Alcohol-the water of (50~100).
It is further preferred that improve the preparation method of the crystal modification thing of chemical drugs material powder property as described above,
Described alcohol is ethanol, and wherein ethanol is to meet medicinal alcohol as defined in Chinese Pharmacopoeia.
The present inventor is creatively using hydroxypropyl methylcellulose as crystal surface dressing agent, by suitable mechanical agitation,
Dressing agent is penetrated into medicine crystal gap, makes to produce adhesion by dressing agent between crystallization and crystallization, fine crystal passes through crystallization
The mutual wedging or filling effect of surface gap form the larger particles with certain plasticity.Its caused beneficial effect is：
(1) the corner angle crystallized are reduced, and mobility increase, are easy to filling and tabletting；
(2), by wetting action of the dressing agent to crystallization, be advantageous to eliminate crystal surface electrostatic that may be present, avoid tying
The brilliant raw material clustering phenomena when being mixed with other auxiliary materials, make API dispersibility increase, incorporation time compares customary preparation methods
Shorten, so as to reduce broken caused sliver phenomenon of the vertical compression auxiliary material in mixed process；
(3) plane of crystal gap is reduced, and the air that punch die need to exclude during tabletting is reduced, and makes the compressibility of particle strengthen；
(4), by the plasticity and stickiness of plane of crystal dressing agent, contribute under action of mechanical pressure to make tight between particle
Close combination, the tablet of formation have larger hardness and are not easy sliver；
(5) selected dressing agent has stronger hydrophily and certain surface activity, makes the gap easily quilt on trim surface
Water penetrates into be leached as fine crystal again, and is easy to API dissolutions；
(6) only need less vertical compression auxiliary material and disintegrant to form disintegration and the good tablet of dissolving out capability, be advantageous to contract
The profile of tabloid, save supplementary product consumption and facilitate patient swallow.
In addition, inventor has been unexpectedly discovered that dressing agent used can in the checking that multiple kinds are carried out with this technology
Form package action on drug crystallization surface, reduce the contact surface of medicine and other auxiliary materials, can avoid to greatest extent medicine with
Interaction between other auxiliary materials, so as to avoid product caused by crystal transfer occurs under the induction of auxiliary material for raw material from storing
The dissolution rate of phase declines, and can reduce impurity of the product in storage period and generate.Material crystal after modification, its granularity, flowing
Property with vertical compression auxiliary material more closely, for small dose drug, be more easy to be well mixed, the uniformity of dosage units of gained tablet has substantially
Raising.Finally, trim unexpectedly obtains while acquirement can meet the micromeritis characteristic requirements of material of tabletting
The beneficial effect that product quality and stability significantly improve.
Specific embodiment
Following examples further describe the preparation process and beneficial effect of the present invention, and embodiment is only used for the mesh of illustration
, do not limit the scope of the invention, while those of ordinary skill in the art according to the obvious change made of the present invention and
Modification is also contained within the scope of the invention.
Embodiment 1：Hydroxypropyl methylcellulose-paracetamol crystal modification thing tablet forming technique (API：87.30%)
Paracetamol (100 mesh) 10.10kg
Dressing agent A-1 2.10kg
Preparation technology：
1st, dressing agent is prepared
Hydroxypropyl methylcellulose (3~10mPas) 0.10kg is taken, is dissolved under agitation in 2.40kg water, obtains dressing agent A-1.
2nd, prepared by trim
(1) take paracetamol (acicular crystal) to crush, cross 100 mesh sieves, obtain I.
(2) I is put in high-speed mixing granulating machine, opens stirring at low speed, be slowly added into dressing agent A-1, open low speed cutting granulation,
It is 4.0A to mix to cutting current, obtains II.
(3) by II in fluid bed granulator, 70 DEG C of EAT of control, humidity 45%~65%, control moisture 1.5%~
2.5%.Gained intermediate products cross 30 mesh sieves, obtain hydroxypropyl methylcellulose-paracetamol crystal modification thing 10.15kg.
3rd, tabletting
Preparation technology：Four kinds of materials above except for magnesium stearate are taken in three-dimensional mixer, to be mixed with 8r/min
10min, add magnesium stearate and continue to mix 5min, obtain mixture 11.30kg.By mixture in tablet press machine with㎜ is put down
Molded tablet, the qualified tablet 1.93 ten thousand of paracetamol tabletses that content specification is 0.5g/ pieces, average piece weight is 0.572g is made
Piece.
Comparative example 1-1：PVP K30-paracetamol crystal modification thing tablet forming technique (API：87.48%)
Paracetamol (100 mesh) 10.10kg
Dressing agent B 2.10kg
Preparation technology：
1st, dressing agent is prepared
0.10kg PVP K30s are taken, are dissolved under agitation in 2.40kg water, obtain dressing agent B.
2nd, prepared by trim
(1) take paracetamol (acicular crystal) to crush, cross 100 mesh sieves, obtain I.
(2) I is put in high-speed mixing granulating machine, open stirring at low speed, be slowly added into dressing agent B, opened low speed cutting granulation, mix
It is 4.0A to be bonded to cutting current, obtains II.
(3) by II in fluid bed granulator, 70 DEG C of EAT of control, humidity 45%~65%, control moisture 1.5%~
2.5%.Gained intermediate products cross 30 mesh sieves, obtain PVP K30-paracetamol crystal modification thing 10.10kg.
3rd, tabletting
Preparation technology：Four kinds of materials above except for magnesium stearate are taken in three-dimensional mixer, to be mixed with 8r/min
10min, add magnesium stearate and continue to mix 5min, obtain mixture 11.15kg.By mixture in tablet press machine with㎜ is put down
Molded tablet, the qualified tablet 1.92 ten thousand of paracetamol tabletses that content specification is 0.5g/ pieces, average piece weight is 0.570g is made
Piece.
Comparative example 1-2：Carmethose-paracetamol crystal modification thing tablet forming technique (API：
87.57%)
Paracetamol (100 mesh) 10.10kg
Dressing agent C 2.0kg
Preparation technology：
1st, dressing agent is prepared
Carmethose 0.05kg is taken, is dissolved under agitation in 2.45kg water, obtains dressing agent C.
2nd, prepared by trim
(1) take paracetamol (acicular crystal) to crush, cross 100 mesh sieves, obtain I.
(2) I is put in high-speed mixing granulating machine, open stirring at low speed, be slowly added into dressing agent C, opened low speed cutting granulation, mix
It is 4.0A to be bonded to cutting current, obtains II.
(3) by II in fluid bed granulator, 70 DEG C of EAT of control, humidity 45%~65%, control moisture 1.5%~
2.5%.Gained intermediate products cross 30 mesh sieves, obtain carmethose-paracetamol trim 10.10kg.
3rd, tabletting
Preparation technology：Four kinds of materials above except for magnesium stearate are taken in three-dimensional mixer, to be mixed with 8r/min
10min, add magnesium stearate and continue to mix 5min, obtain mixture 11.15kg.By mixture in tablet press machine with㎜ is put down
Molded tablet, the qualified tablet 1.925 ten thousand of paracetamol tabletses that content specification is 0.5g/ pieces, average piece weight is 0.569g is made
Piece.
Comparative example 1-3：Paracetamol wet granule compression tablet technique (API：83.6%)
Preparation technology：Paracetamol, sucrose, Celluloasun Microcrystallisatum is taken to open high-speed stirred in efficient wet granulator
After premixing material 3min, 18% starch slurry is slowly added into, opens low speed cutting granulation, it is 4.3A to mix to cutting current, obtains wet
Grain；By gained wet granular in fluid bed granulator, 70 DEG C of EAT of control, humidity 45%~65%, drying to moisture 2%~
3.5%, obtain dry particle；By dry particle with 16 mesh sieve whole grains, conforming particle is obtained.By conforming particle in three-dimensional mixer,
Add carboxyrnethyl starch sodium, with 8r/min mixing 20min, add magnesium stearate and continue to mix 5min, obtain mixture 11.80kg.Will be mixed
Compound in tablet press machine with㎜ flat-die tablettings, obtained content is 0.5g/ pieces, averagely piece weight is 0.602g to acetyl ammonia
Base phenol piece 1.95 ten thousand.
Embodiment 2：Hydroxypropyl methylcellulose-Sulpiride crystal modification thing tablet forming technique (API：77.93%)
Sulpiride (100 mesh) 10.20kg
Dressing agent A-2 2.40kg
Preparation technology：
1st, dressing agent is prepared
Hydroxypropyl methylcellulose (3~10mPas) 0.05kg is taken, is dissolved in 2.45kg containing alcohol water (percentage by weights under agitation
For ethanol:Water=50:50) in, dressing agent A-2 is obtained.
2nd, prepared by trim
(1) take Sulpiride raw material to crush, cross 100 mesh sieves, obtain I.
(2) I is put in high-speed mixing granulating machine, opens stirring at low speed, be slowly added into dressing agent A-2, open low speed cutting granulation,
It is 3.6A to mix to cutting current, obtains II.
(3) by II in fluid bed granulator, 70 DEG C of EAT of control, humidity 45%~65%, control moisture 1.0%~
2.0%.Gained intermediate products cross 30 mesh sieves, obtain hydroxypropyl methylcellulose-Sulpiride crystal modification thing that content is 97.8%
10.02kg。
3rd, tabletting
Preparation technology：Four kinds of materials above except for magnesium stearate are taken in three-dimensional mixer, to be mixed with 8r/min
10min, magnesium stearate is added, continue to mix 5min, obtain mixture 12.52kg.By mixture in tablet press machine with㎜ is shallow
Cavity plate tabletting, 9.66 ten thousand, the qualified tablet of Sulpiride tablet that content specification is 0.1g, average piece weight is 0.129g is made.
Comparative example 2-1：Sulpiride crystallization direct tablet compressing technique (API：76.03%)
Preparation technology：Four kinds of materials above except for magnesium stearate are taken to mix 10min in test-type mixer, add
Enter magnesium stearate, continue to mix 5min, obtain mixture 1.31kg.By mixture in tablet press machine with㎜ scrobicula molded tablets
(loose pieces, can not suppress).
Comparative example 2-2：Sulpiride wet granule compression tablet technique (API：75.67%)
Preparation technology：Sulpiride, lactose, Celluloasun Microcrystallisatum are taken in efficient wet granulator, it is pre- to open high-speed stirred cutting
After mixed material 3min, stirring at low speed cutting is opened, slowly enters the 4% hydroxypropyl methylcellulose aqueous solution, is 4.0A to cutting current is stirred,
Discharging, obtains wet granular；By gained wet granular in fluid bed granulator, 70 DEG C of EAT is controlled, humidity 45%~65%, is dried
To moisture 1.0%~2.0%, dry particle is obtained；By dry particle with 18 mesh sieve whole grains, conforming particle 12.40kg is obtained.Will be qualified
Particle adds carboxyrnethyl starch sodium in three-dimensional mixer, with 8r/min mixing 20min, adds magnesium stearate and continues to mix 5min, obtain
Mixture 13.1kg.By mixture in tablet press machine with㎜ scrobicula molded tablets, it is 0.1g, averagely piece weight that content specification, which is made,
For 0.134g 9.63 ten thousand, the qualified tablet of Sulpiride tablet.
Embodiment 3：Hydroxypropyl methylcellulose-Amlodipine Besylate Tablet crystal modification thing tablet forming technique (API：3.93%)
Amlodipine Besylate Tablet (100 mesh) 10.10kg
Dressing agent A-3 2.20kg
Preparation technology：
1st, dressing agent is prepared
Hydroxypropyl methylcellulose (3~10mPas) 0.10kg is taken, is dissolved in 2.40kg containing alcohol water (weight percent under agitation
Than for ethanol:Water=30:70) in, dressing agent A-3 is obtained.
2nd, prepared by trim
(1) take Amlodipine Besylate Tablet raw material to crush, cross 100 mesh sieves, obtain I.
(2) I is put in high-speed mixing granulating machine, open stirring at low speed, dressing agent A-3 is slowly added in granulator, opened low
Speed cutting granulation, it is 3.8A to mix to cutting current, obtains II.
(3) by II in fluid bed granulator, 70 DEG C of EAT is controlled, humidity 45%~65%, is dried, controls moisture
2.0%~2.5%.Gained intermediate products cross 30 mesh sieves, and it is 98.2% hydroxypropyl methylcellulose-Amlodipine Besylate Tablet knot to obtain content
Brilliant trim 10.03kg.
3rd, tabletting
Preparation technology：Four kinds of materials above except for magnesium stearate are taken in three-dimensional mixer, to be mixed with 8r/min
10min, add magnesium stearate and continue to mix 5min, it is 3.93% (equivalent to containing Amlodipine 2.834%) mixture to obtain API
49.98kg.Mixture is 5mg/ pieces, be averaged in tablet press machine with 11.0 × 5.5 ㎜ abnormal shape punch die tablettings, obtained content specification
Piece weight is 0.178g 27.54 ten thousand, the qualified tablet of amlodipine besylate tablets.
Comparative example 3-1：Amlodipine Besylate Tablet technique of direct powder compression (API：4.0%)
Preparation technology：Four kinds of materials above except for magnesium stearate are taken in three-dimensional mixer, to be mixed with 8r/min
20min, add magnesium stearate and continue to mix 5min, it is 4.0% (equivalent to containing Amlodipine 2.839%) mixture to obtain API
49.98kg.Mixture is 5mg/ pieces, be averaged in tablet press machine with 11.0 × 5.5 ㎜ abnormal shape punch die tablettings, obtained content specification
Piece weight is 0.177g 27.67 ten thousand, the qualified tablet of amlodipine besylate tablets.
Comparative example 3-2：Amlodipine Besylate Tablet wet granule compression tablet technique (API：3.99%)
Preparation technology：Amlodipine Besylate Tablet, lactose, Celluloasun Microcrystallisatum is taken to open high-speed stirring in efficient wet granulator
After mixing cutting premix material 3min, stirring at low speed cutting is opened, slowly enters the 2% hydroxypropyl methylcellulose aqueous solution, to stirring cutting electricity
Flow for 4.0A, discharging, obtain wet granular；By gained wet granular in fluid bed granulator, 70 DEG C of EAT of control, humidity 45%~
65%, dry to moisture 1.5%~2.5%, obtain dry particle；By dry particle with 18 mesh sieve whole grains, conforming particle is obtained
43.85kg.By conforming particle in three-dimensional mixer, add PVPP, with 8r/min mixing 20min, add magnesium stearate
Continue to mix 5min, it is 3.99% (equivalent to containing Amlodipine 2.832%) mixture 49.80kg to obtain API.By mixture in pressure
With 11.0 × 5.5 ㎜ abnormal shape punch die tablettings in piece machine, the benzene sulfonic acid that content specification is 5mg/ pieces, average piece weight is 0.178g is made
27.65 ten thousand, the qualified tablet of amlodipine.
Embodiment 4：The quality research of crystal modification thing tabletting
1st, dry jet mixing pile contrasts
One of dry jet mixing pile for mainly improving of the present invention is mobility, and evaluation index is discharge rate, its advantage
Data are detected by embodiment with comparative example to be explained.Discharge rate is tested using HYL-102 types Hall flowmeter.It is right
Sample than test includes：Material crystal, crystal modification thing, wet granulation gained particle and the vertical compression lactose as object of reference
(German import100), test result is shown, the micromeritis index of crystal modification thing be improved significantly.Contrast knot
Fruit is shown in Table 1.
Table 1：Dry jet mixing pile contrasts (n=3)
Do not have mobility：Determinand can not flow out 5.0mm bores funnel automatically, it is necessary to can be interrupted outflow by vibration.
2nd, contrasted with the mixed material compressibility of auxiliary material and products thereof dissolution rate
Research process of the present invention are found：The poor crystal form and larger kinds of API use direct compression of full-powder, tablet press machine is most
Big compression force is unable to reach parameter needed for normal tabletting, occur it is straight permitted to reduce tabletting speed also can not normally tabletting situation (such as
Comparative example 2-1), and preferable pressure value and tabletting speed then can be obtained using the tabletting of crystal modification thing, and 0 can be obtained
The qualified product of its dissolution rate；For the kind unstable to wet granulation dissolution rate, it can be changed using the tabletting of crystal modification thing
It is apt to its stability (such as embodiment 2 and comparative example 2-2)；In the screening of dressing agent species, carmethose and PVP
Trim dissolution rate prepared by the other auxiliary materials such as K30 is undesirable, particularly easily draw it is wet cause trim gradually to harden, go out to focus on
The situation that phase dissolution rate declines, wherein PVP K30 becomes apparent, and use low viscosity hydroxypropyl methylcellulose trim 0 day and
Dissolution rate in probation is preferably (embodiment 1, embodiment 2 and embodiment 3).Comparing result is shown in Table 2.
Table 2：Compressibility and the contrast of product dissolution rate
Dissolution rate test basis：Samples sources 1：Chinese Pharmacopoeia version in 2010 two " paracetamol tabletses "；Sample comes
Source 2：Chinese Pharmacopoeia version in 2010 two " Sulpiride tablets "；Samples sources 3：Chinese Pharmacopoeia Commission's " amlodipine besylate tablets "
(exposure draft of issue on March 24th, 2014)
3rd, content and impurity contrast in the product content uniformity and probation
Embodiment 3 is low dose of specification tablet.The modification crystallized by P-TOLUENE SULFO ACID 99's Amlodipine, it is straight with conventional full powder
Connect pressed disc method to compare, the mobility of material is preferable before tabletting, and the uniformity of dosage units of tablet is improved；And because dressing agent is to benzene
The package action of sulfonic acid Amlodipine, the contact surface of Amlodipine Besylate Tablet and vertical compression auxiliary material lactose is avoided to greatest extent,
Reduce the amino and impurity (the Amlodipine lactose of lactose ketone group condensation reaction generation because of Amlodipine Besylate Tablet
Adduct), make list miscellaneous and substantially reduced with always miscellaneous, shown using crystal modification technology in the amlodipine besylate tablets containing lactose
In be improved the advantage of chemical stability.Comparing result is shown in Table 3.
Table 3：Content and impurity contrast in amlodipine besylate tablets uniformity of dosage units and probation
Test stone foundation：Chinese Pharmacopoeia Commission's " amlodipine besylate tablets " (on March 24th, 2014 issue solicit
Opinion original text)
4th, the contrast of product economy benefit and social benefit
Relatively conventional wet granule compression tablet, the weight for needing dried material can be reduced using trim tabletting, when shortening technique
Between, supplementary product consumption is reduced, so as to reduce piece weight, is advantageous to reduce tablet profile, and efficiency can be improved；Relatively direct tabletting work
Skill, although adding the pretreatment process of one of raw material before tabletting, the normal production of high content specification kind can be advantageous to, entered
One step improves product quality, makes to be not suitable for the crystal formation medicine acquisition that conventional wet pelletizing press sheet is difficult to carry out direct pressed powder again
A kind of simple technical solution.Comparing result is shown in Table 4.
Table 4：The contrast of product economy benefit and social benefit
By above example as can be seen that the present invention can make to be not suitable with the crystal formation medicine of direct tablet compressing in the formulation
API brings up to more than 75%, without being limited by kind.To different cultivars, the concentration and ratio of dressing agent need to be only adjusted；
To damp and hot unstable kind, also the solvent in gained trim can be made to be easy to volatilize by adjusting concentration of alcohol in dressing agent, with
Profit uses relatively low drying temperature, shortens API heated times, improves the stability of product.Empirical tests, this technical operation letter
It is single, strong applicability, fit entirely into industrialized production.
Claims (7)
- A kind of 1. crystal modification thing for improving chemical drugs material powder property, it is characterised in that：The crystal modification thing is to repair Decorations agent is filled, binds and coalesced the medicine-containing particle being integrated between chemical drugs raw material crystal, and described dressing agent is hydroxypropyl Methylcellulose, the viscosity specification of described dressing agent hydroxypropyl methylcellulose is 3~10mPas；The preparation method of the crystal modification thing for improving chemical drugs material powder property, comprises the following steps：(1) chemical drugs material crystal is pulverized and sieved；(2) under mechanical stirring, modification agent solution is mixed with chemical drugs material crystal, and makes dressing agent brilliant to chemical drugs raw material It is filled, binds between body and gathers into medicine-containing particle；(3) obtained medicine-containing particle is dried；(4) dried medicine-containing particle is sieved, obtains crystal modification thing；Chemical drugs raw material described in step (1) is paracetamol, Sulpiride, Amlodipine Besylate Tablet；Modification agent solution described in step (2) is the hydroxypropyl methylcellulose solution of mass concentration 0.5%~5.0%.
- 2. a kind of preparation method for the crystal modification thing for improving chemical drugs material powder property, it is characterised in that this method includes Following steps：(1) chemical drugs material crystal is pulverized and sieved；(2) under mechanical stirring, modification agent solution is mixed with chemical drugs material crystal, and makes dressing agent brilliant to chemical drugs raw material It is filled, binds between body and gathers into medicine-containing particle；(3) obtained medicine-containing particle is dried；(4) dried medicine-containing particle is sieved, obtains crystal modification thing；Chemical drugs raw material described in step (1) is paracetamol, Sulpiride, Amlodipine Besylate Tablet；Dressing agent described in step (2) is the hydroxypropyl methylcellulose that viscosity specification is 3~10mPas；Modification agent solution described in step (2) is the hydroxypropyl methylcellulose solution of mass concentration 0.5%~5.0%.
- 3. improve the preparation method of the crystal modification thing of chemical drugs material powder property, its feature according to claim 2 It is：The granularity of chemical drugs material crystal after crushed is 80-150 mesh in step (1).
- 4. improve the preparation method of the crystal modification thing of chemical drugs material powder property, its feature according to claim 2 It is：Modification agent solution described in step (2) is the hydroxypropyl methylcellulose solution of mass concentration 2%~4%.
- 5. improve the preparation method of the crystal modification thing of chemical drugs material powder property, its feature according to claim 2 It is：The solvent for being used to prepare modification agent solution in step (2) is that weight ratio is (0~75):Alcohol-the water of (25~100).
- 6. improve the preparation method of the crystal modification thing of chemical drugs material powder property, its feature according to claim 5 It is：The solvent for being used to prepare modification agent solution in step (2) is that weight ratio is (0~50):Alcohol-the water of (50~100).
- 7. according to the preparation method of the crystal modification thing for improving chemical drugs material powder property of claim 5 or 6, it is special Sign is：Described alcohol is ethanol.
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Citations (3)
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| CN1732905A (en) * | 2004-08-09 | 2006-02-15 | 赵力 | Directly tabletting xylitol powder and its production method |
| CN101390840A (en) * | 2008-11-18 | 2009-03-25 | 江苏江山制药有限公司 | Production method of high-assay calcium ascorbate granules capable of directly being compressed |
| CN101474162A (en) * | 2009-01-19 | 2009-07-08 | 浙江天新药业有限公司 | Preparation method of naproxen granule for direct tablet forming |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732905A (en) * | 2004-08-09 | 2006-02-15 | 赵力 | Directly tabletting xylitol powder and its production method |
| CN101390840A (en) * | 2008-11-18 | 2009-03-25 | 江苏江山制药有限公司 | Production method of high-assay calcium ascorbate granules capable of directly being compressed |
| CN101474162A (en) * | 2009-01-19 | 2009-07-08 | 浙江天新药业有限公司 | Preparation method of naproxen granule for direct tablet forming |
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