DE1619792A1 - Method of making capsules by coacervation - Google Patents

Description

IHE KATIOKAi CASH BEGISTBR COMPANY Dayton, Ohio (Y, St _c A ~)

Patent application Rr ,:
Our ace «.» 100ö / 9ariaany

StHi HBHS ¹ XBIiLEU YOU KAiPSSKJ H) WGK

The invention relates to a method of mass production of capsules, with an inner phase or a core of liquid or i'eekem fabric by means of a ^ uBaamenhanging, seamless Wall made out of fabric replaced by coaserving will,.

As described in the German patents or if t 1 122 495, bit water can be immiscible substances _r 3dB. Oils can be encapsulated by preparing a solution of two hydrophilic polymeric substances, e.g. "gum ar &bicu" tind gelatin ", the solution containing the oil, which is to form the inner phase of the finished capsules, in an emulsified form Löeung ^ irö then changed so that _t dl3 two colloids having "the Missed Geng © © © 8 citi-e electrical charges to form a complex and calibrated to deposit as a result of the process of Koasservierung AELE flilBßig® phase, after which the abgeeobiedene flUseige phase or daa Koazerrat the small particles, spheres or droplets of the oil "which dieperglert bind ₉ in the aqueous phase overlooks and encapsulates"

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10.5.1St> 7 BAD ORJGlNAL

In this way, oil solutions of dyes or Printing inks for the production of so-called »carbon-free "Durehsο chalk paper be encapsulated while oily vents other substances, a * B «fragrances., slightly oxidizing substances or moisture-sensitive substances to prevent dying. Oxidising, Moisture, etc. can be protected.

In some of these applications, e.g. for carbon-free thermosetting paper, it is not only imperative, but also desirable that the capsules and the encapsulated inner phase of each individual capsule are very small (preferably microscopic), - however, there are also possible applications for through Preservation manufactured capsules? where it is permissible and in many cases even desired that the capsules and the encapsulated inner phase have larger dimensions, i.e. on the order of traditional pills. Tablets and the like are ₀ ,. For various reasons, s © alt capsules come with a

Dur cha «eeer of 0.5 to 1.5 om advantageous. Should atopleleweise

A light fiB 01 against evaporation or an oxidizable one Fabric barren Ul be protected to eu their use against oxidation and f Ur the specific use-not necessarily small capsules required, then it can wirtschaftliohor or aweokaäBiger be ₉ to encapsulate the oil in large capsules. Since the surface of a large sphere is smaller than the branch surface of a view corresponding to the volume of this large sphere! smaller spheres, so less encapsulation "~ material required" Except for the savings achieved by 4aduroh

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there is nooh the further advantage that the inner Phase after their release therefore breaking the capsules less is heavily contaminated by the capping material,

Ss can ewsokm & ßlg eein encapsulate large balls or particles of a liquid or of a solid other reasons au further, a "B. to provide catalysts, fertilizers, herbicides 1, pest control agents or medication in capsule units for a desired dose. You can also make capsules with an insect repellent, a fungicidal agent, or some other means of treating the soil, which are so large that they fall through the foliage and do not stick to the latter like small, dusty capsules. -

So far it has been difficult, relatively large balls and Particles, i.e. KUg * loheη or Teilohen in the order of magnitude from 0.5 to 1.5 it Burohsssaer duroh the previous short encapsulate the described coaservation process in large quantities. This difficulty is based on the fact that the liquid phase separating out of the system or the Coaservate usually has the shape of small KÜgelohen and not without further ado a relatively large KUgeIonon or part of the inner phase around a cohesive and sufficiently dloken, resistant, seamless over do it,

Eb has now been found «that when the calibrated out of the system separating liquid Phsuse la threadolienförniger, i.e. stretched and not in a spherical shape with corresponding mobility

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This is far more teaser than the previously used spherical coater council for coating and encapsulating large! particles or spheres of the inner phase are suitable.

With the term "fädehenftfrmlg" as used in the description and claims? is a leloht recognizable, specific physical fora der la. the aqueous carrier liquid denotes suspended liquid Koaservatphafie. In this state, oil has the appearance of a liquid coazerrate phase of interwoven threads, the blocks of which are of the order of magnitude of a few / µm (beiapiolBweice 5 to 15 / etc.) and whose length is few? Millimeter or 1 cm and more. Under the microscope, the individual Koaserr & t ~ threads in their flexible form are generally not reactive, but form arbitrary circles and loops.

The subject of the invention let »omit a process for the manufacture« ·

put τοη capsules by bringing about the üoazerrierirag in

narrow • in an aqueous solution of at least one hydrophilic polymer, whereby the separated liquid Koaservatphaee brought to it is, calibrated for particles of a solid or liquid, in this Solution to disperse nucleating substance and deposit liquid · to form walls on these, which subsequently hardened will. *

The method according to the invention is characterized in that that the pH and temperature of the solution are within oinae Range can be set, which is chosen so that the Koazerratphaee becomes ffidchen-shaped instead of spherical "

10.5 * 1967

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Divide the coaservate phase by corresponding a bins and maintaining the p2t ~ value and / or the! «» temperature des SyBterns in the cum encapsulate large particles or balls the inner phase generates better suitable Pgirlfora or in such an unsettled way it has been observed that pH value and temperature in the same relationship "stand together" By lowering the pH, the mobility of the Coaservate phase decreased, which is evidently due to either Bringing about an even more elongated porst of one of its molecules or by producing a further intermolecular one What seratoffbinäung or other effects are obtained. Lowering the temperature also increases mobility the Padοheη decreased as a result of an increase in viscosity. It has been observed that there is a rather high degree of mobility I do not properly take praise of the inner phase lying around while having very little mobility viscous for this purpose and "through practical experiments a pH value range and a sea temperature range can therefore be found" which firstly cause threading and, secondly, these threads are flexible enough to be calibrated around larger spheres of the inner phase.

For example, ± n a system then described in Example 1 in more detail, are dissolved in the gelatin and carrageenan in water, © in pH range of about 6.5 to 6.53 and a Semperaturbereich of about 46 to 48 ⁰ C bevorsugt.

009835/0483

Hähert SiOH the pH value of the lower limit of the said range, or it is lower, then eiOh dl · the temperature should! Approximate temperature range or represent the upper limit liber lie gene and vice versa.

The system should be stirred or otherwise kept in motion at a rate sufficient to keep the inner phase evenly suspended during the encapsulation period. The speed of the Bührene dos system can be very low, ie. it can be, for example, 10 VtELfaehangen / mln . However, it can also be much higher, but not so high that the resulting shear forces remove the coating from the capsules or pull the coaeervate threads or the spheres of the inner phase apart;

In the following examples, those used are hydrophilic Colloids or polymers gelatin, carragheen * guaai arabicun and Ethylene male in the acid anhydride misoh polymer ieat · See according to the invention 7experienced can be applied quite generally to Sy · teas, in where gelatin is one of the colloids and with one or more a number of negative colloids, s «B < Carragheen, ethylene maleic acid β anhydr id-Mis ο hpoiymeris at en etc .. can be paired.

A large number of substances are suitable for forming the inner phase, such as mineral oils, silicone oils, esters with a high boiling point, organic tin catalysts, etc. Various substances such as dyes, fragrances, insecticides, herbicides, fertilizers, medicaments can be contained in the liquid forming the inner phase _f catalysts etc. be dissolved or dispersed »

009835/0483

Follow the examples "ollen ^ m further Yeranechtuilicfcurig the practical implementation and the advantage * of the license to serve,

example 1 The following substances are used:

To this end, solution k - Bb was dissolved in 936 g of gelatin in 7 _f 59 l of water at 33 ° C. For the gelatin, sohwaine skin gelatin with a high bloon strength and an electrical point was used with the θ and 9 values, ^

L6Bun <t B - Hiereu were 93.6 g of waeaer in hot Xöelichsn carrageenan (QeXoarin if <3 "trademark of ¥ irna Marint Colloiöra, Inc., Hew Tork, HY ·) in 18.7 1 Waaoer at 53 ⁰ C hergeetelit .

Yerdttnnong Mit Waaeer - To adjust the density, 50% 5 1 W (VBe he bit a content of 1.0 1 Arlex (goods nee i ο ho η from Atlaa Chemical Induatriee for an 83% by weight aqueous solution of sorbitol) warped

Inner Phaae - 2530 g fluoreemierond ·· Pigaent (Velva-Glo

P-15000-G-317, goods of the iinia fiadieant Color Co, for an organic Harapigeent) were mixed in 2810 g of a silicone oil L-45 with a viscosity of 1000 Oentietolc "" and 11 230 g of a silicone oil "L-45" with a Viscosity of 10,000 centiatokce (L-45 is a Varenseionen from PirBa Union Carbide Corp.). This inner Pbaee was degassed because air bubbles in the finished capsules create even spots in the capsule walls. It is about an extrudable hard plastic. 10.5,1967 009135/0483 _B A0 OFUGINAU

A ^ Ll geme in e a _t process η ---- Bern for diluting water (which contains the above-mentioned amount of Ar lex), solution A (gelatin solution) was added and the pH was adjusted to 6.51. The pH of solution B (Carragheen solution) was brought to 6.51. The temperature of the diluted solution A and the solution B was 47.5 ⁰ C, the solution B was in a weak Fora beam during a time period ron about 3 1/2 hours the solution A ge.miao.ht (by a mechanical stirrer with about 14 revolutions / min) _o After half an hour the addition of the internal phase was begun by extruding at a pressure of 1 kg / cm at room temperature ,, the internal phase was introduced dureh a chopper, mainly the particles in a size of 6 up to 9 am and partly also below. When the system obtained was examined under a microscope during the organic part of this period of time, an escape phase in the form of large, mobile spheres that soaked the small droplets (diameter about 0.8 mm) of the inner phase over the The total amount of the inner phase was added over a period of 1 1/2 hours, during which the coconut phase turned into threadbare droplets of ordinary size. wherein the temperature after the completion of addition was 45.8 ⁰ C and the pH unaitte-Ibar · 6.52 of the internal phase. NaOH 5 the T2 hours, "in which the solution B was added /, the temperature was 55 _t 5 ° ^C and the pH 6.55, and ee was observed that formed on 1.5 mm large drops heavy Koazervatwände had and the coacervate phase increased by 6 to 9 mm large drops of the inner; Phase around.

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The temperature of the Hasse was now ^{lowered to 4-5 °} C. The pH was 6 * 53. Mused was (not in the Koazervatsystem) where the ixt Abkühleystem kaitoe tap water, approximately 2 hours until the temperature of the mass was 37 ⁰ C ,. During this cool down period, the pH was maintained between 6.51 and 6.55 and 600 com Arlex was added.

After the temperature reached about 44.5 ⁰ C during this Abkühlperlode (at a pH value of 6.53), had formed oieh mm to 3 large drops, heavy walls "after the temperature had reached 40 ⁰ C _t were with The unaided eye of the coacervia can be calibrated on the 6 to 9 mm large drops of the innesan Phaaö.,

liachdem the temperature of the mass 36 ⁰ O had reached two hours further cold water was added "to the Chill 25 ⁰ C was. During this period 1,400 co »Arlex sugeeetst. Bas coacervate remained fädohenförmig and move to below approximately 33 ⁰ C "■

To further lower temperature did at 10 ⁰ C zq, the cooling water Sis added, "To this end was were about 1 1/2 stood required. During this period 1 000 ecm of Arlex were added ο

After reaching the temperature of 10 ⁰ O the pH value of the system was lowered to 4.5 and held for half an hour before 940 com glutaral & ehyd zuu Vernstsen (or varieties) of the uel & tine walls were added to the capsules in suspension, one was. Idter Arlex sugesetat.

May 10, 1967

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The circulating Eiswaaser was drained and the capsules standing over Haoht under constant listening, so that they allowed to warm to room temperature.

Impeccable strong capsules (with wet walls) with 6 to 9 bob in diameter were added by adding one Liter of Arlex may still look used up Gelatin separated. The separated capsules were placed in another container and then immersed in ionized water washed and coated with a surface that is soluble in water « active substance and a preservative that is soluble in water. fabric treated - the capsules were stored in this aqueous mixture «

Example 2

SOLUTION A - To this was added 40 g of gelatin dissolved in the same manner as Example 1 in 320 cc of water at a temperature between 55 and 55 ⁰ C ,.

Β -. » For this purpose 3 * 8 g Carragheen (gel ear in HWG)

dissolved to 55 ⁰ C in 640 oom water at 53 and the pH adjusted to 6.51 6 ₉ 53rd

Water r aur dilution - 2 500 oem with a content of TO ecm Arlex »

finer phase - 300 com »octyl phthalate (di (2-ethylhexyl) phthalate) *

May 10, 1967,

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General PROCEDURE "- Dee EUR dilution serving, the water containing Arlex was ssugesetet the toeung A (gelatin solution) and the pH to 6.51 to 6.55 and the temperature 'set at 41.7 ⁰ C, the solution was Danaoh! B (Carragheen * solution) In the form of a faint stream of oil from solution A and the water used for dilution, it was passed over a period of "about half an hour". Haoh Zuaetean about half of the solution B had since then converted the precipitated ctelatine coacerrate from the spherical fora into the pJtheiform form. At that time, the substance of the inner phase near the bottom of the blalcapeel cell was introduced into a triohero, which could be opened to control the inflow speed 5 whether · tee At the beginning de · to · e na was the internal phase of the flUeeigen Terkapeelungemiechung 6 _r 53 and the temperature of pH-fert 40.5 ⁰ C. the Hleohung was stirred very langeam. The addition of the inner Phaeo took about 10 minutes.

Half an hour after the addition of the inner phase had been completed, capsules with a throat called eu half a centimeter Eapeelwande were visible. The temperature of the system was about "held 4-1.5 ⁰ O before the long amen cooling dee Sy et" for half an hour to 40.5 bi started me. During this time of almost constant tenitexaturation, the pH value of the system tended to rise and rose to

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“Brought to a range between 6.60 and 6.65 to get a * better Capsule wall formation on the K & peoln With 1.5 o »Jtarchaeeeer au achieve,,

Within a time version "of two hours, the temperature at 30 ⁰ C was lowered while the pH to 6.60 biö 6.65

the Syetea was held .. Then / during β ine β time itr auras of t 1/2 were cooled to 10 ⁰ O with an ice water bath «At this temperature the pH value was reduced to 4? 5 eesenlct, and after it had been kept at its value for half an hour, 40 ecm of grlutaraldehyde were added to harden the gelatine walls. Then the constant was etehengelaeeen for 24 to 36 hours under constant long periods of time, so that ee could warm to room temperature.

During the slow cool down and cool down with you was added, 1 ©, as required, to increase the density of the systems eo that the capsules with heavy η walls were kept in suspension *

After the crosslinking was complete, the capsules were removed from the encapsulation system, washed with deionized water and treated with a surfactant prior to drying in a stream of air.

Example 3

Solution A - Hierssu, 40 g of gelatine (of the gla ic ho a type as in Example 1) were dissolved in 320 ecm «asaer at 53 to 55% *

Solution B - To this was added 40 g Guami-arabloo "in 320 cc of water dissolved at 53 to 55 ⁰ C *

Solution C - To this end, 40 com 2 # strength ethylenic acid anhyazide copolymer (EMA-21) was dissolved in water and 40 ecm 2 # strength ethylene maleic anhydride hisohpolyinoriaate (EMA-31) in water and the pH value was reduced to 9.0 at low temperature ingeetellt (MA-21 and EKA- »31 are trademarks of the Moneaato Chemical Co. for various types of Itiiylemaaleii ^ äiareiuiuih ^ d ^ iö * Hiechpolymerisaten) <

Vardünnungawaager - 2 400 com with a & ®lu & lt of 20 ooa Ar lex and a temperature of 53 to 55 ⁰ O.

Inner phase - 300 ecm mootyl phthalate (ie, example 2).

General Yerfahrea - Solution A (oilate solution) was added to the water containing the Arlex and the pH was adjusted to 9.0. Then solution B (thornntiarabicum solution) was added, followed by the addition of solution C. The pH value of this Mieehung ~ was adjusted to 6 33 ^ Me 6.38 and the mixture to about 38 ⁰ C cooled ,,

The deposited gelatin coacervate gradually changed from the spherical shape to the fadohanfona. Ale a sufficient amount Koauervat in Jüdchenform was present, the internal phase was dee in the soil Hähe dee YerkapselungsgefäSes means of a! "Richteγβ supplied whose AusfluBöiiauag mm Sontrdlicren the Zuf! ^ Was veretöllbar speed. The XTsKrührgeeohwindiglceit the Kapaelaischuag was before the beginning of the addition of the internal phase, which takes about 15 minutes are required verlang-B "at" £ ÜR di © reBtliche Bauer of the procedure was further de long '' ^ 009835 / 0483- '

May 10, 1967- BAD ORIGINAL

During periods of 1 1/2 hours, cooling the lliochung to about 35 ⁰ C, during this time wurd "the pH word '' long raised at 6.48 to 6.52 Ms on the fädehenfurmige gelatin to keep movable so that 3you can see around the capsules <. Intestinal the system with the aforementioned pE ~ value iansrhalb a further two hours was added slowly until cooled to 20 ⁰ G was followed by cooling to 10 ⁰ C dee system in iron EiRbad wherein SWEi hours l $ agtiasi was stirred

At 10 ⁰ C the pH value of the system was lowered to 5 _P 45 "This value was maintained for half an hour * before 40 com glutaraldehyde was added to harden (harden) the gelatine walls"

The density of the? Erkapeelimg @ iii © 3hung was as required by adding even more Arles b © adjusted that the with Heavy “Wand®” capsules were kept in suspension.

Under constant langeaaen ßühren the system was iiaeht Bteliengel & seea, so that it could 3I warm to Hauiatemperatisr _o Dieee TIMË; 8panne of 16 hours is sufficient © © us to crosslinking of the ßelatinewänds of 0.5 cm Kapse3ji aim to ER ^

The Kapoe3ji were removed from the Veria? EelungBmi © Qhung, Wash with deionized water, with surface active Fabric treated and dried in a stream of air "

May 10, 1967 009835 / CU83

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Claims (1)

^ 619792 Godfather nt ana pt tic ha ι 1λ method ssma Manufacture of capsules by bringing about the coaservation in an aqueous solution undeetene of a hydrophilic polymer, whereby the deposited liquid · Koaservatphaee made πίτα * on particles of a fairy clay or liquid, in this solution diapered core-forming substance to deposit and liquid au form, which are hardened in a flowing manner, characterized by the fact that the pH value and the temperature of the solution are set within a range "which" is chosen so that the "body" phase is thread-like instead of spherical, 2 «7er drive according to claim!, Characterized in that the Solution »contains at least two polymers in dissolved form, and the Koaaervatphaae is a complex of these substances. 3ο ancestors according to claim 2, characterized in that Polymeric gelatin and carragheen are. 4, A method according to claim 2, characterized gekenneeichnot, DAFL the polymers gelatin, arabic Guami tind a Äthylennaleineäureanhydrid-Miechpolymerisat "ind _o 10.5.1967 BAD ORiQINAi