CA2079911A1 - High molecular weight polyvinylpyrrolidones and method for their preparation - Google Patents

Abstract

An uncrosslinked, water-soluble polyvinylpyrrolidone having a K-value in excess of 120 and containing less than about 0.1 percent by weight of residual monomer. A method for preparing the high molecular weight polyvinylpyrrolidone is also disclosed.

Description

WO91~15522 PCT/VS91/02115 207991~

HIGH MOLECULAR WEIGHT POLYVINYLPYRROLIDONES
AND METHOD FOR THEIR_PREPARATION

BACKGROUND OF THE INVENTION

I. Field of the Invention The invention relates to a novel high molecular weight water-soluble polyvinylpyrrolidone. In addition, the invention relates to a novel method for the production of water-soluble polyvinylpyrrolidones having a K-value of from about 120 to 150.

II. Backqround of the Invention Polyvinylpyrrolidone is a well-known polymer having numerous applications in the pharmaceutical, cosmetic, agricultural, food, and other industries.
Various methods for its preparation from the monomer N-vinyl-pyrrolidone are known. Normally, the polymeri-zation is carried out either in aqueous solution or in suspension in an organic or non-solvent in the present of a free radical initiator.
One of the problems with solution polymerization methods for the polymerization of N-vinyl-pyrrolidone is that an upper limit of the molecular weight has become an . .. .. . . . .

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W091/lSSt2 PCT/US91/02115 20799l1

- 2 -obstacle. In particular, the solution polymerization processes known give commercially useful products having K-values of from about 10 to 9o. As used herein, the X-value is the so-called Fikentscher K-value which is obtained by capil~ary viscometry utilizing the relative viscosity of a 0.1% w/v solution in water. (See, U.S. Patent 4,190,718, columns 5 and 6.) ~his X-value i~ related to the molecular weight of the polymer in a well-known manner and is conven-tionally u-~ed to characterize the molecular weight of poly-vinylpyrrolidone.
one of the problems with the solution polymeriza-tion processes i8 that the viscosities of dilute aqueous solutions of polyvinylpyrrolidone products having ~-values up to 90 are gulte low. For example, they normally are in lS the range of less than 2 mPa. 5 in 2% aqueous solution.
For various uses, such as, thickeners, cosmetic formulations, printing inks, and the like, higher Vi9-cosities are reguired. For example, other polymers, such as, polyacrylic acids in 1 to 3% solutions, exhibit 20- vi~cosities of-100 mPa.s.
Numerous attempts have been made to produce higher molecular weight polyvinylpyrrolidone which exhibits higher viscosities in aqueous ~olution. Generally, these have used the crosslinking of polyvinylpyrrolidone using crosslinking agents. (See, for example, U.S. Patent 4,433,112.) In this method, a starting material of poly-vinylpyrrolidone having a R-value of from 30 to 90 is treated by heating an aqueous solution of the polyvinylpyr-' ~ ' .

_ 3 _ 2079911 rolidone in the presence of a water-insoluble organic peroxide and the absence of air. Generally, these methods start from an already polymerized polyvinylpyrrolidone.
The polymerization of N-vinylpyrrolidone in the presence of a free radical initiator as well as the mechanism of the polymerization is known. The polymeri-zation consists of a seguence of four steps, namely, (l) initiation: (2) propagation; ~3) transfer: and (4) termina-tion. In general terms, these steps may be depicted as follows:
l. Initiation I - Rd - 2R-R- + M - M-2. Propagation M- + M - M - M- - - M-

3. ~ransfer 3a. ~o monomer - M + M - P + M-3b. To polymer - M- + P - - ~ M + ----M-

- 4. Termination 4a. Coupling - - ----M- + ---M- - ----M - M -~ - ~ 4b.-Disproportionation ~
- M- + ---M- - P + M-~-CH=CH2 In the foregoing formulas, the symbols have the following meanings:

W O 91/15522 PC~r/US91/02115 207991i . 4 _ R a radical from the free radical initiator M monomer M radical monomer - M- polymerized monomer radical P polymer - M-M - higher molecular weight polymer M- CH-CH~polymer with terminal unsaturation ., A~ the polymerization proceeds and the amount of higher molecular weight polymer concentration in the reaction mixture increases, and the visco~ity also increasQs. The increased viscosity has the effect of hampering the movement of the various moieties at their various states of polymerization in the mixture. This, in turn, decrea~es th~ possibility and the probability of the individual entities in the mixture ~rom coming together to forc additional polymer whether the entlties are in the radical form or the polymer ~orm. In essence, the various entities in the reaction mixture increasingly lose their mo~ility due to the increased viscosity of the mixture.
Also, of course, for any given level of viscosity of the mixture, the larger molecular weight moieties will always ¦ -have l~s mobility in the mixture than the lower molecular weight moieties.~
- As a practical matter,~this lack of mobility is adver~e to the propagation step but favors termination making it difficult to obtain a product having a molecular ,~ . , ~ .
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W091/l~S22 PCT/US91/02115 weight in excess of that represented by a R-value of about 90.

SUM~aRY OF THE INVENTION
We have discovered a novel water-soluble poly-vinylpyrrolidone having a K-value in excess of 120 and con-tàining less than about 0.1% by weight of residual monomer without crosslinking. We have ~urther discovsred that the high molecular weiyht polyvinylpyrrolidone of the invention may be prepared by sub~ecting a solution of N-vinylpyrroli-done monomer in water to polymerization conditions utiliz-ing a free radical initiator and addlng water and initiator to the reaction mixture incrementally in amounts and in time periods during the polymerization so that the propa-gation phase of the polymerization is maximized and the termination phase is minimized by the control of the process parameters. In addition, by adding a chelating agent to the r~action mixturs, we have found that it is possible to minimize the residual amount of vinylpyrroli-done monomer in the polymeric product.
The product obtained is highly useful since it is not only of a high molecular weight, it exhibits excellent solubility in water. As used herein, high or excsllent -solubility means.a~.solubility ratio of.5 as in accordance with the description in Pre~arative Methods of Polvmer Chemis~v; sorenson and Campbell, Interscience, 1961, p. 54. - :

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W091tl~522 PCTtUS91/02115 -207~91~ - 6 -Specifically, we have discovered that control of water and initiator addition allow one to control the individual phases of the polymerization so as to allow increased mobility of the reacting moieties and thus allow the reaction to proceed to higher molecular weight final products than has heretofore been possible. By controlling the addition of water and making the addition of initiator incremental and spacing it over the course of the reaction, it is now possible to increase the propagation phase so as to reach higher molecular weights.

~AILED DESCRIPTION OF THE PREFERRED EMBODI~ENTS
Important control parameters for the inventive proces~ are:
; a) The initial charge of initiator must be accurately controlled and treated. Thus; it is best to malntain the initiator between about 30 to 40-C until it is added to the reactiYe mixture. Also, the amount should be accurately measured to be within the ranges speci~ied here- !
ir~. ~
b) The temperature should be controlled within the specified range herein throughout the reaction.
While-the reaction is exothermic, it proceeds ' - - ` relatively slowly; thus moderate cooling-is re-quired during the reaction.
c) It is important to control the viscosity of the rsaction mixture, particularly during the ~ .
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reaction period from 4 to 7 hours after initia-tion of the reaction. This is achieved by adding water incrementally to maintain the viscosity constant during this period. The constant vis-cosity at this stage of the reaction permits growth (propagation) of the molecular chains.
d) Atmospherlc environment must be kept inert, i.e., with a nitrogen or inert gas purge.
~hese parameters are discussed in detail herein-;i lO below.
The initial reagents need not be purified, although reactions have been carried out with N-vinylpyr-rolidone which has been treated with activated carbon.
While the reaction rate is somewhat faster than those with lS non-treated monomer, it is imperative that the monomer be filtered to remove all traces of carbon, which otherwise, can stop the reaction befor~ high conversions are reached.
The initial concentration of monomer can have a significant effect on obtaining the inventive product. The inltial monomer concentration should be kept in-the range fro~ about 25 to 40% by weight based on the total weight of water and monomer. If the initiaI monomer concentration is .,:
` below about 25% by weight,--the inventive product is not obtained in any useful- yield.; When the initial monomer concentration is greater than about 40%, increased -agitation is-required to achieve uniformity of the reaction mixture becau~e of the relatively high viscosity. The graater agitation results in increased shear which produces ~'i . - . ~ . .

an undesirable shift in favor of the termination phase and adverse to the propagation phase. Most preferably, we have found that a monomer concentration of 27 to 28% by weight is most desirable.
s - Of particular importance with the present inven-tion is utilizing an incremental addition of the initiator, i.e., adding tho initiator to the reaction mixture more than one time. This has the e~fect of malntaining the reaction mixture viscosity uniform. It also increases the initiator ef~iciency resulting in an increase in the molecular weight of the vinyl product and a decrease in the ~mount of residual monomer. Specifically, we have found that the total amount oi initiator added should be in at least two separate additions, the first, initially to begin the reaction, and the second at a later point in the reaction. lt iB also po6sible to add the initiator in three or four or more increments. We have found that two or three increnents is preferred.
~he total amount of initiator added generally is in the range from about 0.-Ol to 2.0% by weight based on the monomer and preferably, from-about O.l to 0.2. The amount added at each incremental addition would be an appropriate hal~, third, or the liXe of the total amount to be added.
~ The timing of the addition of the initiator may .
be varied over the-course of the total time;period of the reaction. Thus, if three additions are used (including the initial addition of initiator), the second and third addi-tions could be spaced at one-third intervals over the .`,'.

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W O 91/15522 P~r/US91/02115 g entire course of the reaction. Similarly, the addition of initiator when only two additions are made could be at the half-time of the reaction. However, we have found in a preferred embodiment that when two additions of initiator are utilized (one in addition to the initial addition of initiator), the second is made at approximately the three-quarter point in the reaction.
We have also found that the addition of a buffering and chelating agent is critical in obtaining a product with low residual monomer. This agent performs a dual function in the reaction. Specifically, it complexes with traces.of heavy metals introduced by the aqueous medium or by the reactor, which metals normally contaminate the product and poison the catalytic initiator. ~he buffering agent also controls the pH at a critical level of not lQss than 5.5, preferably to a level on the basic side between about 6.1 and about 10. Below a pH of 5.5 the vinylpyrrolidon~ rate Or polymerization is too slow to compete with the more active guaternized comonomer. thus, when the level approaches 5.5, additional guantities of~-- buffer are added to increase basicity. Generally, the amount of buffer employed represents between about 0.01 to . 0.5 weight S,- preferably between.about 0.04 to 0.3 weight of!--the vinylpyrrolidone-~monomer. .Suitable~agents which 25 -: combine buffering and chelating activity are.those-which have a pH greater than 5..and.include ethylene diamine : tetraacid disodium salt, tetrasodium pyrophosphate,.-.. ~nhydrous dibasic sodium phosphate + monobasic potassium ,. .

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5~22 PCT/US91/02115 2079911 - lO -phosphate, borax, sodium carbonate + sodium bicarbonate, tribasic sodium phosphate and calcium hydroxide. These buf~ering agents are employed as 0.005 molar to saturated aqueous solutions at 25-C. If the amount of buffer is too great, the ash content of the product may increase beyond product specification. For example, for pharmaceutical end uses, the ash should be less than about 0.1% by weight.
Howover, for non-pharmacoutlcal uses, hlgher ash contents can be tolerated, e.g., up to about 0.5% by weight.
However, if the amount of buffer ls too low, the residual monomer content will be intolerable.
During the course of the polymerization, the viscosity of the reactlon system increases. The:viscosity can be measured in a variety of manners, e.g., torque mea-lS surements and the li~e. Typical of such devices are theHeller HST-lO stir tester. We have discovered that by ini-~` tiating the addition of water to the reaction mixture at a point in the reaction after a given amount o~ conversion to polymer has been achieved, and by adding this water in a controlled manner, the viscosity of the reaction mixturecan be maintained within a desired range of values so as to the propagation phase of the reaction and minimize the ...
termination phase.- This results in achieving the desired - higher molecular-weight product. Normally,-~the water is 25- added-over a~period of time at a constant feed rate-with appropriate stirring to:maintain the viscosity constant.
While the addition of water may be started at various times during the reaction and continued for various periods of ~ ~ I

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, WO91/1~522 PCT/US91/0211~

time during the reaction, we have found that it is best to add the water after a monomer conversion of from about 75 to 90% and preferably, from about 80 to 82%. This corresponds to a reaction time of from about 210 to 240 minutes after the initiation of the reaction, when the reaction is carried out at approximately 57-58-C.
Depending on the other parameters under which the reaction i~ carried out, the time of addition o~ the water and the period of addltion over which the water i9 added can be varied. What i4 important, however, is the discovery that by the additlon of water in this manner a~ well as the variation of the other significant par~meters as discussed h~reinabove, the propagation phase of the reac~ion can be prolonged leading to higher molecular weight products.
Normally, the polymerization reaction is carried out under an inert atmosphere. We have found that a nitrogen purge is most desirable, although other inert gases can be used.
The temperature at which the reaction is carried out does have an effect on the ultimate K-value o~ the polymer. Also, understandably, the temperature has an effect on the total time needed to carry out the reaction.
Lower temperatures would require a more prolonged reaction ~ time, whareas higher temperatures wouId lead to a shorter and perhaps uncontrollable polymerization as well~as : -- possible degradation of ingredients and/or product. -We have discovered that the preferred temperature range for .:

, WO91~1~522 PCT/US91/02115 20~-99~ - 12 -the reaction is from about 55 to 65 C and most preferably, from about 57 to 60 C.
An important aspect of the invention is the con-version of the product into a dry powder. Thus, for many applications, the product must be redissolved in water and generally, dissolution rate decreases with decreasing partlcle size. Normally, this would be achieved by removing the water from the reaction mixture and pulverizing the product. However, care must be taken in these Sinal steps to avoid degradation of the product (resulting in a decreased molecular weight). In parti-cular, we have found that the most desirable procedure is to utllize a drum dryer to produce the polymer in sheet form. Alternatively, a belt dryer may be used. The sheet is immediately passed through a pin shredder to breaX it .~
into flaXes and flakes are then ground to a desired powder ~ize. P~rticularly lmportant ln this procedure i8 that the product solution be dried as soon as possible after the reaction is complete to avoid any detrimental change in the product. - --In particular, using either d D or belt drying, ; a product having a water content below about 4.5 weight percent wlthout any K-value degradation is obtained the _- drying temperature is generally in the range from about 250 -- 25 to 260 C for belt drying and about 290 to 330-C-for d D
drying. -~
The dried product is then ground in a manner to mlnimize ~-value degradation. While a variety of grinding . . .

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, WO91/1~522 PCT/US91/02115 . . .

devices may be used, we have found a F~tzmill to be parti-cularly satisfactory. In particular, acceptable powder was produced using a Fitzmill with a 0.094 inch screen and rotor speed of 3600 rpm. the desirable product is in the form of a powder of which 80% is between 16 and 40 mesh and less than 10% passes a 40 mesh screen (U.S. Standard).
The following example illustrates the present inventlon:
For this reaction, a 12 liter reactor equipped with a condenser, an anchor agitator with a speed/torgue readout, a thermocouple, a nitrogen inlet, and a dropping ~unnel were utillzed. All of the reagents were used without purification. Nitrogen was bubbled through the reaction mixture during the entire course of the reaction.
lS 4,541 grams of deionized water and l.69 grams of tetrasodium pyrophosphate were added to the reactor and I mixed at llO rpm for 5 minutes. The agitation was stopped and then 1,687 grams of vinylpyrrolidone were added after 'J it was assured that the tetrasodium phosphate had been ~' ' 20 completely diluted. The agitator was again turned on and -~intained ~t approximately llO rpm.- A nitrogen purge was ' initiated through the reaction mixture. The reaction - mixture was heated to and held at a temperature of 53-54-C
~ '''" and'then l.67 grams of t-butylperoxypivalate was added.

'- 25 - This time was'taken as time zero;~ Any residual initiator--~
": ' ~' clinging-to the'sides was washed from the interior of-the reactor with a small amount of water. The reaction exotherm brought the temperature into the range of from ,.............. - - - ' -2a7 99 11 - 14 -about 57 to 60-C. This temperature range was maintained durinq the next 420 minutes of the reaction. Neither heating nor cooling was required to maintain the tempera-ture. (If needed, heat may be supplied at approximately 57.5-C and terminated at 58.5-C to maintain the reaction temperature unifor~.) After 210 minutes, the addition of deionized water was begun at a feed rate of 10.4 grams per minute.
The total amount of water added in this manner was 2,187 grams so that the feed was completed a~ter a reaction time of 420 minutes (a total feed time of 210 minutes). The water was added continuously using a dropping funnel. The addition rate of water was monitored by measuring the torgue of the polymerization mixture. In this example, the agitator was set at 110 rpm and the torque was maintained to at least the value observed at 210 minutes.
At this point, the conversion of monomer was about 80 to 82%. The reaction mlxture had a Broo~field ~ viscosity of 40,000 cps at 57-C, and the X-value of the ; 20 polymer was 105 + 2. The torque was 14.5 oz-inch.- ~-~
- - At 330 minutes, a second addition of-t-butylper-oxypivalate (1.77 grams) was effected and any residual initiator washed from the inside of the flask with a small amount of water. At~this polnt, the conversion was between 25--~85 and 87%. This second amount of initiator was added at-a tim~ when the concentration of monomer and polymer was 23%
by w~ight.- --I
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2079~11 At 420 minutes, the polymerization was terminated by heating the reaction mixture to 80 ~ 2-C within a period of 15 minutes and holding it at this temperature for an additional 15 minutes to thus polymerize remaining monomer.
5 At this polnt, the conversion of the monomer was 98 to 99.5%, and the concentration of polymer/monomer about 20~.
At 450 ~inutes, the reactlon was terminated by turning off the nltrogen purg~ and cooling the reactor. The reactor was discharged at 55-60-C, the residual monomer of the 10 polymer product in aqueous solution was less than 0.2~
which is the limit of detection and the R-value of the polymer was 119-125.
A series of polymerizations were carried out in glass wher~in the amount of chelatlng and buffering used 15 (tQtrAsodium phosphate) was varled with the remaining reac-tlon parameter~ being the 3ame as descrlbed above. The re~ults are deplct~d ln the Table. As shown thereln, whlle ~ it is possible to achleve K-values greater than 120 even in - the ~bsence of the chelatlng agent, the percent of resldual - 20 vinylpyrrolldone monomer is extremely high (0.23%).- In contrast, wlth even a relatlvely small amount of the TSPP, (0.01 welght %), the residual monomer is minimized.
- For the results tabulated in the Table, the residue on~ignition-~and residual vinylpyrrolidone monomer J 25 were determined as foIlows~
- -- Re~idue on ~qnition lO g of sample wero weighed in a crucible that had prevlously been ignited, cooled, and weighed. The .. ., . , .. , .. , , . , . .. ,, ., " . ., " . . ~, . .. . .. .. . .

W091/1~522 PCT/USgl/02115 2~799~ - 16 -crucible was heated gently at first until the sample was thoroughly charred. It was then cooled and the residue moistened with 2.0 ml (1:1) of sulfuric acid and heated gently until white fumes no longer evolved. The sample was then ignited at 800-C + 25-C until the carbon was consumed.
It was cooled in a desiccator, weighed and the ash content was calculated as follows:

% ash ~ W2 W0 100 ' 10 W, - Wo wherein W 8 crucible weight Wl - ~ample and crucible before ashing W2 - sample and crucible after ashing ..' Determlnatlon o~ Percent VinvlDvrrolidone A saople was weighed into a 250 ml Erlenmeyer flask, the sample was dissolved in 10 - 20 ml of di~tilled water or reagent grade alcohol as required. 10 ml of 5%
sodium acetate i8 added. If the solution is cloudy, reagent alcohol is added until the solution clears. The ,, .
contents are mixed well and then titrated with a 0.1 N
iodine solution until a straw color appears. An additional - 5 ml o~ the iodine solution is added. The total amount of - iodine added is recorded.
-The;flask is swirled and set aside for S minutes.
If the color disappears-at the end of this time, additional ml o~ iodine are added and the contents are allowed to stand for 3 minutes. The amount of iadine f --addltional iodine solution added is recorded.

2~7991~

The solution is then titrated with O.l normal sodi~m thiosulfate until lt is a light yellow. 5 ml of starch indicator is added. If alcohol is used as a solvent, the solution should be titrated without the starch because starch gives a poor endpoint. The titration is continued until a 5harp colorless endpoint is o~tained.
The percent vinylpyrrolidone i~ then calculated using the following ~ormulas l. t(mll x N~) - (mlth~O x NthlO)] 5~5 ~ VP ~
g sample 2. t(~l~ x N~) (mlth~O x Nth~o)~ 555 . % VP ~
g a~pl- x S o11ds .

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Claims (10)

WHAT IS CLAIMED IS:

1. Polyvinylpyrrolidone which is water-soluble and non-crosslinked, has a K-value in the range from about 120 to 150, and a residual monomer content of less than about 0.1 percent by weight.

2. The polyvinylpyrrolidone of claim 1 in the form of a dry powder.

3. The polyvinylpyrrolidone of claim 2 wherein about 80% of the powder is between about 16 and 40 mesh and less than about 10% is less than 40 mesh.

4. The polyvinylpyrrolidone of claim 3 having a water content of less than about 4.5%.

5. A method for producing the polyvinylpyrroli-done of claim l comprising the steps of:
a) forming mixture of N-vinylpyrrolidone monomer, a chelating buffer, and water;
b) subjecting the reaction mixture to polymerization conditions in the presence of an initiator for a period of time to convert substantially all of the monomer to polyvinylpyrrolidone;

c) during the polymerization, maintaining the viscosity of the reaction mixture sufficiently constant so as to maximize the propagation phase and minimize the termination phase of the polymerization.

6. The method of claim 5 wherein the initial reaction mixture contains from about 25 to 40 percent by weight monomer bascd on the weight of water and from about 0.05 to 0.5 weight % of chelating buffer.

7. The method of claim 5 wherein the polymeriza-tion is carried out at a temperature in the range from about 55 to 65°C.

8. The method of claim 1 wherein the viscosity is kept constant by the incremental addition of water and initiator to the reaction mixture.

9. The method of claim 5 wherein after termina-tion of the reaction, the product is dried in a belt or drum dryer and the dried product is ground to a powder of which about-80% is between 16 and 40 mesh and less than about 10% is less than 40 mesh.

10. The method of claim 9 wherein the product is dried to a water content of less than about 4.5%.