CA1264163A - Citrate esters and methods - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Citrate esters are formed utilizing organic titanates as a catalyst allowing excess alcohol to be removed. Four citrate esters have been found which provide advantageous plasticizing properties to PVC compositions which include superior toxicity test results and superior soapy water extraction test results. The four citrate esters are. acetyltri-n-hexyl citrate, n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrate, and acetyltri-n-(octyl/decyl) citrate. Articles formed from the PVC plasticized mixtures are extremely useful in the medical or health care field as they demonstrate a low order of toxicity.

Description

~4~63 Citrate esters are useful as plasticizers for poly-vinyl chloride (PVC) resins as certain of these esters provide a low order of toxicity when compared to ph-thalate esters ~hich have been conventionally used. Other advantages have been noted using certain citrate esters as plasticizers in PVC com-positions and articles, including improved resistance to soapy water extraction and low temperature and transport properties.
The preparation of the citrate esters has been found to be significantly enhanced by the utilization o~ certain organic titanate catalysts which allow the excess alcohol to be removed after the esteri~ication step.
Citrate esters commercially produced usiny citric acid have long been available and have been used as plastici-zers for PVC resins. However, the performance of articles produced ~rom the PVC resin composi-tionsl whe-ther utilizing citrate esters known to date or conventional phthalate plasti-cizers, has had many inherent disadvantages. For example, medical-grade PVC compositions are used to form bloocl bags, tubing and a variety of health-related articles and in recent years toxicit~ has been a major concern for manufacturers of such articles. Recent reports have identified di-2-ethylhexyl phthalate (DEEIP) or (DOP) and di-2-ethyl-hexyl adipate (DEHA) as hepatocarcinogens in rodents. While certain of the phthal-ates have excellent plasticizing qualities, their suspected carcinogenic nature renders them doubtful candidates for -future medical-grade uses. As an alternative, known citric acid esters such as acetyltri-n-butyl and tri-n-butyl citrate were tried as PVC plasticizers in medical-grade applications but it was determined that these compounds were not entirely satis-~actory due to their high soapy water extraction percentages ~6~3 70033-8 and would therefore not be useful in many medical area applica tions. Also, it has been found that new production techniques had to be devised for the newer citric acid esters which were determined -to have sui-table toxicity and physical characteris-tics when used as PVC plasticizers.
The present invention seeks to provide PVC plastici-zers which provide superior toxicity test results in biological studies.
Further, the present invention seeks to provide plasticizers for PVC compositions which can be processed without difficulty using conventional extrusion, calendering, or plastisol techniques.
Thus, the present invention seeks to provide new citric acid esters namely: acetyltri-n hexyl citrate, n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrate, and acetyltri-n-(octyl/decyl) citrate which can be used as plasticizers having desirable physical characteristics when imparted into PVC compositions.
Additionally, the present invention seeks to provide PVC compositions and formed articles therefrom having superior results in toxicology studies concerning dermal toxicity, oral toxicity and genetic assays.
The present invention also seeks to provide a new process for the low temperature manufacture of the four new citric acid esters utilizing organic titanates to provide eco-nomical and efficient production methods.
According to one aspect of the present invention there is provided a polymeric composition comprising a polyme.r and a plasticizing amount of a citrate selected Erom the group con-sisting of acetyltri-n-butyl citrate, acetyltri-n-hexyl citrate, ;~ 'l ~64~3 70033-8 n-butyryltri-n-hexyl citrate, acetyltri-n-lhexyl/octyl/decyl) citrate and acetyltri-n-(octyl/decyl) citrate, wherein said ci.trate has an aconita-te level of less than 0.20% and wherein said citra-te also has heat stability characteris-tics, when tested at 150C for two hours, of a color not greater than 50-60 APHA and a mild odor at 25C.
According to a ~urther aspect of the presen-t invention there is provided a medical article formed from a polyvinyl chloride composition comprising a polyvinyl chloride resin ana a plasticizing amount of a citrate ester selected from the formula:

CH2 -COORl I

( H2-COOR3 where Rl, R2, and R3 = CH3 to C18H37 R4 = CH3 to C7H15' said citrate having an aconitate level of less than 0.20% and having heat stability characteristics when tested at 150C for two hours, of a color not greater than 50-60 APHA and a mild odor at 25C.
According to another aspect of the present invention there is provided a medical article formed from a polymeric composition comprising a polymer, a plasticizing amount of a citrate ester selected from the formula:

\

where Rl, R2, and R3 = CH3 to C18H37 R4 = CH3 to C7H15 - 3a -a stablizer and a lubri.cant, and wherein said citrate ester has heat stability characteristics, after heating at 150C for two hours, of a color not greater than 50-60 APHA and a mild odor at 25C and an aconitate level of less than 0.20%.
According to a still further aspect of the present invention there is provided a citrate ester selected from the group consisting of acetyltri-n-butyl citrate, acetyltri-n-hexyl citrate, n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/
octyl/decyl) citrate and acetyltri-n-(octyl/decyl) citrate, said citrate having heat stability characteristics, after heat-ing at 150C for two hours, of a color not greater 5Q~60 APHA
and a mild odor at 25C and having an aconitate level of less than 0.20%.
According to another aspect of the present invention there is p~ovided a method of producing a citrate ester selected from the group consisting of acetyltri-n-butyl citrate, acetyl-tri-n-hexyl citrate, n-butyryltri~n-hexyl citrate, acetyltri-n~
(hexyl/octyl/decyl) citrate and acetyltri-n-(octyl/decyl) citrate, which method comprises heating citric acid and an alcohol selected from the group consisting of n-butyl alcohol, n-hexyl alcohol, n-(octyl/decyl) alcohol and n-(hexyl/octyl/
decyl) alcohol in the presence of an organic titanate, at a temperature below about 150C to effect esterification, removing the excess alcohol, and acetylating or butyrylating the ester by adding sulfuric acid and acetic or n-butyric anhydride while maintaining the temperature below approximately 110C until the acetylation or butyrylation reaction is complete.
According to a further aspect of the present invention there is provided the process of forming a citrate ester of the formula:

- 3b -'~
~' f H2 -COOR

\

where Rl, R2 and R3 = CH3 to C18H37 R4 CH3 to C7H15, comprising the steps of heating a suitable alcohol and citric acid in the presence of an organic titanate at a temperature of below approximately 150C to effect esteriEication, removing the excess alcohol, and alkoxylating the ester by adding a suitable anhydride and sulfuric acid while maintaining the temperature below approxi-mately 110C until the alkoxylation reaction is co.mplete.
Other objectives and advantages of the present inven-- 3c -,,j tion wi]l be clemonstrated to those skilled in the art as set forth in detail below.
~ hus in a first aspect this invention pro~ides citrate esters of -the formula:

R4COOC~COOR2 where Rl, ~2~ and R3 = CH3 to C18H37; and R4 = CH3 to C7EIlS
and more specifically acetyltri-n-hexyl citrate, n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrate, and acetyltri-n-(octyl/decyl) citrate are produced utilizing an organic titanate catalyst. These esters have been found useful as medical-grade plasticizers in PVC compositions. The plasti-cizers have a low order of toxicity and impart to PVC the proper balance of physical properties needed in health care and medical-grade uses. The production steps ~or the citric acid esters include low temperature esterification a-t 150C or below, removal of any excess alcohol and thereafter, alkoxyla-tion. Conventional neutralization and finishing steps are then carried out. The alkoxylation step is carried out at a temper-ature less than approximately 110C.
A PVC resin can be combined with one of the above-mentioned citric acid esters, along with suitable stabilizers and lubricants, to form a plasticized PVC which can be extruded, calendered or otherwise processed into suitable articles o~ manu~acture including blood bags, tubing and other prodwcts. Articles so made have a low order of toxicity and provide superior extraction properties, particularly in soapy water extraction tests. The soapy water extraction test is a standard test, the results of which closely resemble the results obtained with body fluids such as human blood.

~26~63 The four preferred forms of the citrate esters are as ~ollo~s:

1. acet~;~rl-n-hexyl citrate~

CH3COOC-COOC6Hl CH2COOC~H13

2. n-but.yryltri-n-hexyl citrate:

C3H7cc\cc6Hl3 acetyltri-n-(hexyl/octyl/decyl) citrate:

CH2COOC6_l0H13-21 CH3COOC-cOOc6_l0 H13-21 CH2COOC6_l0~13-21 4. acetyltri-n-(octyl/decyl) citrate:

CH2COOC8_l0H17-21 CH3COOc-coocg-loHl7-2l CH2COOCB_lo H17-21 The preferred method of manufacture of the above-identified citrate esters comprises low temperature esterification below 150C and preferably at a temperature range of from 125C to 130C of the proper alcohol (such as n-hexyl alcohol for acetyltri-n-hexyl citrate) with citric acid in the presence of the organic titanate, tetra-n-butyl titanate, removal of any excess n-hexyl alcohol, and then alkoxylation of the esters produced with an acid anhydride. At esterification temperatures above 150C
citrates undergo rapid degradation resulting in numerous products of decomposition. At temperatures somewhat below 150C the major decomposition product is an aconitate ester. The alkoxylation takes place at a t2mperature of below approximately 110C.

Tetra-n-butyl titanate is preferred since the ester interchange which ta~es place between the titanate alkyl groups and citrate alkyl groups does not result in the introduction of alkyl groups not normall~
present in the citrate esters.

The preferred PVC composition comprises blending and milling a medium molecular weight PVC resin with one o~ ~he above citrate esters on a two to one ratio, resin to plasticizer, along with stabilizers, lubricants and extenders as required. Articles manufactured from the preferred PVC compositions include blood bags, tubing and other articles for the medical and health care ~ields.

Certain citrate esters, namely acetyltri-n hexyl citrate, n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrate and acetyltri-n-(octyl/decyl) citrate have been found to be particularly useful in medical applications when compounded with PVC
resins through conventional plastisol, calendering or extrusion techniques. Such plasticized PVC exhibits good clarity, good low temperature properties, low volatility and low extractability into various media. Also, a low order oE acute toxicity has been shown and complete compatibility with medium molecular weight PVC resins make the four named esters unique and valuable. Studies have shown that the four citrate esters are not toxic substances, primary skin irritants or ocular irritants to unrinsed eyes and oral administration has produced no signs of systemic toxicity and has shown no mortality in fasted mice or rats. Genetic toxicology assays for detecting mutagenic activity at the gene or chromosomal level have shown that these esters do not induce gene mutation in either microbial cells or in mammalian cells in vitro or chromosomal mutatlon in vivo or in vitro . Studies have also shown that under in vivo conditions, these citrate esters hydrolyze rapidly and completely in concentrations at expected realistic levels of human exposure.

Preparation of the citrate e5ters are as follows:

Example 1 : Preparation of acetyltri-n-hexyl citrate 330 lbs. of n-hexyl alcohol, 180 lbs. of citric acid, 1.54 lbs. of tetra-n-butyl titanate and 15 gallons of heptane are charged to a vessel equipped with agitator, thermometer, vapor column, condenser and a decanter set to allow removal of water formed during the reaction while refluxing heptane. The esterification is effected at 140C to maintain the aconitate (THA) level below .5~ for general production. As shown in Fig. l the aconitate level can be kept well below the .2% range ~y longer reaction times at lower temperatures with the optimum time, and aconitate levels reached by temperatures of from approximately 125C to 130 C. As shown, at a temperature of approximately 130C a unique result is achieved in that the aconitate formation levels out to provide a citrate ester having excellent purity. During esterification water is periodically removed from the decanter in order to maintain proper temperature and reaction rates. The esterification is continued at 140C until the esterification mixture tests .5% maximum acidity calculated as citric acid although lower temperature esterification and acidity percentage may be used for higher purity products as mentioned above. Next, the vessel is cooled to 120C and any water is removed from the separator and any heptane therein is also removed for future use. The reflux line of the vessel is closed and pressure on the system is reduced slowly. The kettle is heated to 130 - 140C and steam is introduced to help remove any residual alcohol. This vacuum steam stripping is continued until alcohol cannot be detected by conventional laboratory tests. When no more alcohol can be found, the steam is discontinued and the temperature is reduced to 100C and the vacuum is broken with nitrogen gas.

Next, 0.4 lb. concentrated sulfuric acid (H2SO4) is charged into the vessel after which it is sealed and approximately 107 lbs. of acetic anhydride (in a determined molar amount) are added at a slow rate so that the temperature does not exceed 110C. When all the anhydride has been added, agitation of the mix continues for approximately one hour until the acetylation reaction ha;. been completed.

Next~ a full vacuum is put on the system and enough heat is added for distillation to proceed at a sui'cable rateO This step continues until acetic acid is shown to be 5% or less by conventional lab tests whereupon the mixture is cooled to 75C for neutralization.

The remaining steps of neutralization, bleaching, washing, etcO are carried out as in conventional esterification processes.

Example 2 : Preparation of n-butyryl~ri-n-hexyl citrate:

. .
The vessel used in example 1 is again charged with 330 lbs. of n-hexyl alcohol, 180 lbs. of citric acid and 1.54 lbs. of tetra-n-butyl titanate. Esterification is carried out as in example, 1 as is the heptane-alcohol strlp. Butyrylization is thereafter done with the addition of 0.4 lbs. of concentrated sulfuric acid and 166 lbs. of n-butyryic anhydride as shown above in the acetylation process. The butyric acid may be removed as shown above or by neutralization.

Examples 1 and 2 produce esters with the following characteristics:

ANALYT I CAL DATA
Property Citrate n-Butyryltrl-n-hexyl Purity wt% 99 99 Golor AP~A 50 max. 50 max.
Neut. No. mg KOH/g 0.2 max. 0.2 max.
Moisture K.F. 0.25 max. 0.25 max.
S. G. Q 25/25C 1.0045-1. 0055 0.991-0.995 R. I. @ 25/25 C 1.445-1.447 1.444-1.448 Viscosity @ 25C cps 25-35 25-35 Odor @ 25C Little or none Little or none Heat Ctability (2 Hrs. @ 150 C) Color APHA 50-60 50-60 Neut. No. mg KOH/g 0.2 max. 0.2 max.
Odor @ 25C ~ild Mild It has been determined that a citrate ester yield can be achieved of 99-~% purity with a minimum oE a conitate forma--tion and unacetylated esters by lowering the esterification temperatures to 130C or below with a preferable temperature range of 125C to 130Co Figure 1 and Table 1 demonstrates the percentage of tri-n-hexyl aconitate (THA) formed during the production of acetyltri-n-hexyl ci-trate whereby the reaction is terminated at appro2imately 0.2~ acidity, as citric acid. As shown in Figure 1 and I'able 1 below, the aconitate levels range from approximately 0.14 to 0.19 with a reaction time of from 25 to 19 hours at temperatures of from 125C to 130C. It has been determined that by lowering the temperature from 140C to 130C an additional reaction time of only 90 minutes is required with the aconitate level dropping from 0.35 to 0.19%, a decrease of approximately 45~. As shown, the aconita-te level can be tremendously decreased by lowering the temperature approximately 10 degrees from 140C to 130C without substan-tially increasing the reaction time based on 0.~% acidity (cit-ric acid) as the reaction completion indicator. As shown in Figuxe 1 a stabilization of the aconitate formation occurs during esteri~ication at a critical temperature of approxi-mately 130C providing a technique for the manufacture of high purity esters having low aconitate levels. Lower aconitate percentages and other impuritie~ provide the high quality plas-ticizer needed for medical-grade products.

~2~ 3 Reaction Time and Aconitate Formation Rates at Various TemperatUres _ _ EsterificationReaction Final THA ~ Acidity As Temperature ( C)Time (Hrs.) Content (~) Citric Acid . . _~ .___ . ._ _ __ 120 24 1/4 0.07 0.17 125 25 0.14 0.17 130 I9 0.19 0.17 140 17 1/2 0.41 0.16 150 13 .59 0.19 It is believed that acids such as citric acid with 1GW pK
values exhibit a synergistic effect with titanate catalysts at low temperatures in the 150C or lower range. Phthalic acid which has a high pK value will not undergo esterification with the titanate catalysts at these low te~peratures.

Also, other organic titanate catalysts can be used to produce the four esters of this invention such as tetrakis-2-ethylhexyl titanate althouyh superior results have been demonstrated using tetra-n-butyl titanate.

PREPARATION AND TESTING OF PVC COMPOSITIONS

FORMULATION PARTS BY WEIGHT

Resin (Medium Molecular Weight PVC) 100 Plasticizer 50 Stabilizer (Calcium/Zinc) 2.5 Lubricant (stearic acid) 0.25 The above formulation was blended and milled for 5-10 minutes at 325 to 340F. The milled stock was pressed (3 min. at 340-360F and 32,000 psi) to 40- and 70-mil sheets, and aged for 48 hours at room temperature for evaluation. All tests were made with samples cut from 70-mil pressed stock except for extraction tests which were obtained on 40-mil samples. The performance data was obtained by accepted ASTM methods with modifications as detailed below in Table 2.

Tensile Strength Determined with Instron TT, 1100 Ultimate Elongation series (2 in./min.) using a Modulus (100% elongation) dumbbell-shaped s~ecimen Test (ASTM D638) carried out at 70 + 5~F.
Hardness Determined with Shore ~urometer A
(ASTM D676) ~10 sec.) at 75 + 5 F.
Torsional Flex (T4 and T~) Determined with Torsion Fle~
(ASTM D1043) Tester of Clash and Berg design.
T is the temperature at which t~e Modulus of Rigidity is 10,000 psi; T is the temper~ture at which ~he Modulus of Rigidity is loo ,ooo psi.
Brittle Point Determined by impact method using (ASTM D746) Scott Tester, Model E.
Volatile Loss (A/C) Determined on specimens 2 inches in (ASTM D1203) diame~er heated in activated carbon at 70 C for 24 hours. Results are expressed as percent of plasticizer lost.
Water extraction (Tap) Determined on specimens 2 inches in Soapy Water Extraction diameter sus~ended in appropriate (1% Ivory Flakes) liquid at 60 C for 24 hours.
Oil Extraction Results are expressed as percent (ASTM NO. 3) of plasticizer lost.
Migration Loss (silica) Determined on specimens 2 inches in diame~er heated in silica (100 mesh), at 70 C for 24 hours. Results are expressed as percent of plasticizer lost.
Volatile Loss (air) Det8rmined by Oven Method (24 hr. at 100 C) on specimens 2 inches in diameter. Results are expressed as percent of plasticizer lost.

TABLE 2. PLASTICIZER PERFORMANCE DATA
PLASTICIZER DEHP DEHA#1 ~2 ~3 $4 ~5 HARDNESS, Durometer A, lo Sec.79 78 78 81 81 87 87 TENSILE, psi2748 1797 2862 2978 2924 2743 2789 ULTIMATE
ELONGATION, ~395 414 400 390 427 364 374 100% MODULUS, psi 1368 1092 1348 1574 1362 1656 1704 r (1 ~8 psi), 4 C. -8.4 -30.8 -7.6 -9.1 -11.9 -6.9 -4.0 (100 ooo psi), ~ C. -38.8 -66.5 -35.6 -41.6 -48.7 -53.1 -59.7 BRITTLE POINT, C. -24.5 -56.5 -18.5 -26.0 -33.5 -36.8 -37.8 YOLATILE LOSS, ~air),% 4.8 7.1 12,1 2.6 107 .3 .1 VOLATILE LOSS, (A~C),~ 3.4 7.6 7.0 1.7 1.4 2.8 4.5 WATER EXTRACTION, ~ .7 1.5 1.2 1.9 1.7 1.5 3.3 SOAPY WATER
EXTRACTIOM, %2.7 11.0 9.5 5.4 2.2 3.4 2.4 OIL EXTRACTION, % 11.4 34.7 10.9 13.8 15.7 15.2 19.3 SILICA GEL MIGRATION,% 12.2 23.0 l7.0 4.4 3.6 4.8 7.4 ~1 - acetyltri-n-b~tyl citrate ~2 - acetyltri-n-hexyl citrate ~3 - n-butyryltri-n-hexyl citrate #4 - acetyltri-n-(hexyl/oc~yl/decyl) citrate ~64~3 ~5 - acetyltri-n-~octyl/decyl) citrate The plasticizer perform~nce data in Table 3 demonstrates 'che results of tests with citric esters/expoxidized soybean oil (ESO) blends. ESO is commonly used in conjunction with ~EHP at levels in the range of 1-5% based on DEHP as an aid in stabilization. The ratio of 2.5/g7.5 ESO/citrate was used as a base point in the studies. Test results on this combination are shown in column 1. A significan~
improvement in properties, particularly soapy water extrac~ion is noted.

TABLE 3 (PLASTICIZER PERFORMANCE DATA) PLASTICIZER2.5ESO 20ESO 40 ESO 40ESO 4~ ESO
PE~CENTAGES: 97 5 $2ao #2 60#2 60#3 60 ~5 HARDNESS, Durometer A, 10 Sec. 81 80 80 81 85 TENSILE, psi 2907 3010 3079 3165 3097 ULTIMATE
ELONGATIO~, % 422 424 420 428 395 100~ MODULUS, psi 1415 1429 1491 1514 1779 T4 (1~8 psi) C. -9.5 -7.8 -7.7 -8.2 -5.4 T (100,00O0 psi~
4 C. -41.8 -41.3 -39.3 -~1.8 -50.3 B~ITTLE POINT, C. -26.5 -25~5 -20.5 -24.5 -26.5 VOLATILE LOSS, (Air),% ~.4 2.1 1.5 .8 .5 VOLATILE LOSS, (A/C),% 1.3 1.6 1.4 .9 1.1 WATER EXTRACTIONt % 1.3 .9 .6 .8 1.0 SOAPY WATER
EXTRACTION, % 2.9 2.9 6.4 4.8 3.8 OIL EXTRACTION, % 13.0 11.6 10.1 10.0 12.9 SILICA GEL MIGRATION,% 5.7 5.3 4.7 4.0 2.5 ESO - Ester/epoxidized Soybean Oil ~2 - acetyltri-n-hexyl citrate ~3 - n-butyryltxi-n-hexyl citrate #5 - acetyltri-n-(octyl/decyl) citrate Since ESO is less expensive than citrates, a reduction in plasticizer cost results if ESO can be substituted for part of the citrates. Results of tests with higher ESO/citrate ratios as shown in columns 2-5 of Table 3 and a significant improvement in properties up to and perhaps bey~ad the ratio of 20/80 ESO/citrate ratio as shown.

Various other PVC compositions can be formulated and the examples and illustrations shown herein are for illustrative purposes and are not intended to limit the scope of the invention.

Claims (97)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A polymeric composition comprising a polymer and a plasticizing amount of a citrate selected from the group consisting of acetyltri-n-butyl citrate, acetyltri-n-hexyl citrate, n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrate and acetyltri-n-(octyl/decyl) citrate, wherein said citrate has an aconitate level of less than 0.20% and wherein said citrate also has heat stability characteristics, when tested at 150°C for two hours, of a color not greater than 50-60 APHA and a mild odor at 25°C.

2. A polymeric composition according to claim 1, wherein the aconitate level is less than 0.2% when the esterification mixture from which said citrate is produced tests about 0.6%
maximum acidity calculated as citric acid.

3. A polymeric composition according to claim 1, wherein the citrate is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, and wherein said citrate has an aconitate level of not greater than 0.18%
when the esterification mixture from which said citrate is produced tests about 0.9% maximum acidity calculated as citric acid.

4. A polymeric composition according to claim 1, wherein the citrate is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of less than 0.20% when the esterification mixture from which said citrate ester is produced tests in the range from about 0.6% to 0.2% acidity calculated as citric acid.

5. A polymeric composition according to claim 1, wherein the citrate is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of not greater than 0.15% when the esterification mixture from which said citrate ester is produced tests in the range from about 0.9% to 0.45% acidity calculated as citric acid.

6. A polymeric composition according to claim 1, wherein the citrate is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of not greater than 0.10% when the esterification mixture from which said citrate ester is produced tests in the range from about 0.9% to 0.35% acidity calculated as citric acid.

7. A polymeric composition according to claim 2, wherein said citrate is acetyltri-n-hexyl citrate.

8. A polymeric composition according to claim 2, wherein said citrate is n-butyryltri-n-hexyl citrate.

9. A polymeric composition according to claim 2, wherein said citrate is acetyltri-n-butyl citrate.

10. A polymeric composition according to claim 2, wherein said citrate is acetyltri-n-(octyl/decyl) citrate.

11. A polymeric composition according to claim 2, wherein said citrate is acetyltri-n-(hexyl/octyl/decyl) citrate.

12. A polymeric composition according to claim 1, wherein the polymer is polyvinyl chloride and said selected citrate having heat stability characteristics, when tested at 150°C for two hours, of a color not greater than 50-60 APHA and a mild odor at 25°C, and also having an aconitate level of less than about 0.2% when the esterification mixture from which said citrate is produced tests 0.5% maximum acidity calculated as citric acid.

13. A polymeric composition according to claim 8, wherein the polymer is polyvinyl chloride and wherein said citrate has a low order of toxicity.

14. A polymeric composition according to claim 12, wherein the polymer is polyvinyl chloride and wherein said citrate has an additional heat stability characteristic, after heating at 150°C for two hours, of a neutralization number, mg KOH/g, of not greater than about 0.2.

15. A polymeric composition according to claim 1, wherein the polymer is polyvinyl chloride and the citrate is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of less than 0.20% when the esterification mixture from which said citrate is produced tests about 0.6% maximum acidity calculated as citric acid.

16. A polymeric composition according to claim 1, wherein the polymer is polyvinyl chloride and the citrate is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of not greater than 0.18% when the esterification mixture from which said citrate is produced tests about 0.9% maximum acidity calculated as citric acid.

17. A polymeric composition according to claim 1, wherein the polymer is polyvinyl chloride and the citrate is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of less than 0.20% when the esterification mixture from which said citrate ester is produced tests in the range from about 0.6% to 0.2% acidity calculated as citric acid.

18. A polymeric composition according to claim 1, wherein the polymeric is polyvinyl chloride and the citrate is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of not greater than 0.15% when the esterification mixture from which said ester is produced tests in the range from about 0.9% to 0.45% acidity calculated as citric acid.

19. A polymeric composition according to claim 1, wherein the polymer is polyvinyl chloride and the citrate is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of not greater than 0.10% when the esterification mixture from which said ester is produced tests in the range from about 0.9% to 0.35% acidity calculated as citric acid.

20. A polymeric composition according to claim 15,17 or 19, wherein said citrate is acetyltri-n-hexyl citrate.

21. A polymeric composition according to claim 15, 17 or 19, wherein said citrate is n-butyryltri-n-hexyl citrate.

22. A polymeric composition according to claim 1, wherein the polymer is polyvinyl chloride and the citrate is acetyltri-n-hexyl citrate having heat stability characteristics, when tested at 150°C for two hours, of a color not greater than 50-60 APHA and a mild odor at 25°C and also having an aconitate level of less than about 0.2% when the esterification mixture from which said citrate is produced tests 0.5% maximum acidity calculated as citric acid.

23. A polymeric composition according to claim 22, wherein said citrate has a low order of toxicity.

24. A polymeric composition according to claim 22, wherein said citrate has an additional heat stability characteristic, after heating at 150°C for two hours, of a neutralization number, mg KOH/g, of not greater than 0.2.

25. A medical article formed from a polyvinyl chloride composition comprising a polyvinyl chloride resin and a plasticizing amount of a citrate ester selected from the formula:
where R1, R2, and R3 = CH3 to C18H37 R4 = CH3 to C7H15, said citrate having an aconitate level of less than 0.20% and having heat stability charateristics when tested at 150°C for two hours, of a color not greater than 50-60 APHA and a mild odor at 25°C.

26. An article according to claim 25, wherein the esterification mixture from which said citrate is produced tests about 0.6% maximum acidity calculated as citric acid.

27. An article according to claim 25, wherein the citrate ester is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of not greater than 0.18% when the esterification mixture from which said citrate is produced tests about 0.9% maximum acidity calculated as citric acid.

28. An article according to claim 25, wherein the citrate ester is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of less than 0.20% when the esterification mixture from which said citrate ester is produced tests in the range from about 0.6% to 0.2% acidity calculated as citric acid.

29. An article according to claim 25, wherein the citrate ester is selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said citrate having an aconitate level of not greater than 0.15% when the esterification mixture from which said citrate ester is produced tests in the range from about 0.9% to 0.45% acidity calculated as citric acid.

30. An article according to claim 26, wherein said citrate is acetyltri-n-hexyl citrate.

31. An article according to claim 26, wherein said citrate is n-butyryltri-n-hexyl citrate.

32. An article according to claim 26, wherein said citrate is acetyltri-n-butyl citrate.

33. An article according to claim 26, wherein said citrate is acetyltri-n-(octyl/decyl) citrate.

34. An article according to claim 26, wherein said citrate is acetyltri-n-(hexyl/octyl/decyl) citrate.

35. An article according to claim 26, 30 or 31, which article is a blood bag.

36. An article according to claim 26, wherein said citrate ester is n-butyryltri-n-hexyl citrate, and further comprising a stabilizer and a lubricant, said citrate having heat stability characteristics, after heating at 150°C for two hours, of a color not greater than 50-60 APHA, and a mild odor at 25°C and also having an aconitate level of less than about 0.2 percent when the esterification mixture from which citrate is produced tests 0.5 percent maximum acidity calculated as citric acid.

37. An article according to claim 36, which article is a blood bag.

38. An article according to claim 37, wherein said citrate has a low order of toxicity.

39. An article according to claim 37, wherein said citrate has an additional heat stability characteristic, after heating at 150°C for two hours, of a neutralization number, mg KOH/g of not greater than about 0.2.

40. A medical article formed from a polymeric composition comprising a polymer, a plasticizing amount of a citrate ester selected from the formula:
where R1, R2, and R3 = CH3 to C18H37 R4 = CH3 to C7H15 a stabilizer and a lubricant, and wherein said citrate ester has heat stability characteristics, after heating at 150°C for two hours, of a color not greater than 50-60 APHA and a mild odor at 25°C and an aconitate level of less than 0.20%.

41. A medical article according to claim 40, comprising a blood bag.

42. A medical article according to claim 41, wherein said citrate has a low order of toxicity.

43. A medical article according to claim 42, wherein said citrate has an additional heat stability characteristic after heating at 150°C for two hours, of a neutralization number, mg KOH/g of not greater than 0.2.

44. A medical article according to claim 40, 41 or 43, wherein said polymer is a polyvinyl chloride resin.

45. A citrate ester selected from the formula:
where R1, R2, and R3 = CH3 to C18H37 R4 = CH3 to C7H15 said ester having an aconitate level of less than 0.20% and having heat stability characteristic, after heating at 150°C
for two hours, of a color not greater than 50-60 APHA and a mild odor at 25°C.

46. An ester according to claim 45, selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said ester having an aconitate level of less than 0.20% when the esterification mixture from which said citrate is produced tests about 0.6% maximum acidity calculated as citric acid.

47. An ester according to claim 45, selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said ester having an aconitate level of not greater than 0.18% when the esterification mixture from which said citrate is produced tests about 0.9% maximum acidity calculated as citric acid.

48. An ester according to claim 47, wherein said aconitate level is not greater than 0.15%.

49. An ester according to claim 47, wherein said aconitate level is not greater than 0.10%.

50. An ester according to claim 45, selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said ester having an aconitate level of less than 0.20% when the esterification mixture from which said citrate ester is produced tests in the range from about 0.6% to 0.2% acidity calculated as citric acid.

51. An ester according to claim 45, selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said ester having an aconitate level of not greater than 0.15% when the esterification mixture from which said citrate ester is produced tests in the range from about 0.9% to 0.45% acidity calculated as citric acid.

52. An ester according to claim 45 selected from the group consisting of acetyltri-n-hexyl citrate and n-butyryltri-n-hexyl citrate, said ester having an aconitate level of not greater than 0.10% when the esterification mixture from which said citrate ester is produced tests in the range from about 0.9% to 0.35% acidity calculated as citric acid.

53. An ester according to claim 46, wherein said ester is acetyltri-n-hexyl citrate.

54. An ester according to claim 46, wherein said ester is n-butyryltri-n-hexyl citrate.

55. A citrate ester selected from the group consisting of acetyltri-n-butyl citrate, acetyltri-n-hexyl citrate, n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrate and acetyltri-n-(octyl/decyl) citrate, said citrate having heat stability characteristics, after heating at 150°C
for two hours, of a color not greater 50-60 APHA and a mild odor at 25°C and having an aconitate level of less than 0.20%.

56. An ester of claim 55, wherein said citrate has an additional heat stability characteristic after heating at 150°C
for two hours, of a neutralization number, mg KOH/g of not greater than 0.2.

57. An ester of claim 55 consisting of acetyltri-n-butyl citrate.

58. An ester of claim 55 consisting of acetyltri-n-hexyl citrate.

59. An ester of claim 55 consisting of n-butyryltri-n-hexyl citrate.

60. An ester of claim 55 consisting of acetyltri-n-(hexyl/octyl/decyl) citrate.

61. An ester of claim 55 consisting of acetyltri-n-(octyl/decyl) citrate.

62. A method of producing a citrate ester selected from the group consisting of acetyltri-n butyl citrate, acetyltri-n-hexyl citrate, n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrate and acetyltri-n-(octyl/decyl) citrate, which method comprises heating citric acid and an alcohol selected from the group consisting of n-butyl alcohol, n-hexyl alcohol, n-(octyl/decyl) alcohol and n-(hexyl/octyl/decyl) alcohol in the presence of an organic titanate, at a temperature below about 150°C to effect esterification, removing the excess alcohol, and acetylating or butyrylating the ester by adding sulfuric acid and acetic or n-butyric anhydride while maintaining the temperature below approximately 110°C until the acetylation or butyrylation reaction is complete.

63. A method according to claim 62, wherein the citrate ester produced is at least 99% pure.

64. A method according to claim 62 further comprising the step of neutralizing the citrate ester after the acetylation or butyrylation reaction.

65. A method according to claim 62, wherein the esterification is conducted at a temperature not greater than approximately 140°C.

66. A method according to claim 65, wherein the alcohol is n-hexyl alcohol, the anhydride is acetic anhydride and the acetyltri-n-hexyl citrate produced has heat stability characteristics, after heating at 150°C for two hours, of a color not greater than 50-60 APHA and a mild odor at 25°C.

67. A method according to claim 65, wherein the alcohol is n-hexyl alcohol, the anhydride is n-butyric anhydride and the n-butyryltri-n-hexyl citrate produced has heat stability characteristics, after heating at 150°C for two hours, of a color not greater than 50-60 APHA, and a mild odor at 25°C.

68. A method according to claim 65, wherein the alcohol is n-hexyl alcohol, the anhydride is acetic anhydride, the esterification is conducted at a temperature not greater than approximately 130°C and the acetyltri-n-hexyl citrate produced has heat stability characteristics, after heating at 150°C for two hours, of a color not greater than 50-60 APHA, and a mild odor at 25°C and also has an aconitate level of less than about 0.2 percent when the esterification mixture from which said citrate is produced tests 0.5 percent maximum acidity when calculated as citric acid.

69. A method according to claim 65, wherein the alcohol is n-hexyl alcohol, the anhydride is n-butyric anhydride, the esterification is conducted at a temperature not greater than approximately 130°C and the n-butyryltri-n-hexyl citrate produced has heat stability characteristics, after heating at 150°C for two hours, of a color not greater than 50-60 APHA, and a mild odor at 25°C and also has an aconitate level of less than about 0.2 percent when the esterification mixture from which said citrate is produced tests 0.5 percent maximum acidity when calculated as citric acid.

70. A method according to claim 65, wherein the alcohol is n-butyl alcohol, the anhydride is acetic anhydride and the esterification is conducted at a temperature of approximately 140°C to produce acetyltri-n-butyl citrate.

71. A method according to claim 65, wherein the alcohol is n-hexyl alcohol, the anhydride is acetic anhydride and the esterification is conducted at a temperature of approximately 140°C to produce acetyltri-n-hexyl citrate.

72. A method according to claim 65, wherein the alcohol is n-hexyl alcohol, the anhydride is n-butyric anhydride and the esterification is conducted at a temperature of approximately 140°C to produce n-butyryltri-n-hexyl citrate.

73. A method according to claim 65, wherein the alcohol is n-(hexyl(octyl/decyl) alcohol, the anhydride is acetic anhydride and the esterification is conducted at a temperature of approximately 140°C to produce acetyltri-n-(hexyl/octyl/decyl) citrate.

74. A method according to claim 65, wherein the alcohol is n-(octyl/decyl) alcohol, the anhydride is acetic anhydride and the esterification is conducted at a temperature of approximately 140°C to produce acetyltri-n(octyl/decyl) citrate.

75. A method according to claim 65, wherein the alcohol is n-butyl alcohol, the anhydride is acetic anhydride and the esterification is conducted at a temperature not greater than approximately 130°C to produce substantially pure acetyltri-n-butyl citrate having a low aconitate level.

76. A method according to claim 65, wherein the alcohol is n-hexyl alcohol, the anhydride is acetic anhydride and the esterification is conducted at a temperature not greater than approximately 130°C to produce substantially pure acetyltri-n-hexyl citrate having a low aconitate level.

77. A method according to claim 65, wherein the alcohol is n-hexyl alcohol, the anhydride is n-butyric anhydride and the esterification is conducted at a temperature not greater than approximately 130°C to produce substantially pure n-butyryltri-n-hexyl citrate having a low aconitate level.

78. A method according to claim 65, wherein the alcohol is n-(hexyl(octyl/decyl) alcohol, the anhydride is acetic anhydride and the esterification is conducted at a temperature not greater than approximately 130°C to produce substantially pure acetyltri-n-(hexyl/octyl/decyl) citrate having a low aconitate level.

79. A method according to claim 65, wherein the alcohol is n-(octyl/decyl) alcohol, the anhydride is acetic anhydride and the esterification is conducted at a temperature not greater than approximately 130°C to produce acetyltri-n-(octyl/decyl) citrate.

80. A method according to claim 62 r wherein the esterification is conducted at a temperature of not greater than approximately 130°C.

81. A method according to claim 66, 67 or 68, wherein said organic titanate is tetra-n-butyl titanate.

82. A method according to claim 62, 69 or 70, wherein said organic titanate is tetra-n-butyl titanate.

83. A method according to claim 71, 72 or 73, wherein said organic titanate is tetra-n-butyl titanate.

84. A method according to claim 74, 75 or 80, wherein said organic titanate is tetra-n-butyl titanate.

85. A method according to claim 76, 77 or 78, wherein said organic titanate is tetra-n-butyl titanate.

86. A method according to claim 79, wherein said organic titanate is tetra-n-butyl titanate.

87. A method according to claim 62, 67 or 70, wherein removing the excess alcohol consists of removing the alcohol by steam stripping.

88. A method according to claim 71, 72 or 73, wherein removing the excess alcohol consists of removing the alcohol by steam stripping.

89. A method according to claim 74, wherein removing excess alcohol consists of removing the alcohol by steam stripping.

90. A method according to claim 62, 70 or 71, wherein said citrate produced has heat stability characteristics, after heating for two hours at 150°C, of a color not greater than 50-60 APHA and a mild odor at 25°C.

91. A method according to claim 73 or 74, wherein said citrate produced has heat stability characteristics, after heating for two hours at 150°C, of a color not greater than 50-60 APHA and a mild odor at 25°C.

92. A method according to claim 70, 71 or 72, wherein said citrate produced has a heat stability characteristic, after heating at 150°C for two hours, of a neutralization number, mg KOH/g, of not greater than about 0.2.

93. A method according to claim 73, 74 or 80, wherein said citrate produced has a heat stability characteristic, after heating at 150°C for two hours, of a neutralization number, mg KOH/g, of not greater than about 0.2.

94. A method according to claim 75, 76 or 77, wherein said citrate produced has a heat stability characteristic, after heating at 150°C for two hours, of a neutralization number, mg KOH/g, of not greater than about 0.2.

95. A method according to claim 78 or 79, wherein said citrate produced has a heat stability characteristic, after heating at 150°C for two hours, of a neutralization number, mg KOH/g, of not greater than about 0.2.

96. A method according to claim 80, wherein said citrate ester is substantially pure and has a low aconitate level.

97. The process of forming a citrate ester of the formula:
where R1, R2 and R3 = CH3 to C18H37 R4 = CH3 to C7H15, comprising the steps of:
heating a suitable alcohol and citric acid in the presence of an organic titanate at a temperature of below approximately 150°C to effect esterification, removing the excess alcohol, and alkoxylating the ester by adding a suitable anhydride and sulfuric acid while maintaining the temperature below approximately 110°C until the alkoxylation reaction is complete.