JPH08876B2 - Method for producing polymer composition - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to a polymer composition containing a citric acid ester,
For example, it relates to a method for producing a PVC composition. In the following description, PVC will be described as a representative example of a polymer, but it will be apparent to those skilled in the art that the idea of the present invention can be applied to other polymers.

Citrate esters are useful plasticizers for polyvinyl chloride (PVC) resins. This is because some of these esters show a low degree of toxicity as compared to the conventionally used phthalates. When certain citrate esters were used as plasticizers in PVC compositions and PVC articles, improved resistance to soapy water extraction and other advantages including low temperature and migration properties were observed.

PV using some citrate as a plasticizer
Medical articles formed from the C composition provide an improved environment for whole blood and platelets as compared to PVC formulations using conventional plasticizers. Such medical articles may consist of: 1. Bags for storage of whole blood, filled red blood cells, platelets and plasma; 2. Intravenous tubing for transport of blood, blood products and quality intravenous fluids; 3. Indwelling intravenous and intra-arterial catheters; and 4. (a) renal dialysis equipment; (b) corpuscle oxygenators such as those used in open heart surgery; (c) membrane oxygenators for pulmonary artery failure; d) Phagocytosis to collect platelets and white blood cells for transfusion; and (e) Intensive plasmapheresis device, flexible material for plumbing in contact with whole blood.

It has been found that the production of citric acid esters is significantly enhanced by using certain titanate catalysts that remove excess alcohol after the esterification reaction step.

Prior Art Citric acid esters produced commercially using citric acid have long been on the market for a long time and are used as plasticizers in PVC resins. However, the performance of articles made from PVC resin compositions has many inherent drawbacks whether using any of the hitherto known citrate or conventional phthalate plasticizers. For example, medical grade PVC compositions have been used to form blood bags, tubing and a variety of health-related articles, and in recent years toxicity has become a major concern in the manufacture of such articles. . Recent reports have confirmed that di-2-ethylhexyl phthalate (DEHP) or (DOP) and di-2-ethyl-hexyl adipate (DEHA) are liver carcinogens in rodents.

DEHA found in whole blood stored in conventional blood bags for 21 days and in platelets stored for 24 hours in in vitro studies
It was demonstrated that the concentration significantly inhibits the growth of human diploid fibroblasts. A study of monkey transfusions revealed physiological and histological liver abnormalities up to 26 months after cessation of transfusions. Patients undergoing renal dialysis received approximately 10 to 20 times the amount of DEHP that caused liver damage in monkeys. DEHP has also proven to be a peroxisome proliferator and possibly a liver carcinogen in animals. These results are based on the standard National Cancer Institute National Institute of Poison Testing Program for rats and mice.
Toxicology Bioassay Program Study)

Industrial attempts to develop alternative PVC plasticizers have met with limited success. Two of the polymers used in a recent comparative study, PVC-TOTM and polyolefin, are currently allowed to store platelets for up to 7 days. This is based both on in vivo survival and function studies and the improved gas permeability of these polymers compared to PVC-DEHP. The above compositions (PVC-DEHP and polyolefins) and all other compositions tried to date proved unsuitable for studies of erythrocyte survival. The compositions described above also exhibit increased osmotic fragility of red blood cells, increased plasma hemoglobin content, and increased red blood cell potassium content. This means an erythrocyte membrane lesion.

Although some phthalates have excellent plasticizing properties, they are suspected of being carcinogenic and therefore doubtful as candidates for future pharmaceutical use. As an alternative, known citric acid esters such as acetyl tri-n-butyl and tri-n-butyl citrate have been tried as PVC plasticizers for pharmaceutical grade applications, but these compounds have high soap water extraction percentages. It has been found that it is not fully satisfactory and therefore not useful for many medical applications. It was also discovered that a new manufacturing technique had to be devised for the novel citrate ester which was found to have suitable toxicity and physical properties when used as a PVC plasticizer.

Problems to be Solved by the Invention It is therefore an object of the present invention to provide PVC plasticizers which give excellent toxicity test results in biological studies.

Another object of the present invention is to provide a plasticizer for PVC compositions which can be easily processed using conventional extrusion, calendering or plastisol methods.

Yet another object of the present invention is the novel citrate ester,
That is: Acetyltri-n- that can be used as a plasticizer having desirable physical properties when added to a PVC composition.
Hexyl citrate, n-butyryl tri-n-hexyl citrate, acetyl tri-n- (hexyl / octyl / decyl) citrate, and acetyl tri-n- (octyl / decyl) citrate.

Yet another object of the present invention is to provide PVC compositions and articles formed therefrom which exhibit excellent results in toxicological studies on skin toxicity, oral toxicity and genetic assays.

Another object of the present invention is to provide a medical article such as a blood bag and a method for producing the same, which provides an improved environment for containing whole blood or platelets.

Another object of the present invention is to provide a method for producing four novel citric acid esters using an organic titanate to provide an economical and efficient production method.

Other objects and advantages of the invention will be apparent to those skilled in the art from the following detailed description.

Means to solve the problem The following formula: (Wherein R ₁ , R ₂ and R ₃ represent CH ₃ to C ₁₈ H ₃₇ and R ₄ represents CH ₃ to C ₇ H ₁₅ ), more specifically acetyltri-n -Hexyl citrate, n-butyryl tri-n
-Hexyl citrate, acetyl tri-n- (hexyl / octyl / decyl) citrate, and acetyl tri-n- (octyl / decyl) citrate, are prepared using organic titanate catalysts, such esters being PV
It has been found to be useful as a pharmaceutical grade plasticizer for C compositions. The plasticizer has a low degree of toxicity and imparts to PVC the properly balanced physical properties required for health care and pharmaceutical grade applications. The process of making the citrate ester involves esterification, removal of excess alcohol, and subsequent acylation. Then the conventional neutralization and finishing steps are carried out. The acylation step is performed at a temperature below about 110 ° C.

Plasticized PVC resin by combining one of the above citrate esters with suitable stabilizers and lubricants.
And the PVC can be extruded, calendered or otherwise processed into suitable products including blood bags, tubing and other products. The articles produced in this way have a low degree of toxicity and give good extractability, especially in soapy water extraction tests. Soken water extraction test is a standard test,
The results are very similar to those obtained with body fluids such as human blood.

Medical articles molded from the PVC compositions using the citrate ester described above exhibit improved stability when used to store whole blood or platelets.

The four preferred forms of citrate are: 1. Acetyltri-n-hexyl citrate. 2.n-butyryl tri-n-hexyl citrate 3. Acetyltri-n- (hexyl / octyl / decyl)
Citrate 4. Acetyl tri-n- (octyl / decyl) citrate The preferred method for producing the citric acid ester described above,
At a low temperature in the temperature range of 150 ° C., preferably 125-130 ° C., a suitable alcohol (eg n-hexyl alcohol in the case of the production of acetyltri-n-hexyl citrate) is added,
Esterified with citric acid in the presence of an organic titanate (tetra-n-butyl titanate), an excess of n
-Removing the hexyl alcohol and then reacting the formed ester with an acid anhydride. When esterification is carried out at a temperature above 150 ° C., the citric acid ester undergoes rapid decomposition and numerous decomposition products are formed. At temperatures slightly below 150 ° C, the major degradation product is the aconitate ester. The reaction of the formed ester with the acid anhydride occurs at temperatures below about 110 ° C. Tetra-n-
Butyl titanate is preferred. This is because the transesterification that occurs between the alkyl group of the titanate and the alkyl group of the citric acid ester does not result in the introduction of an alkyl group that is not normally present in the citric acid ester.

A preferred PVC composition comprises mixing and pulverizing a medium molecular weight PVC resin with one of the above citrates in a ratio of 2 to 1, optionally with stabilizers, lubricants and extenders. . Articles made from the preferred PVC compositions include blood bags, tubing and other articles in the medical and health care fields.

Medical products such as blood bags are made of pharmaceutical grade ingredients.
A PVC composition having a PVC resin, a citric acid ester plasticizer and the following other components can be produced and produced: parts by weight (a) PVC resin having an intrinsic viscosity of 0.97 100 (b) n-butyryl tri- n-hexyl citrate 50
(C) Epoxidized soybean oil 10 (d) Stabilizer Ca / Zn 1 (e) Lubricant (stearic acid) 0.1 components are mixed and melted in a conventional manner. The ingredients are mixed and melted by conventional means such as using a blender at temperatures in the range of 310-360 ° F (154-182 ° C) and then pelletized from the extruder. The pellets are then remelted in an extruder and mixed to form a film, molded article, etc. in a second extrusion.

The film stock is then cut and sealed together to form a bag for storage of whole blood, packed red blood cells, platelets, plasma and intravenous solutions. Such blood bags generally consist of transparent sachets having one or more openings for filling and emptying or for tube insertion.

Action Certain citric acid esters, namely acetyltri-n-
Hexyl citrate, n-butyryl tri-n-hexyl citrate, acetyl tri-n- (hexyl / octyl / decyl) citrate and acetyl tri-n- (octyl / decyl) citrate are the conventional plastisol method,
It has been found to be particularly useful in medical applications when compounded with PVC resin by calendering or extrusion. Such plasticized PVC has good transparency, good low temperature properties, low volatility and low extractability for various media. It has also been shown to have low acute toxicity and its complete compatibility with medium molecular weight PVC resins makes the above four named esters unique and valuable. Studies have shown that the four citrate esters are not toxic substances, are not directly skin irritating or eye irritating to the unwashed eye, and that when given orally, they produce signs of systemic toxicity. No death was observed in normal or fasted mice or rats. In genetic toxicological detection to detect mutagenicity in gene or chromosomal quantities, these esters induce either genetic mutations in microbial cells or mammalian cells in vitro or chromosomal mutations in vivo or in vitro. It was shown not to. Studies have also shown that in in vivo conditions,
These citrate esters have also been shown to hydrolyze rapidly and completely at concentrations at realistic levels expected to be exposed to humans.

Examples The process for making citric acid esters is as follows: Example 1. Preparation of acetyltri-n-hexyl citrate 330 lbs (150 kg) n-hexyl alcohol, 180 lbs (82 kg) citric acid, tetra-n-butyl. Titanate
1.54 lbs (0.70 kg) and 15 gallons of heptane (56.775
l) is charged to a vessel equipped with a stirrer, a thermometer, a vapor column, a condenser and a decanter installed to remove the water formed during the reaction while refluxing heptane. Esterification is performed at 140 ° C and the aconitate (T
HA) level is kept below 0.5%. The aconitate level can be kept in the range of 0.2% or less by making the reaction time longer and performing it at the lower temperature for the optimum time, and the temperature of about 125 to 130 ° C can obtain the aconitate level in this range. You can At a temperature of about 130 ° C., the unique result is obtained, in which the aconitate formation becomes constant and a citric acid ester with excellent purity is obtained. During the esterification, water is regularly removed from the decanter to maintain proper temperature and reaction loss. The esterification reaction continues at 140 ° C until the esterification mixture analyzes as citric acid for a maximum acidity of 0.5%, but uses a lower temperature esterification reaction and a lower acidity to obtain a purer product. be able to. Next, the container 12
Cool to 0 ° C. and remove the water from the separator and also the heptane therein for future use. Close the reflux line of the vessel and allow the system pressure to cool down. The kettle is heated again to 140 ° C. and steam is introduced to help remove residual alcohol. This vacuum vapor extraction is continued until no alcohol is detected by conventional laboratory tests. When the alcohol was not found any more quickly, the steam was stopped, the temperature was lowered to 100 ° C, and the vacuum was broken using nitrogen gas.

Next, 0.4 lbs (0.18 kg) of concentrated sulfuric acid (H ₂ SO ₄ ) was filled into the container, then the container was sealed, and about 107 lbs (49 kg) of acetic anhydride (predetermined molar amount) was added at a temperature of 110 ° C. Add at a slow rate so as not to exceed. After the total amount of acetic anhydride has been added, stirring of the mixture is continued for about 1 hour until the acetylation reaction is complete.

Then apply a sufficient vacuum to the system and apply sufficient heat to
Distillation proceeds at a suitable rate. This step is continued until the acetic acid shows less than 5% in conventional laboratory tests, at which time the mixture is cooled to 75 ° C. to neutralize it.

The remaining steps of neutralization, bleaching, washing, etc. are carried out in the same manner as in the conventional esterification step.

Example 2. Preparation of n-butyryl tri-n-hexyl citrate: The container used in Example 1 was again charged with n-hexyl alcohol 33.
Charge 0 pounds (150 kg), citric acid 180 pounds (82 kg) and tetra-n-butyl titanate 1.54 pounds (0.70 kg). The esterification reaction is carried out as in Example 1 with heptane-alcohol withdrawal. Butyrylation is then carried out in the acetylation step by adding 0.4 lbs (0.18 kg) concentrated sulfuric acid and 166 lbs (72 kg) n-butyric anhydride as previously described. Butyric acid may be removed as described above or by neutralization.

In the conventional esterification step, alcohol withdrawal can be carried out without detrimental consequences when using acid catalysts such as sulfuric acid, methanesulphonic acid or p-toluenesulphonic acid. However, in the preparation of the citric acid esters of the present invention, it has been found that alcohol withdrawal cannot be performed using these acid catalysts due to aconitate formation, poor color, low yields and other purity problems. It was The method of the present invention offers distinct advantages over conventional methods.

It has been found that by lowering the esterification temperature to 130 ° C. or preferably in the range 125 to 130 ° C., the citrate ester yield can be made highly pure and aconitate formation and non-acetylated ester can be minimized. The table below shows the proportion of tri-n-hexyl aconitate (THA) produced during the production of acetyltri-n-hexyl citrate, according to which the reaction shows an acidity of about 0.2% as citric acid. Has stopped at. The aconitate level is about 0.14 at a reaction time of 25 to 19 hours and a temperature of 125 to 130 ° C.
The range is from ~ 0.19. It was found that by lowering the temperature from 140 ° C to 130 ° C it took only 90 minutes to reduce the aconitate level from 0.35 to 0.19% (a decrease of about 45%). As shown, aconitate levels substantially increase the reaction time based on acidity 0.2% (citric acid) as a reaction completion indicator by lowering the temperature from 140 ° C to 130 ° C by about 10 ° C. Can be greatly reduced without. Stabilization of aconitate levels occurs at a temperature of about 130 ° C. in esterification, which provides a method for producing high purity esters with low aconitate levels. Lower proportions of aconitate and other impurities provide the high quality plasticizer required for medical grade products.

It is believed that acids such as citric acid, which have a low pK value, show synergistic effects with titanate catalysts at low temperatures in the range of 150 ° C or lower. Phthalic acid, which has a high pK value, does not undergo esterification with titanate catalysts at these low temperatures.

Also, other organic titanate catalysts such as tetrakis-2-ethylhexyl titanate can be used in the preparation of the four esters of the present invention, although superior results can be obtained with tetra-n-butyl titanate. Proved.

Preparation and Testing of sets formed parts by weight of the resin of the PVC composition (medium molecular weight of PVC of) 100 plasticizer 50 Stabilizer (calcium / zinc) 2.5 lubricant (stearic acid) 0.25 The above formulation 325-340 ° F ( 5-10 at 163-171 ℃
Mix and pulverize for a minute. Press pulverized material [340-360 ° F
(171-182 ℃) and 32,000psi for 3 minutes] 40-
And -70 mil sheet and aged for 48 hours at room temperature for evaluation. All tests were run with samples cut from 70 mil press stock, except for the extraction tests run on 40 mil samples. Performance data was obtained with modifications to the accepted ASTM method, as detailed below.

# 1-Acetyl tri-n-butyl citrate # 2-Acetyl tri-n-hexyl citrate # 3-n-Butyryl tri-n-hexyl citrate # 4-Acetyl tri-n- (hexyl / octyl / decyl) citrate # 5-Acetyltri-n- (octyl / decyl) citrate The plasticizer performance data in Table 5 shows the results of tests with citrate / epoxidized soybean oil (ESO) blends. ESO combined with DEHP, 1-5% based on DEHP
It is usually used as a stabilizing aid in an amount in the range of. 2.5 /
The ratio of 97.5 ESO / citrate was used as the starting point for the study. The test results for this combination are shown in the first column. Significant improvements in properties, especially in soapy water extraction, are noted.

ESO-ester / epoxidized soybean oil # 2-acetyl tri-n-hexyl citrate # 3-n-butyryl tri-n-hexyl citrate # 5-acetyl tri-n- (octyl / decyl) citrate ESO is a citric ester Since it is cheaper than ESO, if ESO can be substituted for part of the citric acid ester, the cost of plasticizer will be reduced. Higher ES in columns 2-5 of Table 5
Test results using the O / citrate ratio are shown, and significant property improvements are shown up to and possibly above the ESO / citrate ratio of 20/80.

PVC plasticized with di-2-ethylhexyl phthalate (DEPH) or tri-2-ethylhexyl trimellitate (TOTM) for in vitro evaluation of whole blood and platelets
Performed in blood bags made from the composition and compared to bags using the citrate ester of the invention. The results show in Table 6 that whole blood and platelet properties are improved when stored in PVC blood bags formed with the improved citrate ester. In these studies, as shown below, glucose depletion indicates increased consumption by live blood cells.

Platelets were stored in the blood bag for 7 days before use of polyolefin polymer, as shown in Table 7 below.
Platelet count decreased by 47% for PVC bags and 38 for PVC bags plasticized with TOTM.
%, And for PVC bags plasticized with the novel citrate ester, the platelet count was reduced by only 25%.

These test results indicate that the viability of platelets in the novel citrate plasticized PVC composition is greater than that in the polyolefin or PVC-TOTM composition.

PV suitable for extrusion of tubes, rolling into sheets or films to form blood bags and other medical articles
The C composition comprises a plasticizer of the general formula: In the formula, R ₁ , R ₂ and R ₃ are CH ₃ to C ₁₈ H ₃₇ , and R ₄ is CH ₃ to C ₇ H ₁₅ .

The above plasticizer has an intrinsic viscosity of PVC resin of about 0.90 to
1.20, medium molecular weight PVC as determined by viscosity
Resins; calcium / zinc stearate sold under many trade names; and lubricants such as stearic acid are incorporated into PVC compositions having pharmaceutical or FDA approved ingredients. Alternatively, the medical article can be formed from a PVC composition with epoxidized soybean oil added in the range of 0 to 30 parts by weight. The starting formulation may contain the following components : Component parts by weight (a) PVC resin (intrinsic viscosity 0.9 to 1.20) 100 (b) citrate 40-70 (c) epoxidized soybean oil 0-30 (d) stabilizer 0.5-5.0 (e) Lubricant 0.050-0.5 A typical blood bag 10 having a tube 11 containing platelets 15 and formed using the citrate plasticizer of the present invention is shown in FIGS. Spouts 12 and 13 are bag 10
Can be used to fill or empty and the spout 13 is shown with the tube 11 inserted into it. The bag 10 is formed from the PVC composition of the present invention by heat sealing a panel cut from a PVC sheet of suitable thickness conventionally manufactured in the industry. Tube 11 is made from a PVC composition using the citrate ester of the present invention and may be extruded or otherwise molded to the desired thickness, diameter and length.

Various other PVC compositions can be formulated, and the examples and descriptions provided herein are for purposes of illustration and not for limiting the scope of the invention.

[Brief description of drawings]

FIG. 1 shows a typical blood bag formed using the citrate plasticizer of the present invention; and FIG. 2 is a side view of the blood bag of FIG. The symbols in each drawing are as follows: 10: blood bag; 11: tube; 12: spout; 13: spout; 15: platelet

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Edward P. Flapyer, Chelsea Places, 27284, Kernersville, North Carolina, USA 1770 (56) References JP-A-59-33343 (JP, A) JP-A-SHO 59-8744 (JP, A) JP 51-17967 (JP, A) JP 57-207635 (JP, A) JP 52-141853 (JP, A) JP 49-54323 (JP, A) JP-B-55-34935 (JP, B2) US Patent 2445911 (US, A)

Claims (14)

[Claims] 1. A citric acid of the formula: R ₁ OH or R ₂ OH and / or R
Heating with one or more alcohols in the form of ₃ OH (where R ₁ , R ₂ and R ₃ are CH ₃ -C ₁₈ H ₃₇ ) in the presence of an organic titanate for esterification; removal of excess alcohol 2) after heating at 150 ° C for 2 hours by adding the appropriate acid anhydride and sulfuric acid while maintaining the temperature below 110 ° C.
The citric acid is reacted until an ester of the above formula having thermostable properties with a mild odor at 5 ° C. is obtained; (Wherein R ₁ , R ₂ and R ₃ are as defined above and R ₄
Is CH ₃ -C ₇ H ₁₅ ), and a citrate ester having a purity of 99% is produced; and the citrate ester is added to the composition together with a polymer resin; 2. The process for producing a citric acid ester has the formula: The method for producing a polymer composition according to claim 1, which is a step of producing the citric acid ester (acetyltri-n-hexyl citrate) of 1. 3. The process for producing a citric acid ester has the formula: Citric acid ester (citric acid n-butyryltri-n-
The method for producing a polymer composition according to claim 1, which is a step of producing hexyl). 4. The process for producing a citric acid ester has the formula: Citric acid ester [(acetylcitrate tri-n-citrate
(Hexyl / octyl / decyl)], the process for producing the polymer composition according to claim 1. 5. The process for producing a citric acid ester has the formula: Citric acid ester [(acetylcitrate tri-n-citrate
(Octyl / decyl)], the method for producing a polymer composition according to claim 1. 6. A process for the preparation of a polymer composition according to claim 1, wherein the citric acid ester has the additional heat-stability property of showing a color not exceeding 50-60 APHA after heating at 150 ° C. for 2 hours. 7. A process for producing a polymer composition according to claim 1, wherein the citric acid ester is present in the composition in an amount of 40 to 70 parts by weight per 100 parts by weight of the polymer. 8. A citric acid having the formula: R ₁ OH or R ₂ OH and / or R
Heating with one or more alcohols in the form of ₃ OH (where R ₁ , R ₂ and R ₃ are CH ₃ -C ₁₈ H ₃₇ ) in the presence of an organic titanate for esterification; removal of excess alcohol 2) after heating at 150 ° C for 2 hours by adding the appropriate acid anhydride and sulfuric acid while maintaining the temperature below 110 ° C.
The citric acid is reacted until an ester of the above formula having thermostable properties with a mild odor at 5 ° C. is obtained; (Wherein R ₁ , R ₂ and R ₃ are as defined above and R ₄
Is CH ₃ -C ₇ H ₁₅ ), and a citrate ester having a purity of 99% is prepared; and the citrate ester is blended with a PVC resin to form a PVC composition; A method for producing the polymer composition according to item 1. 9. The process for producing a citric acid ester has the formula: 9. The method for producing a polymer composition according to claim 8, which is a step of producing the citric acid ester (acetyl tri-n-hexyl citrate) according to claim 8. 10. The process for producing a citric acid ester comprises:
The following formula: Citric acid ester (citric acid n-butyryltri-n-
The method for producing a polymer composition according to claim 8, which is a step of producing hexyl). 11. The process for producing a citric acid ester comprises:
The following formula: Citric acid ester [(acetylcitrate tri-n-citrate
(Hexyl / octyl / decyl)] is the process for producing the polymer composition according to claim 8. 12. The process for producing a citric acid ester comprises:
The following formula: Citric acid ester [(acetylcitrate tri-n-citrate
(Octyl / decyl)]. The method for producing a polymer composition according to claim 8, which is a step of producing (octyl / decyl). 13. A process for the preparation of a polymer composition according to claim 8, wherein the citric acid ester has the additional thermal stability property of showing a color not exceeding 50-60 APHA after heating at 150 ° C. for 2 hours. 14. The method for producing a polymer composition according to claim 8, wherein the citric acid ester is present in the composition in an amount of 40 to 70 parts by weight per 100 parts by weight of the polymer.