08 December 2010

PVC BLOOD BAG

STUDIES ON PVC BLOOD BAG FORMULATION
USING A NEW PLASTICIZER



Submitted in partial fulfillment of the requirements
for the award of the degree of

BACHELOR OF TECHNOLOGY
IN
POLYMER ENGINEERING


Report of the Project Works Carried Out At

CORPORATE R&D CENTRE
HLL LIFECARE LTD



Submitted By

DEEPAK C
&
UMESH.U






INDEX

INTRODUCTION
1.1 Blood Bags 8
1.2 Manufacture of Blood Bags 11
1.3 Biomedical Characteristics of blood bags 12
1.4 Polyvinyl chloride (PVC) 13
1.4.1 Medical Application of PVC 14
1.4.2 Limitations of PVC and its Plasticizers 16
1.5 Chemistry of PVC and its Plasticizers 20
1.6 DEHP (di (2-ethylhexyl) phthalate) 24
1.6.1 Medically related Exposure of DEHP 24
1.6.2 Attempts to reduce the DEHP leaching 28
1.7 Alternatives Plasticizers for DEHP 28
1.8 Hexamoll DINCH 30
1.9 Epoxidized Soyabean oil 34
1.10 Ca- Zn stabilizer 35
1.11 Liquid paraffin 36
2 EXPERIMENTAL 39
2.1 Materials 40
2.2 Experiment 42
2.2.1 Compounding of Materials 42
2.2.2 Palletizing 44
2.2.3 Extrusion of sheets 45
2.3 High Frequency Welding 47
2.4 Experiments and methods 47
2.5 Chemical Tests 47
a) Residue on ignition 48
b) Preparation of test fluid 48
c) Tests 48
I) Determination of oxidizable constituents 48
II) Determination of Ammonia 48
III) Determination of Acidity or Alkalinity 49
IV) Determination of Evaporation on residue 49
V) Determination of Turbidity and Degree of Opalescence 49
VI) Determination of UV absorbance 50
VII) Leaching studies 50
VIII) Fourier Transform Infrared Spectroscopy 52
2.6) Physical Tests 52
I) Tensile test 52
II) Differential Scanning Calorimetry (DSC) 52
III) Hardness test 53
IV) Water absorption test 53
V) Water Vapor Permeability Testing 53
VI) Transparency tests 54
VII) Gas permeability studies 55
VIII) Test for Plasticizer Compatibility in PVC Compounds
Under Humid Conditions 55

3) RESULTS AND DISCUSSION 56
3.1) Chemical Tests 58
a) Residue on ignition 58
b) Determination of Alkalinity 58
c) Determination of Acidity 58
d) Determination of Ammonia in the Extract 59
e) Determination of Turbidity and Degree of Opalescence 59
f) Evaporation Residue 59
g) Oxidizable Constituents in the extract 59
h) UV absorbance 60
i) Leaching Studies 60
j) Fourier Transform Infrared Spectroscopy 61
3.2) Test for Plasticizer Compatibility in PVC Compounds under
Humid Conditions 62
3.3) Differential Scanning Calorimetry (DSC) 63
3.4) Water Absorption test 64
3.5) Tensile test 65
3.6) Hardness test 67
3.7) Transparency tests 67
3.8) Water Vapor Permeability Testing 68
3.9) Gas Permeability Studies 69

4 CONCLUSION 71
5 REFERENCES 72

























INTRODUCTION
















INTRODUCTION

Blood is a specialized bodily fluid that delivers necessary substances to the body's cells such as nutrients and oxygen and transports waste products away from those same cells. It’s a living tissue that circulates through the heart, arteries, veins and capillaries, carrying nourishment, electrolytes, antibodies, heat and oxygen to the body tissues. Blood makes up about 7% of our body's weight. The average adult has a blood volume of roughly 5 liters. In addition, it plays a vital role in our immune system and in maintaining a relatively constant body temperature. Blood is a highly specialized tissue composed of many different kinds of components. Four of the most important ones are red cells, white cells, platelets, and plasma. In human body one microlitre blood contains 4.7 to 6.1 million (male), 4.2 to 5.4 million (female) erythrocytes, 4,000-11,000 leukocytes and 200,000-500,000 thrombocytes. Red cells, or erythrocytes, are relatively large microscopic cells without nuclei. In this latter trait, they are similar to the primitive prokaryotic cells of bacteria. Red cells normally make up 40-50% of the total blood volume. White cells, or leukocytes exist in variable numbers and types but make up a very small part of blood's volume--normally only about 1%. Leukocytes are not limited to blood. They occur elsewhere in the body as well, most notably in the spleen, liver, and lymph glands. Platelets or thrombocytes are cell fragments without nuclei that release blood-clotting chemicals at the site of wounds. Plasma is the relatively clear liquid water (92+%), sugar, fat, protein and salt solution, which carries the red cells, white cells, platelets, and some other chemicals. Normally, 55% of our blood's volume is made up of plasma. About 95% of it consists of water.
People may need blood transfusion for many reasons. Some reasons are to:
 replace blood that has lost
 restore the bloods ability to carry oxygen
 help control the forming of blood clots
 help control the blood pressure
Approximately eight volunteer blood donors donate about 12.6 million units of whole blood in the United States each year. These units are transferred to about 4 million patients per year. The need for blood is great: on any given day, approximately 32,000 units of red blood cells are needed. Accident victims, people under going surgery and patients receiving treatment of leukemia, cancer or other diseases, such as sickle cell anemia and thalassemia, all utilize blood. Blood transfusions can be life-saving in some situations, such as massive blood loss due to trauma, or can be used to replace blood lost during surgery. Blood transfusions may also be used to treat a severe anemia or thrombocytopenia caused by a blood disease. People suffering from hemophilia or sickle cell disease may require frequent blood transfusions. Early transfusions used Whole Blood, but modern medical practice is to use only components of the blood. Blood bags are used in medical purposes for storing blood or infusion solutions. Blood transfusions become safe, dependable and convenient and a result of three important developments- the landmark discovery of blood groups by Pro. Carl Landsteiner (1900), the safety and effectiveness of citrates for intravenous administration by Hustin (1914) and the development of coagulant solution ACD. Modern blood banking was initiated with the pioneering work of development of PVC bags for blood collection and storage started by Prof.Carl W. Walter of Harvard Medical School in 1947. He had to face several problems in developing his design to a commercial product. After extensive clinical trials conducted in USA, he finally got permission to manufacture this item in 1962.

1.1 Blood bags
Blood was collected into reusable glass bottles in the first half of the twentieth century. Whole blood was transfused. Pyrogenic reactions from contamination due to incomplete cleaning were frequent. Air embolism was a common complication due to the vacuum systems used on glass bottles. Flexible plastic blood bags replaced first replaced glass bottles for collecting blood as early as the late 1940’s. In 1949, the American Red Cross conducted trials of plastic bags. Plastic bags were disposable and, because of their flexibility, facilitated the separation of blood components and the advent of component therapy. Polymers are most important and largest family of materials used in medical technology. With the advent of plastics in the field of medical technology, the use of traditional materials such as glass and metals has been reduced considerably. The utilization of plastics in the medical disposable device sector minimized or avoided the risk of cross- contamination and the infection and the need for resterilization. Various polymers like Poly (vinyl chloride), Polyethylene, Polypropylene, Polystyrene, Polycarbonate, Acetal copolymers and some specialized polymers synthesized through biotechnology route are used for different applications. Of these PVC is the most widely used plastic for disposable medical products. Its use has grown considerably over the past 60 years, to the point where PVC represent more than 27% of all plastics used for different applications.
1.1.1 Storage of blood in Blood bags
Blood bag system consists of disposable bio medical transparent plastic containers for collection, storage, transport, separation and administration of whole blood and blood components. The blood bag consists of single and multiple bags. The donor bag in which blood is collected from donor usually consists of anticoagulant solutions. The flexible blood bag enables storage and separation of blood components in a closed system and thus avoids the risk of contamination. Use of blood bag has made it possible to fractionate single donors blood into multiple components like platelets, plasma, granulates etc and the blood components can be economically and effectively used for multiple patients. It is possible to harvest the specific components of blood that is required and return the other components into donor. The single bag system consists of donor bag, donor tube, puncturable and nonsealable transfusion pot and clamp. The donor tube consists of an integral needle with a tamper proof needle cover, sealed on to the needle holder.
The increased use of blood component transfusion in place of whole blood transfusion and the concomitant use of related procedures such as aphaeresis have created a need for containers that are particularly suitable for the extended storage of whole blood and its cellular components. For the reasons of effective utilization of blood and reduced the burden to the patient, the currently used system for the blood transfusion depends on the component transfusion concept that the blood collected from the donor is separated into components as by centrifugation and only the necessary component is transfused to the patient. The component transfusion can utilize the blood more effectively than the prior art whole blood transfusion. On the other hand, blood collection often uses a multiple blood bag system having a blood- collecting bag and more sub bags. Among the multiple bag systems, a triple bag having a primary bag and two sub bags is often used where in blood collected in the primary bag is separated into three components, erythrocyte concentrate, platelet concentrate, and platelet poor plasma, for effecting centrifugation twice. The need exist especially for containers that maintain the viability of stored blood cells. It is known that the viability of cells during storage is very much influenced by the permeability of containers. For example, when platelet concentrate (PC) are stored in standard containers made of vinyl chloride resin, the pH is notably reduced due to the low gas permeability of the containers. This is in turn lead to the deterioration of platelet function. Accordingly, the platelets can be stored only for limited periods of time following collection. This is of course creates logistic problems for medical institutions,
blood centers, blood donors and recipient and the like.
Hindustan Latex Limited setup its blood bag manufacturing facility in September 1993. HLL Haemopack is manufactured from superior grade PVC based materials, which makes it flexible, and at the same time mechanically strong to withstand certification and rough handling during use. HL Haemopack blood bags systems are available as follows.
Type of Bag
Anti coagulant Solution
Capacity of Main Bag (ml)

Single CPDA 100, 250, 350,450
Double CPDA 350, 450
Triple CPDA & CPD –sagm 350, 450
Quadruple CPDA & CPD-sagm 350, 450
Penta CPDA 350, 450
Transfer CPDA 300

CPDA: - Citrate Phosphate Dextrose Adenine
SAGM: – Saline Adenine Glucose Mannitol
CPD: - Citrate Phosphate Dextrose
1.2 Manufacture of Blood Bags
Blood bag is made by using medical grade PVC resins. The following major steps are involved in the manufacture of blood bags.
1.2.1 Compounding: -
Medical grade PVC material is modified with a number of additives like plasticizer
(eg: - DEHP), Stabilizers, Lubricants etc. The process of incorporation of these additives in PVC material is known as compounding.
1.2.2 Palletizing: -
The compounded material is processed in any of the convenient convectional methods to attain cylindrical and granular shape.
1.2.3 Sheet Extrusion: -
PVC materials are extruded through T die for converting plasticized material in sheet form. Single screw extruders are employed for this purpose. Extruded sheet after slitting is cut into desired size and send it to welding section.
1.2.4 Injection Molding: -
The polymer is preheated in cylindrical chamber to temperature at which it flows and it is forced into a relatively cold closed mold cavity by means high pressure.
1.2.5 Tube Extrusion: -
PVC materials are extruded through die for converting plasticized material into tube form.
1.2.6 Ultra cleaning: -
It is done to remove dust, mold releasing agents and other oily substance from the component.
1.2.7 High Frequency Welding: -
High frequency welding techniques are used in the blood bags. PVC sheet is placed between electrodesand high frequency, high frequency is applied. The PVC gets heated very rapidly and sealing takes place between electrodes. During welding, donor, transfer tubing etc. are kept in correct position. Then clamps are fixed on the tubing. After inspection acceptable bags are sent to labeling section.
1.2.8 Labeling: -
Labels giving information and instructions are pasted on the bags.
1.2.9 Anti coagulant Preparation and Filling: -
Anti coagulant is prepared by mixing pyrogen free distilled water with I.P grade chemicals like sodium citrate, citric acid etc. After mixing the solution is filled in the bag and sent for coagulation.
1.2.10 Autoclaving: -
The blood bag contains anticoagulant are autoclaved in specially designed trolleys.
1.2.11 Drying, Aluminum Foil Packing: -
After reaching the packing section, packing is done in clean laminar flow, sterile area to avoid contamination at this stage.
1.3 Biomedical Characteristics of blood bag
The components which come in contact with blood must be non-toxic, non irritating and non hemolytic. The amount of migration of chemical substances from the blood bag material has to be with in acceptable limits and bio chemical and hematological parameters of blood should be maintained as completely as possible during the storage. The bag material and tubings have to satisfy a number of mechanical, thermal and optical requirements. The bag should also satisfy the requirement of use like ease in processing of blood storage at low temperature etc. Medical grade PVC is used for the manufacture of blood bag since it is free from toxic effects. The main components of blood bag are sheet, tube, transfusion port, needle holder, needle cover and needle. Packing material includes PP cover, Aluminum foil cover and corrugated box. The production facility has been designed in the HLL as per the guidelines given by the Sree Chithira Thirunal Institute .For Medical Sciences & Technology and the clean room is as per the requirements of BS 5295 standard.

1.4 Polyvinyl chloride (PVC)
Polyvinyl chloride (PVC) is one of the most popular polymers used in medical applications. Medical applications account for 0.5% of the total PVC volume used in Western Europe2. The world PVC use was 2.94×107 t in 2004 with a 4.3% annual growth rate3.Plasticized-PVC blood bags have been used since the 1950s for the collection of whole blood, the processing of this into plasma, platelets etc and for storage. Plasticized PVC, the plastic used in the first blood bags introduced by Carl Walter over 40 years ago. The Americans began to use plasticized PVC bags in the Korean War, circa 1950. Since 1990 other polymers have been considered. The superior performance and value of PVC containers led to their wide acceptance as both blood bags and IV solution containers. PVC plays a valuable role in protecting health and improving standards of hygiene and has helped to provide low cost, high technology health care. Bags for the storage of blood and its components, tubing for extracorporeal circulation and endotracheal intubations and intravenous catheters are some of the medical devices where in plasticized PVC are employed. PVC is not a blood-compatible polymer and additives such as plasticizers added to the polymer during processing to impart flexible character to otherwise rigid PVC also contribute too many adverse effects when used in contact with tissue or blood. PVC plays a valuable role in protecting health and improving standards of hygiene and has helped to provide low cost, high technology health care. Lightweight, shatter- resistant, and easy to handle, plastics has pushed aside the traditional material for holding, storing, transferring and dispensing biological liquids. Among the various plastic material PVC has dominated alternative polymers because of its optical clarity flexibility, surface finish, capacity to with stand steam sterilization (up to 1210C also referred to as autoclaving), ability to form tight seals through radio frequency (RF) sealing, resistance to kinking, biocompatibility with a range of solutions and body tissues, and low cost. These excellent and varied properties made PVC one of the most prominent materials for medical device manufacturing. In most of these applications PVC has captured a share of 70- 90% of the total market.




PVC can be used to produce a variety of medical products ranging from rigid components to flexible sheeting. The type and amount of plasticizer used to determine the compounds glass transition temperature, which defines its flexibility and low temperature characteristics. Both flexible and rigid components in PVC have the same material structure; they can be easily assembled by the solvent bond. The two solvents used for the PVC bonding are cyclohexane and methyl ethyl ketone. Rigid parts are suitable for ultra sonic bonding while the flexible extruded or calendared PVC films can be sealed using heat or radio frequency sealing.

1.4.1 Medical application of PVC
PVC based products have important medical application, which include extruded as well as molded products as well as calendared and coating products. Examples include blood bags and tubing, intravenous containers and components, catheters, dialysis equipment and tubing, ear protection, inflatable splints, oxygen delivery components, surgical wire, and thermal blankets. Plasticized PVC has good clarity so that tubes and other products retain their transparency and it is resistant to tearing. Bags are needed for example for taking up of blood as blood storage bag or for the sterile storage of solutions for parenteral injection solutions. For this purpose the bags have to be completely sterile and to this end normally have to be heated to at least 1000C .For this purpose the thermoplastic polymeric materials has to be thermally stable, at least up to the temperature to which it is used for sterilization. Medical products made from PVC can be sterilized by steam, ethylene oxide, or gamma radiation. Plasticized PVC can have a Tg as low as –40°C and still be suitable for steam sterilization at 121°C. Plasticized PVC maintains its product integrity during cold and hot conditions. It is resistance to kinking in tubing reduces the risk of fluid flow being interrupted. Low cost, broad Tg spectrum, wide processing-temperature range, high seal strength, thermoplastic elastomer–like material properties, high transparency, wide range of gas permeability, and biocompatibility these are some characteristics that make PVC attractive. Excellent chemical resistance, Excellent electrical properties, Low Moisture Absorption, Ease of fabrication, Good dimensional stability, Self-extinguishing, Weldable and cementable Easy Maintenance, High level of abrasion resistance, Extremely Bleach and Stain resistant, Moisture Proof, these are some of the properties of PVC.
Therefore the key advantageous of PVC over other materials for medical devices are:
• Sterilization: Plasticized PVC maintains its product integrity under hot and cold temperatures
• Transparency: Plasticized PVC has good clarity so that bags , tubes and other products retain their transparency
• Flexibility: for the easily storage of blood.
• Strength: Resistance to tearing.
PVC is the choice of medical applications not only because of its performance characteristics but also because it is also inexpensive and allows hospitals to use quality disposable items that reduce infection rates.
PVC is the material of choice in many medical applications not only because of its performance characteristics, but because it is also inexpensive and allows hospitals to use quality disposable items that help reduce infection rates. Plasticizers are added to PVC to make it flexible. Since the 1940s, the most commonly used plasticizer has been from the family of phthalate compounds and of these, by far the most widely used is DEHP (di-2-ethylhexyl phthalate), sometimes known as DOP (di-octyl phthalate).


1.4.2 Limitations of Flexible PVC
Despite all the superb attributes and wide applications of PVC. It has been at the centre of a controversial debate during the last two decades. A number of diverging scientific, technical and economic opinions have been expressed on the question of PVC and its effect on human health and the environment. Over the past several years, a number of publications concerning toxic emissions, effect of plasticizers on animals and humans have been reported. Most commonly cited short comings of PVC are:
• Toxic effluents during manufacturing
 Leachable plasticizer
 Dioxin and HCl generation upon incineration
 Chemical interaction with drugs or package contents
a) Toxic effluents during manufacturing
Poly (vinyl chloride) contains more than 50% chlorine by weight. As a result of PVC's relatively high chlorine content, its production, use and disposal give rise to emissions of dioxin, vinyl chloride monomer, and their dangerous, chlorinated organic pollutants. During the manufacture of PVC 90% of the vinyl chloride has polymerized. Leftover Vinyl chloride monomer is drawn off using a vacuum and largely recovered. Traces of vinyl chloride are remained in the PVC material and these leach out into the containers during its usage. Thus Vinyl chloride, the essential building block of PVC is a proven human carcinogen. Workers in PVC production facilities and residents of neighboring communities are inevitably exposed to vinyl chloride monomers. VCM the building block of PVC has been proven to cause liver cancer in workers in the industry. Greenpeace point out the dangers of an accident that could cause the release of large amounts of VCM into the environment. High-level exposure to vinyl chloride, its health risk at lower exposure levels remains controversial. Industry representative’s point out that prior to discovery of the cancers, PVC workers did not experience particularly negative symptoms or toxic effects other than light-head¬ed¬ness. Some studies, however, indicate that vinyl chloride may have a role in other cancers as well as possible birth defects. The critical volumes data refer to amounts of water or air that would be contaminated to maximum allowable levels per the Swiss ministry. These above data offer a means of comparing the relative significance of each type of emission. An April 1993 report from the European Council of Vinyl Manufacturers acknowledges that certain dioxins are formed when hydrochloric acid is mixed with ethylene to form EDC (oxychlorination). According to Ronald Cascone, a researcher at Chem. Systems, Inc. of Tarrytown, New York, these dioxins are not of concern, as they appear in minute quantities among a range of other toxic substances, all of which must be handled appropriately.


Process-related emissions from production of PVC resin

b) Leachable plasticizer
One of the limitations in using plasticized PVC is the possibility of plasticizer migration over time for various service conditions. Plasticizer can be removed from PVC by contact with air, water or an absorbent solid material. Plasticizer loss reduces the flexibility and in some extreme cases it result in noticeable shrinkage. As the plasticizer is not chemically bound to the polymer; it is leached out from the products during storage or while in use. The loss of plasticizer due to leaching is found to affect adversely the function of product in two ways one it affect the mechanical properties such as abrasive, compressive and tensile strength of the polymer article changes considerably. It affects the flexibility and transparency of the product loose drastically. Leaching of DEHP from any given PVC product is dependent on many factors which include: concentration of the phthalate in PVC matrix (greater concentration leads to greater leaching), Vapor pressure of the plasticizer(greater vapors pressure leads to more leads to leaching), surrounding temperature(greater temperature leads to leaching), size of the sub chains, presence of secondary plasticizer to reduce leaching, the degree of “curing “ of the plasticizer and the polymer, the type of surrounding media, application of pressure or agitation, and storage or use time. Three factors which affect the plasticizer retention 1) molecular weight (smaller the molecular weight greater is the volatility and diffusion of the plasticizer 2) linearity {Diebal (2002) found out that branched plasticizers perform better than linear plasticizer in extremely acidic and caustic environments} 3) Polarity
In modern medical technology many plasticized PVC device come in contact with blood, blood components or medical drug solutions while undergoing different medical procedures such as heamodialisis, transfusion of whole blood, platelets or plasma, extracorporeal oxygenation, cardiopulmonary bypass and administration of intravenous fluids. During these medical procedures there are chances of leaching out of DEHP into surrounding media such as blood or blood components, IV fluid or medications. This extraction occurs either by DEHP directly leaching out of PVC product or when an extracting material diffuses into the PVC matrix dissolves the plasticizer and the two diffuses out together. The overall loss of plasticizer from PVC products will depend on both the diffusion constants with respect to the PVC and the solubility or volatility at the surface.
c)Dioxin and Hydrochloric acid emission during the disposal of PVC by incineration
As the number of disposable medical products in use increase, the public concern about the environmental and biological risks of their disposal will also grow.
Dioxin, the most potent carcinogen ever encountered, is created during all phases of PVC production, as well as in its disposal by incineration or accidental fire. Dioxin is made up of 75 different compounds. A more complex name for these compounds is chlorinated diobenzo-p-dioxins (CDDs), which are commonly referred to as polychlorinated dioxins. Dioxins occur as by-products in the manufacture of organochlorides in the incineration of chlorine-containing substances such as PVC in the bleaching of paper, and from natural sources such as volcanoes and forest fires. There have been many incidents of dioxin pollution resulting from industrial emissions and accidents; the earliest such incidents were in the mid 18th century during the Industrial Revolution. Municipal waste incinerators are a leading source of dioxin, and half of the chlorine in incinerators that ends up in dioxin comes from PVC waste. Dioxin quantities are commonly measured by their toxic equivalents (TEQ) relative to the most toxic form, 2,3,7,8 TCDD. While the European report acknowledges that even with all the controls in place, minimal dioxin releases continue, other observers agree with Cascone that PVC manufacture is not a significant source of dioxin contamination. 1989 Danish study reported that doubling the amount of PVC led to a 34% increase in dioxin formation. In a 1987 study in Pittsfield, Massachusetts, however, increasing PVC concentrations caused no corresponding increase in dioxin emissions. Chlorine found in wood and paper may contribute just as much to dioxin formation as that in PVC, according to some researchers. Dioxin formation is affected primarily by the incinerator’s operating conditions. A 1986 Swedish study found that the emissions of certain persistent organo-chlorines could be reduced to 2% of their original level just by optimizing the turbulence and air-flow within the combustion chamber
Dioxins are extremely toxic and potent environmental contaminants. They modulate and disrupt multiple growth factors, hormones; immune system and developmental process. Over the last few years, an increasing number of reports have appeared about the reproductive problems in both wildlife and humans. Nanogram to microgram/Kg body weight doses of dioxin on a single day during pregnancy was found to cause permanent disruption of male sexual developments in rodents, including delayed testicular decent, lower sperm counts and feminized sexual behavior. The study of The American Public Health Association revealed that a prenatal exposure to dioxin in rodents substantially increased the risk of breast cancer later in life.
d) Chemical interaction with drugs or package contents
The DEHP that has been leached out from IV bags may interact with the content of the solutions stored in, which in turn affect the delivery of appropriate amount of therapeutic drugs and thus alter their effects on human. These interactions may have important implications in patients. Petersen. et. al (1975) found that DEHP might compete for the same binding protein sites as the drug dicumarol, significantly increasing the coagulation time of mouse blood. They further demonstrated that DEHP increases hexabarbital (a barbituate) sleep time in rats by increasing the retention time for hexabarbital (due to DEHP’s liphophilic characteristics). Mahomed, et.al. (1998) found that the concentration of the drug diazepam (Valium) fell around 80% in glass and to 50% in a PVC container after four hours and to an even lower concentration in the PVC container after eight hours of storage.


1.5 Chemistry of PVC and its plasticizers
Flexible PVC plays a major role in medical device manufacturing. The specific characteristics of vinyl medical devices are achieved through the addition of a wide variety of additives. Around 98% of the total consumption of PVC for medical applications is used for the production of flexible products like bags, tubes, gloves, etc. PVC is a relatively rigid and brittle amorphous polymer. The vinyl monomer consists of a carbon- carbon double bond with one pendent chlorine and three hydrogen atoms. It polymerizes through a free radical mechanism, the resulting polymer having the repeating unit -CH2CHCl- . In the amorphous structure, the individual molecules of the polymer lack mobility because of the strong chemical bond between hydrogen and chlorine atoms of adjacent polymer chains. Flexibility of PVC can be achieved by blending with plasticizers. Poly (vinyl chloride), PVC, has a polyhalogenated chain with chlorine atoms covalently linked to atoms of carbon, providing thus many points of dipolar interaction along its chain which give rise to strong interchain interactions and consequent rigidity of the polymeric material. Plasticizing additives break interchain dipole interaction providing a material with mobility and flexibility characteristics of a polymer with less interchain interaction. Plasticizers are clear, organic liquid materials that are added to PVC formulations to obtain flexible products. The use of plasticizer involves the introduction of a low molecular weight substance into the structure that act as a molecular lubricant, physically separating the chains and allowing them some mobility, thus giving the flexibility. The larger the volume of the plasticizer, greater the flexibility and softness. In order to get the property of flexibility the plasticizers should be highly compatible with the polymer resin and should become an integral part of the matrix. Plasticizers allow PVC to be softened and shaped into many designs without cracking. Obviously, large volume of plasticizer increases the flexibility and softness of the material. In reality, the mechanism of plasticization is a little complex. The incorporation of plasticizer into PVC involves the penetration of the plasticizer into PVC resin particles, which cause them to swell.
During this process, the polar groups in the PVC are separated and polar groups in the plasticizer are able to interact with those of the resin. The structure of the resin is then re-established with all incorporation of the plasticizer in polymer structure. This effectively provides 'free volume' in the polymer that allows for molecular flexibility. Unplasticized PVC has negligible free volume. The incorporation of plasticizer decreases the interaction forces of adjacent chains, lower the glass transition temperature of the polymer and produce chain mobility and material flexibility. It is important to note that the nature of the plasticizer molecule, in relation to its molecular size, polarity, solid-gel transition temperature and the precise characteristics of the plasticizer- polymer interaction, controls the effectiveness of the plasticizer, both with respect to the flexibility introduced and to the retention of the plasticizer in the material


Many putative plasticizers fail to interact with the PVC resin and produce little or no flexibility, whilst some give flexibility but the final structure is such that the plasticizer cannot be retained under operational conditions and is lost over time, causing a reversion to the brittle state. The plasticizer used in the compounding of PVC is mainly responsible for building the desirable characteristics for medical applications such as transparency, flexibility, strength, elongation, and stability at low and high temperature, permeability to oxygen, water and carbon dioxide in the desired range [2]. The addition of plasticizer reduces the tensile strength and elastic modulus of PVC but increases the elongation at tensile failure at ambient temperature. The specific characteristics of vinyl medical devices are achieved through the addition of a wide variety of additives. PVC is a unique polymer because of its need for and ability to accept large quantities of additives to achieve specific qualities. It is a relatively rigid and brittle polymer; flexibility is achieved through the addition of chemical plasticizers. PVC consumes approximately 90% of the plasticizers produced globally. Other polymers can be made more or less flexible through the rearrangement of polymer chains or the addition of additional polymers to the mixture instead of adding Plasticizers [5]. There are several different types of plasticizers that can be used in PVC. These include adipate esters, phosphate esters, citrates, trimellitates esters, sebacate azelate esters and phthalate esters. They vary in their characteristics and performance, each having relative advantages and disadvantages under different circumstances.
While there are numerous plasticizers on the market, the largest group, accounting for about 70% of consumption of millions of pounds per year, is the phthalate esters. Phalate esters are prepared by the esterification of two moles of a monohydric alcohol with one mole of Phthalic anhydride. It accounts for some 18% of total phthalate production in the United States, down from more than 30% in the mid-1970s. Five producers (Exxon, Eastman Chemical, Aristech, BASF, and Monsanto) account for more than 90% of U.S. phthalate production. Eastman Chemical and Aristech are the largest U.S. producers of DEHP
There are several different types of plasticizers that can be used in PVC. These include adipate esters, phosphate esters, citrates, trimellitates esters, sebacate azelate esters and phthalate esters. They vary in their characteristics and performance, each having relative advantages and disadvantages under different circumstances.
While there are numerous plasticizers on the market, the largest group, accounting for about 70% of consumption of millions of pounds per year, is the phthalate esters. Phalate esters are prepared by the esterification of two moles of a monohydric alcohol with one mole of Phthalic anhydride. Although phthalate esters can be prepared from many different alcohols, the range of alcohols used to make plasticizers for PVC applications is generally limited from C4 to C13 alcohols. Phthalate esters prepared from alcohols below C4 are too volatile, while phthalate esters prepared from alcohols greater than C13 have limited compatibility. Many commercial grade phthalates are prepared using a mixture of monomeric alcohols, such as butanol with 2-ethylhexanol, or blends of linear heptanol, nonanol, and undecanol, and so forth. Di-2-ethylhexyl phthalate(DOP) which is prepared from 2-ethlhexanol, establishes the standard against which other plasticizers may be compared .Of the twenty-five different phthalate esters, di-ethylhexyl phthalate (DEHP) is the one most commonly used in the production of medical devices. It became the choice plasticizer for PVC because of its easy- to – process, easy to disperse and low cost. It is the most widely used PVC plasticizer in the world. So DEHP is regarded as the international standard plasticizer for PVC.
1.6 DEHP (di (2- ethylhexyl) Phthalate) belongs to the class of agents called hypolipidemic carcinogens capable to produce adverse effect on pituitary gland tissues causing liver abnormality testicular atrophy. It is a colorless, odorless and lipophilic oily liquid that is essentially insoluble in water (.3mg/l). But it dissolves in organic solvents and is miscible with many mineral oils and lipids such that it is reasonably soluble in body fluids. DEHP has been found to be highly compatible plasticizer for PVC resin. . The PVC - DEHP system has extensively been explored for the production of many industrial, household as well as medical products. Because of its ability to provide medical devices with their desired mechanical properties, DEHP became the common plasticizer in medical field also. Red Blood cells can be stored up to 72 hrs in DEHP plasticized blood bags. The required shelf life of red blood cells in storage is a 75% survival for 24 hrs after infusion on the last day of storage. DEHP improves red blood cell storage by reducing haemolysis and membrane loss.
Structure of DEHP: -
Chemical name: 1, 2 Benzene Dicarboxylic acids, bis (2 ethyl hexyl) ester
1.6.1 Medically related Exposure of DEHP
PVC medical devices, such as IV bags and blood bags, typically contain 30-40% DEHP by weight; other devices such as medical tubings may contain as much as 80% DEHP by weight. DEHP is the main plasticizer approved by the US Food and Drug Administration for medical uses. The European Pharmacopoeia also recommended DEHP as a softening agent for disposable medical items such as blood bags and tubings. Because DEHP is not chemically bound to the polymer in a PVC medical device, it can be released when the device is heated or it can leach out when the device comes into contact with certain media such as blood, drugs saline or water. The major factor determining the degree to which DEHP leach out from the medical device are temperature, amount of DEHP in the device ,agitation of the device while in contact with medical solution, storage time of the device while in contact with medical solutions and type of medium which it is stored in or moving through the medical device. Two types of studies are done in order to quantify human exposure to DEHP in the medical setting. The first type measure the amount of DEHP that leaches out from common medical devices such as blood bags , IV bags and tubings , into physiological medium that each device such as blood and saline solution. The second solution measures the amount of DEHP or metabolites found in blood, urine or tissues treated with PVC medical devices.
Several studies found out that DEHP leached from PVC blood bags, IV bags and Tubings into blood, blood products and medical solutions. DEHP has been produced in blood products in concentrations ranging from 4 to 650 mg/liter. In atleast some situations, the DEHP that is leached into the drugs can interfere with their delivery or their effects on human. A result of DEHP leaching PVC medical devices, several manufactures provide warning labels advising against the use of DEHP – plasticized PVC for administration of specific products.
Based on our current scientific knowledge, human exposure to DEHP during manufacture or consumer use occurs primarily through inhalation and oral exposure. In 1970 studies identified and measured DEHP and its metabolites in human tissue and serum. There has been only limited study of dermal exposure to DEHP, but it is thought to be an insignificant mechanism for adverse human health effects. DEHP enters the human body; the compound is rapidly metabolized into various substances that are more readily excreted. The first of these metabolites to be created is mono-ethylhexyl phthalate (MEHP), which is thought to be responsible for much of DEHP’s toxicity. MEHP is primarily formed by the hydrolysis of DEHP in the gastrointestinal (GI) tract and then absorbed (Centers for Disease Control and Prevention (CDC) 2005). The enzymes (lipases and esterases) that break down DEHP into MEHP are found mainly in the GI tract, but also occur in the liver, kidney, lungs, pancreas, and plasma.
MEHP is subsequently further metabolized by different oxidation reactions, creating a number of other metabolites, the most significant of which include (Koch et al. 2006):2-ethyl-5-hydroxyhexyl phthalate (5OH-MEHP), 2-ethyl-5-oxy-hexylphthalate (5oxo-MEHP), 2-ethyl-5-carboxy pentyl phthalate (5cx-MEPP), and(2-(carboxymethyl)-hexyl) phthalate (2cx-MMHP).
These secondary metabolites of DEHP represent the majority of DEHP metabolites (approximately70%) excreted in urine versus MEHP, which is present in urine at approximately 6% of the total amount excreted (Koch et al. 2006). 5OH-MEHP and 5oxo-MEHP are produced by the oxidative metabolism of MEHP and are present at roughly three-to ten-fold higher concentrations than MEHP in urine (Koch et al. 2003). Because the majority of conversion of DEHP to MEHP occurs in the GI tract, exposures to DEHP by ingestion may be more hazardous than by intravenous exposure, which largely bypasses the GI tract. The primary purpose of studying these secondary metabolites is that the long half times of elimination of the carboxy metabolites (5cx-MEPP and 2cx-MMHP) make them appropriate parameters for measuring time-weighted body burden of DEHP, while 5OH-MEHP and 5oxo-MEHP appear to more accurately reflect short-term human exposure to DEHP (Koch et al. 2006). However much less is known about the potential human effects of exposure to these secondary metabolites.
The initial metabolism of DEHP to MEHP is qualitatively similar among mammalian species, so that animal studies are likely to be useful in understanding the consequences of human exposure. The similarity of secondary metabolite creation among non-human species is less well known. There are a number of animal studies that have been conducted over the past several decades looking at potential health effects associated with exposure to DEHP. The primary studies have involved rodents (rats and mice) while more recently studies have been conducted on primates (such as marmosets and cynomolgus monkeys) and pigs. Studies of rats represent the most prevalent source of information on potential health effects associated with varying doses and exposure routes. Parental medical exposure to DEHP of critically ill infants has been shown to exceed general population exposures by several orders of magnitude.
Studies of primates focused on common marmosets (Kurata et al. 1998) and cynomolgus monkeys (Pugh et al. 2000). [3]

Man exposure to DEHP following treatment with PVC medical devices

Treatment Total exposure (mg) Exposure Rate

mg/kg bodyweight Time period
Hemodialysis 0.5-360 0.01-7.2 Dialysis session
Blood transfusion in adults 14-600 0.2-8.0 Treatment
Extracorporeal oxygenation in infants 42.0-140.0 Treatment period
Cardiopulmonary bypass 2.3-168 0.03-2.4 Treatment day
Artificial ventilation in preterm infants 0.001-4.2 Hour

Exchange transfusions in infants 0.8-4.2 Treatment


Environmental Hazards of DEHP is that it doesn’t chemically bound to the PVC polymer matrix and thus can be released through its life cycle. The half-lives of DEHP and phthalate in the environment are relatively short. They have the strong tendency to adsorb on the soil and the sediments can persist in the environment for years. Although DEHP has a low bioconcentration factor, it will preferentially bioconcentrate in aquatic organisms rather than remain in water due to its low water solubility. DEHP doesn’t significantly bioaccumulate in the food chain. DEHP enters the environment through release from manufacturing facilities. Over long periods of time it can migrate to the environment. [Five chemical Alternative Assessment Study] Because DEHP has low vapor pressure, little is found in air. DEHP that is present in the air will adsorb on to dust particles and be deposited on surfaces through gravity, rain or snow. Certain drugs also cause DEHP to leach from PVC intravenous IV bag into solutions. Pearson and Trissel (1993) found that DEHP was leach out from bags into numerous drugs.
In his Handbook on Injectable Drugs, Trissel (1998) identified a wide range of drugs that have been shown to increase the leaching of DEHP from bags. DEHP that leach out into medical solutions may interact with those solutions, affecting the delivery of the appropriate amount of therapeutic drugs and thus altering their effects on human.

Chemotherapeutic : Etoposide (VePesid) Paclitaxel (Taxol), Teniposide (Vumon)
Antianxiety : Chlorodiazepoxide HCL (Librium)
Antifungal : Micronazole (Monistat IV)
Immunosuppressive : Cyclosproine (Sandimmune) and Tacrolimus (Prograf)
Nutritional : Fat Emulsions and Vitamin A
Some drugs also have been shown to increase the leaching of DEHP from PVC plastic into solution

1.6.2 Attempts to reduce the DEHP leaching
A strong controversy over the toxicity of DEHP persists all over the world. Since early 1980’s alarming reports questioning the safety of using DEHP as a plasticizer in medical PVC application have been surfacing. Many investigators have addressed the issue of DEHP leaching and attempt to control the leaching of DEHP. Techniques such as grafting, coating and surface cross-linking with dithiocarbamates inorder to reduce or inhibit plasticizer migrations are among the most attractive ones. In one of the earlier attempts Miyamoto and Sasakawa showed that leaching of DEHP could be inhibited by glow discharge treatment of PVC products. In another study the reduction of DEHP migration was done by modifying the base polymer by radiation or chemical grafting using various monomers and standardized certain methods for reducing the amount of plasticizer migrating into the blood and blood products. A different approach has been proposed by Jayakrishnan and Lakshmi involving surface modification of DEHP- plasticized PVC articles by reacting with sodium sulphide in the presence of a phase-transfer catalyst. This treatment hinders DEHP migration and leakage in the surrounding medium. However, tedious processing steps and high cost hindered the success of these attempts on an industrial level. In another attempt the plasticizer DEHP tried to replace with many other plasticizers like adipates, citrates, trimellitates, carboxylate, etc. In 1980 Jacobson et. al tried Hatcol-200 as a plasticizer in medical PVC.
1.7 Alternatives plasticizers for DEHP
There are a number of non-phthalate plasticizers on the market, often offering an alternative to meet special requirements in flexible PVC. For example, adipates offer low temperature flexibility and low viscosity, while trimellitates offer particular advantages in high temperature cable sheathing applications. Phosphates offer advantages in fire resistance, while alkyl sulphonates are easy to process and offer good weather resistance.
a) Mesamoll (alkyl sulphonates of phenol derivatives) plasticizers from Bayer AG are suitable for use in PVC. The main advantage of Mesamoll in production is that it gels quickly, in particular at low temperatures. Goods made from plasticized PVC containing Mesamoll can be painted and printed on over a long period of time. Bayer adds that good saponification resistance gives PVC products longer durability. In addition, good high frequency weldability permits shorter welding times and greater weld strength.
b) Trimellitate Plasticized PVC: -Grode et al studied the storage of platelet concentrates in PVC bags plasticized with tri octyl tri mellitate plasticiser and showed that such bags possessed sufficient gas permeability to be suitable for extended storage of platelets for at least 5 days. They also found a 30-fold reduction in plasticizer accumulation in platelet concentrates as compared to DEHP plasticized bags. Studies made subsequently confirm that such bags may be used for storing platelet concentrates for at least 5 days at 22oC. While TOTM plasticized containers were found satisfactory for storage of most platelet concentrates, it may be desirable to use more permeable containers if platelet yields are routinely very high.

Types of PVC plasticizers
(North American breakdown)
A distinct advantage of TOTM is its low migration and volatility characteristics. Baxgter Health Care Corporation, USA (PL-1240), M/s Cutter Laboratories, USA (CLX), M/s Tuta Laboratories, Australia and others have been using TOTM as plasticiser for platelet storage bags [1]. A disadvantage of TOTM is that Since TOTM was found to be responsible for high gas transmission; attempts are made to increase gas transmission of plastic films used in the blood bags by increasing TOTM content in the plastic films. Commercially available blood bags have about 41% by weight TOTM content. Amounts of TOTM greater than 41% are no adequately absorbed in the existing resin compounds and the resulting film product is both tacky and unmaleable. The upper limit of about 41% TOTM limits increased gas transmission in blood bags but it limits the maximum storage duration of blood components such as platelets and the quantities of blood components that may be stored in a plastic blood bag of a given size [9].

c) BTHC plasticized PVC: -Blood bags made with n-butyrul, tri n-hexyl Citrate plasticizers have been shown to be effective for storing platelets and their behavior is similar to TOTM plasticized bags. Measurements of pH, pO2, pCO2, glucose, lactate, ATP, total adenine nucleotide, lactate dehydrogenase and platelet factor-4) pF4) showed similar results for BTHC and TOTM plasticized bags during five-day storage of platelets. Results of in vivo studies were similar.
An interesting observation, however, has been made that while statistically significant higher values have been obtained for BTHC plasticized containers than for TOTM, for pH, pO2, The jogjer pH levels obtained for BTHC is similar to the high pH levels observed during the storage of platelets in blow molded polyolefin bags, which have high permeability. This observation indicates that while BTHC and polyolefin containers ensures sufficient oxygenation to maintain an aerobic metabolism, the carbon dioxide permeability is too high and allows too much escape of the gas as indicated by the low pCO2. n-butryl tri-n-hexyl citrate now used in the manufacturing plastic films having high gas transmission but it has higher leaching from PVC than other plasticizers. So it cannot be used because of its coagulation inhibition effect.
d) Polymeric plasticizers are typically polyesters, with a molecular weight range from 1,000 to 8,000. Polyethylene copolymers (EVA’s, VAE’s, etc.) and terpolymers can range up to > 500,000. Polyesters are prepared by the esterification of propylene glycol or butylene glycol with aliphatic dibasic acids. The greater the plasticizer viscosity, or molecular weight, the greater its permanence. Polymeric plasticizers composed of branched structures are more resistant to diffusivity losses than those based on linear isomeric structures; on the other hand they are more susceptible to oxidative attack. The polarity, or the oxygen-to-carbon ratio, also impacts extraction resistance of the polymeric. Lower polarity materials exhibit better extraction resistance towards polar extraction fluids such as soapy water. Glutarate polymerics reportedly have a proven history of providing good weathering resistance


1.8 Hexamoll DINCH
Among the new generation plasticizer Hexamoll DINCH manufactured by BASF has got good attention all over the world recently. Hexamoll® DINCH, for sensitive applications. Since it was first introduced in Asia Pacific in 2002, the demand for Hexamoll® DINCH has been growing steadily and has since been successfully marketed to the toy industry in China. It received a positive review from the European Food Safety Authority in addition to the existing recommendation from the German Federal Institute For Risk Assessment. Hexamoll DINCH is regulated under the global migration with 60 mg per Kilogram food. The plasticizer DINCH (di-isononyl-cyclohexane- 1, 2- dicarboxylate) is obtained by the hydrogenation of the benzene ring that is present in o-phthalates, and this process enables its use in medical devices and in the toy industry. Hexamoll DINCH is the 1, 2-cyclohexanedicarboxylic acid diisonyl ester produced by the hydrogenation of the aromatic ring in diisononyl phthalate (DINP), in the presence of a noble catalyst. BASF says that it is a general-purpose plasticizer, with a well-balanced technical profile and a wide range of PVC applications. The company adds that Hexamoll DINCH exhibits no peroxisome proliferation and has no reproductive toxicity. There is also no genotoxicity, sensitization or persistency. Toxicity studies of DINCH show that it is found to be a non-irritant in both rabbit skin and rabbit eye test. DINCH has very low acute toxicity. It has been evaluated for mutagenicity, both in bacterial and mammalian cell tests, with negative results. As indicated, its performance characteristics in PVC are expected to be similar to the phthalate counterpart, except for having less solvency for PVC. DINCH has recently been introduced by BASF as a candidate for applications with sensitivity for peculiar health and environmental concerns. These sensitivities are also addressed with the recent introduction of a novel triester plasticizer completely devoid of carbon ring configurations; it is claimed for use in medical applications and “low smoke” grade PVC electrical insulations. BASF recommends the use of Hexamoll DINCH in applications that are particularly sensitive based on exposure and toxicological issues such as medical devices (i.e., blood tubes or packaging for nutrient solutions), toys (including those for children under three years of age), and food packaging (as well as artificial wine corks). Hexamoll DINCH offers a very good technical performance and can be processed by existing machinery without any problem.
Hexamoll® DINCH is a clear, colorless plasticizer practically anhydrous liquid with a hardly noticeable odor that was developed for use in applications that are particularly sensitive based on exposure and toxicological issues. It is recommended for use in medical products, toys, and food packaging applications. BASF adds that Hexamoll DINCH can be also be use in sport and leisure products (i.e., gymnastic balls, exercise mats and cushions, and shoes), coating and printing inks, dispersions, textile coatings, and cosmetic applications. It is soluble in the usual organic solvents and is miscible and compatible with all of the monomeric plasticizers commonly used in PVC Hexamoll® DINCH is suitable for use with PVC and other polar polymers. It is compatible with all of the monomeric plasticizers commonly used in PVC. In most cases, only minor formulation and processing parameter adjustments are required to process flexible PVC compounds. Compared to DOP and DINP, Hexamoll® DINCH offers improved low temperature performance. In plastisol applications it offers lower initial viscosity and better viscosity stability. Hexamoll® DINCH is also remarkable for its extremely low migration rate, which is a measure of the amount of plasticizer molecules released by the plastic into a surrounding medium. This makes Hexamoll® DINCH not only ideal for toys, but also the plasticizer of choice in many medical devices. If any field requires extra careful attention to material sensitivity, it would be the medical industry as medical devices made of PVC, such as blood bags and tubing, directly enter the patient's body. Hexamoll DINCH is almost insoluble in water. BASF claims that, compared to DOP and DINP, Hexamoll DINCH offers improved low temperature performance and that in plastisol applications it offers lower initial viscosity and better viscosity stability. Both DINCH and DEHP show similar molecular weights but present some structural differences. The main difference is the flat structure of the benzene ring as opposed to the typical chair structure of cyclohexanes (figure). This different structure can strongly affect the plasticizer–poly (vinyl chloride) (PVC) interaction process. Studies show that DINCH does not pose a threat to human health or environment. Unlike other plasticizers this special plasticizer DINCH has a far more permanent connection with the PVC molecules. Due to manual stress or exposure to liquids the plasticizers could not leave the PVC. This makes it very well suitable for the use in sensible applications like medical field.


Chemical name : 1,2-Cyclohexane dicarboxylic acid, di-isononyl ester
Frank Welle et al studied the migration behavior of various plasticizers including DEHP and DINCH from PVC tubing’s into enteral feeding solutions. In animal experiments DEHP has been shown to impair fertility and cause malformations and has hence been labeled as toxic. Comparison was also been made with the other alternative plasticizers (TEHTM ATBC and DEHA). The results showed that migration in the DINCH system is considerably lower than for DEHP. In addition effects of DINCH are observed at higher exposure doses than DEHP. A comparison of the plasticizer migration is given in figure 2. We can see that compared to DEHP, DINCH show very low migration to the feeder solution from PVC tubes. This aspect can be utilized for the development of blood storage bags.
Another comparative analysis, developed with a traditional industrial plasticizer (DEHP) and a new carboxylate plasticizer (DINCH) with low toxicity, indicated that both plasticizers showed similar viscosities for the formulations used in rotational molding, so the substitution of DEHP for DINCH should not require important changes in the plasticizer content or even the use of viscosity modifiers for use under similar processing conditions.

Schematic three-dimensional representation of DINCH and DEHP.

But some differences in the mechanical properties of DINCH and DEHP plastisols were observed. DINCH-based plastisols showed better behavior than DEHP-based plastisols for low plasticizer contents, but in the typical range used in rotational molding for toys, no significant differences between the two plasticizers were appreciated, and they were perfectly exchangeable.

Mass plasticizer migrated into enteral feeding solution per 3 hours at room temperature and a flow rate of 5 ml h-1 (realistic application conditions)
Both DINCH and DEHP show similar molecular weights but present some structural differences. The main difference is the flat structure of the benzene ring as opposed to the typical chair structure of cyclohexanes (figure). This different structure can strongly affect the plasticizer–poly (vinyl chloride) (PVC) interaction process. Studies show that DINCH does not pose a threat to human health or environment. Unlike other plasticizers this special plasticizer DINCH has a far more permanent connection with the PVC molecules. Due to manual stress or exposure to liquids the plasticizers could not leave the PVC. This makes it very well suitable for the use in sensible applications like medical field.
Comparing DINCH and DEHP based on their aromatic character the former is an alicyclic compound and the latter is an aromatic one. This difference can also contribute different level of hydrogen bonding with PVC. Hydrogen bonding between DINCH and PVC can cause less leaching compared to DEHP where no prominent hydrogen bonding is reported.
1.9 Epoxidized Soyabean oil
Secondary plasticizers are low volatility liquids whose compatibility with PVC is such that they can be used along with primary plasticizers as part of the plasticizer system, but which exude if used as sole plasticizer. Epoxy plasticizers have oxirane oxygen groups in their molecules formed by the epoxidation of olefinic double bonds in their starting raw materials: They are used as co-stabilizers along with suitable mixed metal stabilizers and some of the newer types of stabilizers. Epoxidized soybean oil (ESO) and epoxidized linseed oil (ELO) are the most widely used epoxides. They have the disadvantage of being food nutrients for molds, some bacteria, and fungi.


Sound formulators use epoxides at low levels because the oxirane oxygen group has a strong compatibilizing action with PVC. Use of higher levels of ESO or ELO risks formation of tacky “spew” resulting when the oxirane oxygen is photo-oxidized or hydrolyzed. To get the stabilizing action of oxirane oxygen without the risk of exudation or microbial attack, some formulators use epoxy resins even though these cost more than ESO or ELO.A class of more environmentally benign plasticizers are derived from vegetable oils. Vegetable oil plasticizers provide about fifteen percent of the total US market for plasticizers, and represent about eight percent of the industrial market for vegetable oils .The most significant vegetable oil plasticizer is epoxidized soybean oil (ESO), which holds 43 percent of the vegetable oil derived plasticizer market. ESO is used as a secondary plasticizer (plasticizers used at levels of one to four percent) in flexible PVC. The Viking Products Division of Elf Atochem (Philadelphia, PA) produces ESO plasticizers under the trade name Vikoflexreg., at about $ 0.70 per pound. This is somewhat high in comparison to plasticizers such as DOP, which costs $ 0.53 per pound. However, ESO is a higher value product because of benefits such as its resistance to migration, evaporation and leaching, its low odor, and the stability to light and heat which it adds to PVC. Other epoxidized oils used by in flexible PVC include linseed oil and epoxidized tallates, although these account for less than 9 percent of the vegetable oil plasticizer market. Like ESO, linseed based plasticizers offer the additional benefit of high stability, which makes them competitive in food and medical applications where low levels of metallic stabilizers are required. These can also act as lubricant but also act as secondary stabilizers to PVC due to their epoxy content which can remove HCL from the degrading polymer.

1.10 Ca-Zn stabilizer
Stabilizers have been used in flexible PVC compositions to prevent degradation during processing and forming into finished shapes. Historically, lead-based stabilizer systems were the first commercially successful ones for PVC. They are generally fine particle size basic solids, which disperse readily in flexible PVC compositions so that there are no significant unstabilized volume elements. Atomic chlorine and HCl released from degrading PVC, readily form basic lead chlorides, which do not promote further degradation of PVC. A simple way to generalize the action of heat stabilizers in flexible PVC is the following: thermal degradation of PVC molecules starts at defect structures which may take several forms but involve labile chlorine atoms. Unless an active stabilizer molecule is close to the site from which labile chlorine releases from PVC, a progressive “unzippering” of successive HCl molecules from the PVC is initiated. Stabilizers prevent this as follows:

For many years, the most popular mixed metal stabilizers for flexible PVC were based on barium and cadmium or barium-cadmium-zinc combinations, along with various phosphates and epoxy plasticizers or resins. Today, many mixed metal stabilizers for flexible PVC use zinc compounds, which exchange their anions for labile chorine atoms on PVC molecules. The zinc chloride formed in these exchanges is potent Lewis acid capable of catalyzing catastrophic dehydrochlorination of PVC. Therefore, zinc is backed up by barium or calcium in the stabilizer at a higher level than the zinc. The barium and calcium compounds do not react with the labile chlorine atoms on PVC as actively as the zinc compounds do. Then, by anion exchange, barium or calcium chlorides are formed in the mixed metal system, and the zinc ceases to be part of a strong Lewis acid. The barium and calcium chlorides are weak Lewis acids and promote PVC degradation much less than zinc chloride does. In 1993, Baker and Grossman presented work on cadmium-free mixed metal stabilizers.
1.11 Liquid paraffin
Lubricants are materials that control the fluxing (melting) point in the extruder/molder to achieve the best processing characteristics and physical properties. Lubricants are also added to vinyl polymers to facilitate the extrusion or other melt processing of the structural articles produced. Lubricants are generally classified as external or internal lubricants. An external lubricant provides a lubricating layer between the plastic melt and the metallic surfaces of the processing equipment. The external lubricant serves to coat the individual particles of the polymeric resin and inhibits their adherence to the metallic surfaces. In contrast, an internal lubricant reduces the effective melt viscosity of the vinyl polymer at the processing temperatures in order to improve its flow properties during processing as well as to promote fusion. An internal lubricant is generally needed only for thin extrusions such as films and thin-walled pipe. Liquid paraffin is the lubricant used.
The “melting” behavior of PVC is different from that of semicrystalline polymers. PVC granules have a particulate structure; each granule is an agglomerate of primary particles (“globules”). Each primary particle has an internal fine structure made up of fibrils (“nodules”).The properties of any article fabricated from PVC depend on the original coarse powder structure being destroyed and replaced with a new connected microstructure. This process is known as fusion. Under- or over-fusion results in poor mechanical properties and so it is important to ensure that fusion takes place at the right time during processing. Internal lubricants, which coat the surfaces of the globules to assist the breakdown of the particulate structure, accelerate the fusion process that may lead to over-fusion and polymer degradation. External lubricants, which act between the polymer and metal surfaces, delay fusion. The right choice of internal and external lubricants is therefore critical in the manufacture of products from PVC. External lubricants are normally non polar molecules or alkanes. There usually paraffin waxes mineral oils or poly ethylene. Some stabilizers have oils that carry active ingredients such as external lubricants. External lubricants are normally incompatible with PVC. They help PVC slip over the hot melts surfaces of dies /, barrels and screws without sticking and contribute to the gloss on the end product surface. Extruder motor amperage is affected by small changes of external lubricants. Common problems resulting from over lubrication include: Surging of the extruder, lumpiness of the extrudate incomplete fusing and the necessity of high barrel temperature.
Internal lubricants: They are normally polar molecules. They are usually fatty acid and fatty acid esters or metal esters of fatty acids and are very compatible with PVC. They lower the melt viscosity, reduce internal friction and promote fusion. Common problems of under lubrication are rough extrudate. Adhesion to metal surfaces, melt fracture, quick fusion and abnormally low barrel temperature.
External/Internal Lubricants: They have long hydrocarbon chains, along with amide, alcohol, acids and ester groups. Common types used in PVC are fatty acid amides and oxidized poly ethylene .some of these materials lubricate as external lubricant before melting and internal lubricant after melting.

Requirement for a blood bag
Characteristics Maximum permissible value
Oxidizable constituents 1.5ml
Ammonia 0.8ml
Acidity or alkalinity 0.4ml NaOH solution c(NaOH)=.01mol/l 0.8ml HCL, c(HCL)=.01mol/l
Evaporation residue 5mg
Opalescence Slightly opalascent, but not pronounced than that of reference suspension
UV absorbance In the range of 230nm to 360nm .25for plastic containers with nominal capacity ≤ 100
Extractable plasticizer 15mg/100ml
Residue on ignition 1mg/g
Table: Chemical Limits on Plastic container

Thickness of blood bag : .37- .34mm
Gas permeability :
i) Oxygen permeability : 685 ± 165
ii) Carbon dioxide permeability: 4160 ± 1040
Water vapour absorption : 0.07-0.75%
Hardness : 72-80 Shore A


Scope and Objective of the present study
The aim of present study is to substitute DEHP, using DINCH plasticizer in PVC blood bag. Study involving compounding of medical grade PVC using DINCH plasticizer having various concentrations like 39, 40, 41, 42, 43, 44, 42(modified the compounding principle) and with Epoxy soyabean oil, liquid paraffin oil, calcium Zinc stabilizer using a high speed mixture .Sheets are prepared by extruder. Analyze these sheets using chemical tests like test for ammonia, acidity or alkalinity, residue on evaporation ,opalescence ,oxidisable constituents, residue on ignition, UV absorbance according to the ISO standards 3826. Leaching tests and transparency are also conducted to the ISO standards 3826.TG of the samples are analyzed using DSC. Mechanical tests like hardness tests, tear strength and tensile strength are analyzed. Transparency, water vapor transmissibility, gas permeability, FTIR, tests for plasticizer compatibility in PVC compound under humid conditions are also conducted.












EXPERIMENTAL











Chapter-2
EXPERIMENTAL
In this research work medical grade PVC with k value of 67, supplied by Welset plast extrusion Mumbai and speciality plasticizer DINCH, supplied by BASF was used. Several trials were taken with different combination of plasticizer to achieve right combination of properties.
2.1 Materials
a) Medical Grade PVC
Molecular weight : 200000
Water absorption : 0.07-0.75%
Glass Transition(Tg) : 800C
Tensile Modulus : 426000psi

b) DINCH
Hexamoll DINCH is a clear, colorless plasticizer suitable for PVC is obtained from BASF
Physical properties of DINCH
Chemical Name : Di-isononyl-cyclohexane-1,2-dicarboxylate
Empirical formula : C26H48O4
Molecular weight : 424.7
Boiling Point : 240- 2500C at 4hpa
Vapour Pressure : <2.8x>1500 C at 5mm Hg
Flash Point 2990 C
Solubility 0.01%(200 C)
Density 0.9821(250 C)
Freezing Point -150 C



d) Liquid Paraffin

Appearance A Clear, colorless Liquid
Odor Odorless
Solubility H2o Insoluble
Flash Point > 1820 C
Incompatibility Avoid oxidizing agents

e) Ca-Zn Stabilizer





2.2 Experiment
2.2.1 Compounding of material
The medical grade PVC material is compounded and modified with a number of additives like plasticizer (e.g.:-DEHP), stabilizers, lubricants etc. The process of incorporation of these additives in PVC material is known as compounding.
For this experimental work compounding of medical grade PVC material done with E Epoxidized soyabean oil , Ca-Zn stabilizers and liquid paraffin with high speed mixture. Initially PVC resin, epoxidized soyabean oil, Ca-Zn stabilizers were added to high speed mixture and started the mixture, at 850 C plasticizer were added. After reaching temperature 1050C liquid paraffin was added and material discharged at 1150 C.
The advantages of hot mixing of PVC powders in high-speed mixer are
1) Optimal mixing quality and homogeneity.
2) Short cycle times and high output rates.
3) Very free flowing blends.
4) Pneumatic conveying of dry blends or agglomerates without product segregation.
5) Up to 20-40 % increase in bulk density as a result of sintering thenraising the output rates of processing machine.
6) Low cost and effective lowering of residual VC content, partially because of high mixing temperature more than 800 C.
7) Complete elimination of residual moisture in the material. [PVC Technology by W.V. Titow ]
Timing, sequence and method of additive admixing, as well as the speed programme of the high speed mixer, mixing time and final temperature are some of the factors contributed to the achievement of optimal properties in the PVC composition.










Fig: 2.1 high speed mixtures

Compounding of PVC is done with different composition of plasticizer as given below in table
Different composition
A B C D E F G(modified the compounding)
PVC 100 100 100 100 100 100 100
Plasticizer
(DINCH) 39 40 41 42 43 44 42
Epoxidized
Soyabean
oil 10 10 10 10 10 10 10
Ca-Zn
stabilizer 1.6 1.6 1.6 1.6 1.6 1.6 1.6
Liquid paraffin 0.4 0.4 0.4 0.4 0.4 0.4 0.4

Table 2.1 PVC with different plasticizer combination






2.2.2 Palletizing: In plastic processing industry mainly three types of pelletizer are used :
1. Strand pelletizer
2. Water ring
3. under water pelletiser
In strand palletizing system, the pellets are not consistent in dimensions and having inclination to carry moisture. The wastage is also very high. In water ring palletizing system, the material tends to smear over the die plate and cutting blades, due to dry cutting at the die face. In Underwater palletizing system, the molten polymer emerges from the die holes, cut into pellets by the rotating blades, under controlled temperature of water.
Advantages of underwater pelletizer
• Ideal melt distribution
• Direct introduction of the melt into the cooling circuit
• Closed water cycle
• Variable pellet size from 0.5 mm to 5mm
• Safe palletizing process
• Low downtime & low scrap through automation
• Automatic tool readjustment
• Uniform pellets
• Smooth pellet surface
• No product oxidization
• Clean operation
Compounded PVC is processed into granules using palletizer as the temperature profile given below. Some flexible extruders palletize the flexible powder. This eliminates the problem of feeding powder to a single screw extruder without a crammer. It reduces the problem with moisture and minimizes house keeping. Single screw extruders normally were designed to run CUBES or PELLETS, not POWDER. Running powder can be done, but at a cost. The equipment needed to palletize.
1. Multi or single screw extruder
2. Palletizing head
3. Bulk handling equipment
4. dust collectors

Temperature profile for palletizing
ZONES TEMPERATURE
Zone 1 1500C
Zone 2 1550C
Zone 3 1620C
Die 1630C

Table 2.2: Temperature profile of pelletizer

2.2.3 Extrusion of sheets
Extrusion is a process by which polymeric products whose two dimensions are fixed and third dimension is infinite. Sheet extrusion is typically used to create sheets with a thickness of 0.5 to 25mm, and widths of two to nine meters. The equipment is used for extrusion is the extruder, which ensures steady supply of homogenized polymer, melts. Extruder consists of highly polished screw/screws of well defined geometry, rotating in a hollow cylinder barrel which is heated by means of external heaters. The screw geometry and design depends on the polymer processed and the desired rate of processing. The homogenized melt generated by the screw barrel combination is passed through a screen pack and a breaker plate assembly and fed to a die to impart desired shape to the melt to produce product of desired cross section. The suitability of a polymer to prepare sheet depends on the molecular weight and molecular weight distribution of the polymer. Besides this it is also depends on thermal characteristics such as glass transition temperature (Tg), crystallization temperature (Tc) and degradation temperature (Td). Since in most cases, the preparation of sheets is carried out by melt processing, the strength and the viscosity of polymer melt should be sufficient high to withstand stresses in sheet formation and accordingly the molecular weight processed by the polymer should





Fig2.2: extruder

Importance of each zone
Feed zone: Feeding and pre heating of the material.
Plasticizing zone: heating and agglomeration.
Compression zone: sealing- off of vent zone in support of the plasticizing process.

Sheets of different compositions like 39, 40, 41, 42, 43, 44, and 42 (modified the compounding principle) and have the thickness of about .34mm for the characterization studies and for the molding of blood bags are prepared by using extrusion with T type die. The screw rpm used for processing is 40. Temperature profile as given below:

Zone Temperature( 0 C)
Zone1 168
Zone2 175
Zone3 180
Zone3 190
Die1 197
Die2 197

Table2.3: Temperature profile for sheet extrusion


2.3) High frequency (HF) : High frequency (HF) welding or radio frequency(RF) welding applying is also known as dielectric sealing is the process of fusing PVC sheets together by applying radio frequency energy to the area to be joined. This technology allows for air proof, leak proof, high strength weld. Blood bags for the studies like leaching are prepared by using radio frequency (RF) welding. High frequency welding techniques are used in the blood bag. PVC sheets are placed between electrodes and high frequency is applied. The PVC gets heated very rapidly and sealing takes place between electrodes. During welding, donor, transfer, tubing etc are kept in correct position.

2.4) Experiments and methods:
The blood bag sheets prepared using the above compositions are characterized using various physical and chemical tests. Plastic containers used for the storage of blood and its component should be chosen so as to minimize the leaching of chemical constituents into the product. So the oxidizable constituents, ammonia content, acidity or alkalinity, evaporation residue, turbidity and degree of opalescence should be within the limits. So chemical tests have to be performed. Blood bags are sterilized under the temperature of 1210C and also during the time of separation of blood components, centrifugation is done within the blood bag,so sufficient strength is required, in order to analysis it mechanical test like tensile, tear etc have to be done. Test like water absorption, watervapour permeability, MFI, hardness test, Leaching studies, Transparency test, DSE, Test for plasticizer compatibility in PVC compounds under humid conditions, Gas permeability, FTIR etc have to be done.

2.5) Chemical tests [ISO 3826-1-500]
Take material for testing from the blood derivatives contact materials of the finished, empty and sterilized plastics containers i.e. in the state in which they would be used for transfusion, collection, separation and administration procedures, including the plastic sheets used for collecting bag and the plastic tubing’s used for the collection tube and any parts that come into contact with blood and blood components. Plastic containers used for the storage of blood and its components should be chosen so as minimize the leaching of chemical constituents into the products. So the oxidizable constituents, ammonia content, acidity or alkalinity, evaporation residue, turbidity and degree of opalescence should be with in the limits.

a) Determination of residue on ignition
Weigh 1 g to 2g of the material into a suitable crucible that has been previously ignited, cooled and weighed. Heat to 1000C to1050C for 1 hr. Then ignited to (550±250C). Allow it to cool in a desiccator and weigh. Repeat the ignition until constant mass is obtained. Calculate mass of residue on ignition per gram of the starting material.

b) Preparation of test fluid
The extraction may be performed on pieces of sheeting or raw container. Use pieces with a total surface area of 1500cm2 which include both sides of plastic sheet. Wash this material twice with100 ml water for injection and discard the water after use. Drain the pieces; cover them with 250 ml water for injection and extract for 30 min in pressurized, saturated steam at (121±2)0C.As a comparison fluid treat water for injection in the same manner.

c) Tests
I) Determination of oxidizable constituents
Boil for 3 min 20 ml of the test fluid with 20 ml potassium permanganate solution[c (KMn04 ) = 002mol/1] and 1 ml sulphuric acid [c (H2SO4) =1mol/1]. Add 1 g of potassium iodide and titrate the solution with sodium thiosulphate solution [c (Na2S2O3) =.01 mol/1] until light –brown. Then add 5 drops of starch solution and titrate until colorless.
Calculate the consumption of potassium permanganate solution [ c(KMnO4 ) =.001 MOL/1] For the test fluid and water serving as comparison fluid. The difference between the two values shall not be greater than 1.5ml.
II) Determination of Ammonia
Make alkaline 10 ml of the test fluid by the addition of 2ml of caustic soda [c (NaOH) =1mol/1] dilute with distilled water to 15 ml and then .3 ml Nessler’s reagent.
Prepare the solution simultaneously by making alkaline .8ml of ammonia standard solution [c (NH4)=1mg/l] by the addition of 2ml of caustic soda [c(NaOH)=1mol/l], diluting with distilled water to 15ml and then adding .3ml Nessler’s reagent. After 30 s examine the solution, which shall not be strongly yellow colored than the comparison solution.
III) Determination of acidity or alkalinity
After the addition of 2 drops of phenolphthalein solution 10ml of the test fluid shall not be colored red. However, on the addition of less than .4ml caustic soda [c(NaOH)=.01mol/l],red coloration shall be occur. After the addition of .8ml Hydrochloric acid [c(HCL)=.01mol/l],this coloration shall disappear again. Mon the addition of 5drops methyl red solution, the solution shall have an orange red coloration.
IV) Determination of evaporation residue
Evaporate 100ml of the test fluid on a water bath and dry at 1050C to constant mass.
V) Determination of turbidity and degree of opalescence
Using identical test tubes of colorless, transparent, neutral glass with a flat base and an internal diameter of 15mm to 25mm, compare the liquid to be examined with a reference suspension freshly prepared as described below, the depth of the layer being 40mm. Compare the solution in diffused daylight 5min after preparation of the reference suspension, viewing them vertically against a black background. The diffusion of light shall be such that reference suspension 1 can readily be distinguished from reference suspension 1.
Reagents
i) Hydrazine sulphate solution:- Dissolve 1g of Hydrazine sulphate in water and dilute to 100ml. Allow to stand for 4h to 6h.
ii) Hexamethylenetetramine:- Dissolve 2.5g of hexamethylenetetramine in 25 ml of water in a 100ml glass-flask.
iii) Primary opalescent suspension: - Add to the solution of hexamethylenetetramine, 25 ml of hydrazine sulphate solution mix and allow standing for 24h.
This suspension is stable for 2 months, provided that it in a glass container free surface defects. The suspension shall not adhere to the glass and shall be well mixed before use.
iv) Standared of opalescence:- Dilute 15 ml of the primary opalescent suspension to 1000ml of water. This suspension shall be freshly prepared and may be stored for almost 24h.
v) Reference suspension:- Prepare reference suspension in accordance with table. Mix and shake before use
Reference suspension 1 2 3 4
Standard of opalescence, volume 5 10 30 50
Water, volume 95 90 70 50
Table 3.4: Reference suspension
Expression of results
• A liquid is deemed to be clear, if it clarity is same as that of water or of the solvent use when examined under the condition described below, or if its opalescence is not more pronounced than the of reference suspension
•A liquid is deemed to be slightly opalescent if its opalescent is more pronounced than as described in 2, but not more pronounced than that of reference suspension 2
•A liquid is deemed to be opalescent if its opalescent is more pronounced than as described in 2, but not more pronounced that of reference suspension 3,
•A liquid is highly opalescent if its opalescence is more pronounced than as described in 3, but not more pronounced than that of reference suspension 4.
VI) Determination of UV absorbance
Determine the UV absorbance of the extract in a cell against the blank. The absorbance is determined in the range from 230nm to 360nm.
VII) Leaching studies
Migration of Plasticizers from different compositions of DINCH plasticized PVC was carried out using ethanol.
Reagents
Ethanol, volume traction in the range from 95.1% to 96.6%, density ρ in the range from .805g/ml to .8123g/ml.
Extraction solvent: ethanol: water mixture of density ranging from 0.9373g/ml to 0.9378g/ml as determined with a pycanometer.

Preparation of standard solution:
Solution 1: dissolve 1g of DINCH in ethanol and dilute to 100ml ethanol.
Solution 2: dilute 10ml of solution 1 to 100ml with ethanol.
Standard solution A to E:
Solution A: Dilute 10ml of solution 2 to 50ml with extractant solvent (DINCH content: 20mg/100ml)
Solution B: Dilute 5ml solution 2 to 50ml with extractant solvent (DINCH content: 10mg/100ml)
Solution C: Dilute 2.5 ml solution 2 to 50 ml with extractant solvent (DINCH content: 5mg/100ml)
Solution D: Dilute 1.25ml solution 2 to 50ml with extractant solvent (DINCH content: 5mg/100ml)
Solution E: Dilute 1ml solution 2 to 50 ml with extractant solvent (DINCH content: 5mg/100ml)
Calibration curve
Measure the maximum absorbance of the standard solution at 272nm, using the extraction solvent as the reference solution and plot a absorbance against DINCH concentration.
Extraction procedure
Fill the empty plastic container to half of the nominal capacity through the collecting tube with a volume of extraction solvent heated to 370 C. expel the air completely from the plastic container and seal the collecting tube. Immerse the filled plastic container in a horizontal position in water maintained at (37±1)0 C for (60±1) min with out shaking. Remove the plastic container from the water bath, invert it gently ten times and transfer the contents to a flask.
Measure the maximum absorbance at 272nm using the extractant solvent as the reference solution.
Expression of results
Determine the quantity of extractable DINCH by comparing the results obtained for the plastic container with the calibration curve of absorbance for the standard solution.


VIII) Fourier Transform Infrared Spectroscopy(FTIR)
Fourier transform infrared spectroscopy (FTIR) identifies chemical bonds in a molecule by producing an infrared absorption spectrum. The FTIR generates an infrared spectral scan of samples that absorb infrared light. FTIR is a spectroscopic technique in which infrared light is passed through a sample, which has the characteristic adsorption frequencies in the infrared region. This produces an infrared spectrum, which looks like a series of peaks and valleys on an X/Y graph. This technique is useful both for routine material verification / identification of polymers and identification of trace contaminates via the FTIR Microscope. The prepared sample was scanned in the range of 400 to 4000 cm -1 in a Nicolet 5700 FTIR Spectrometer. FTIR of PVC, DINCH AND DINCH plasticized PVC are taken.
2.6 Physical tests
I) Tensile test
Blood bag sheets having different compositions like 39, 40, 41,42,43,44 and 42 (modified the compounding principle )phr are characterized by using Universal testing machine (Shimadzu SES 1000) with 10 KN load cell and a constant crosshead speed of 20 mm/ min at 240 C. the tests are conducted according to the ASTM D 682. The specimen dimensions are according to the ASTM specifications. Tensile elongation and tensile strength measurements are among the most important indication of strength in a material. It is the measurement of the ability of a material to withstand forces that tends to pull it apart and to determine to what extent the materials stretches before breaking. Tensile modulus is an indication of the relative stiffness of material.
II) Differential Scanning Calorimetry (DSC)
Samples of different compositions (39, 40, 41, 42, 43,44 and 42 (modified the compounding principle ) were characterized by using the DSE Q10.differential scanning calorimetry or DSC is a thermoanalytical in which the difference in the amount of heat required to increase the temperature of a sample and reference are measured as a function of temperature. Both the sample and reference are maintained at the same temperature throughout the experiment. Generally, the temperature program for a DSC analysis is designed such that the sample holder temperature increases linearly as a function of time. The reference sample should have a well-defined heat capacity over the range of temperature s to be scanned. The main application of DSC is in studying phase transitions, such as melting, glass transitions, or exothermic decomposition. These transitions involve energy changes or heat capacity changes that can be detected by DSC with great sensitivity.
III) Hardness test
Shore-A durometer (Blue steel Engineers PVT.LTD) used for the hardness testing of samples as per the ASTM D 2240-97. The hardness test measures the resistance of a material to an indenter or cutting tool. The indenter is usually a ball, pyramid, or cone made of a material much harder than that being tested. A load is applied by slowly pressing the indenter at right angles to the surface being tested for a given period of time. An empirical hardness number may be calculated from knowledge of the load and the cross-sectional area or depth of the impression. Tests are never taken near the edge of a sample nor any closer to an existing impression. The thickness of the specimen should be at least ten and one half times depth of the impression.
IV) Water Absorption Test (ASTM D 570)
The test specimen in the form of a bar 76.2mm (3 in.) long by 25.4mm (1 in.) wide by the thickness of the material is cut form a pressed sheet of thickness 1.25± 0.15mm. It is then weighed. Then the specimen is immersed in distilled water at 50± 20 C for 24hrs.
At the end of 24 h, the specimens shall be removed from the water one at a time, all surface water wiped off with a dry cloth, and weighed. Difference between both weights gives water absorption.
V) Water Vapour Permeability Testing
Water Vapour transmission (WVTR) of the samples for 24 hrs were using an house setup. The technique used to measure water vapour transmission rate was a modification of wet cup method described by ASTM E 96-95. In this method test film covered a 100ml beaker filled with distilled water. The mass of water loss from the beaker was measured as a function of time and the WTVR was calculated as the steady state region using equations given as follows. Thickness of the sample was measured using a thickness guage at a minimum of 15 positions. The standard deviation of thickness for each specimen was less than 5%. A window of known area was cut from two sheets of aluminium foils and the samples were thoroughly fixed between them. Then the aluminium foils with the test sample was mounted on the beaker with the help of adhesive tape. A control set up was also made without the samples.
WVTR= Mass of H2O lost
Time × Area

Sp. WVTR= Mass of H2O lost x thickness
Time × Area


















Inside Oven RH -20%, T=370C

Fig 5: Schematic Representation diagram of the set up for WVTR studies.

VI) Transparency tests

Fill the empty plastics container to its nominal capacity with a volume of primary opalescent suspension diluted to an absorbance of .37 to .43 at 640nm (dilution factor about 1:16) as measured in a cell.
Primary opalascent solution as prepared as follows.
a) Dissolve 1g hydrazine sulfate in water and dilute to 100ml. Allow to stand for 4 to 6 hr.
b) Dissolve 2.5g of hexamethylenetetramine in 25 ml of water in a 100ml glass-stoppered flask
c) Primary opalescent solution is prepared by the addition to the 25 ml of hydrazine sulfate solution to the solution of hexamethylenetetramine. Mix both and allows standing for 24 hr.

VII) Gas Permeability studies
The Gas permeability measurements were made using samples of 90mm diameter and thickness 0.36nm samples were preconditioned according to the ASTM D 618-96. The gas permeability measurements were carried out using oxygen and carbon dioxide in a manomertric gas permeability tester (Model L – 100 Switzerland) at a temperature 230 C. Gas permeability of the container used for blood and blood components storage application is an important parameter. Gas permeability is important so that the living cells of the blood component, such as platelets, can exchange oxygen and carbon dioxide. This allows for the extent viability of the living blood components and longer storage.




Fig 7: Manometric Gas permeability Tester
Lyssy, L 100-5000


VIII) Test for Plasticizer Compatibility in PVC compounds under Humid conditions (D 2383)

Test specimens with one side having a surface area of 25 cm2 from a 0.75-mm(0.029-in.) thick smooth surface plastics sheet(60.05 mm (0.002-im.) is suspended from hooked over distilled water in closed containers so that they do not touch the water layer, sides of the container, or each other. Place the containers in the circulating-air oven at either 60- 6 10C (140 6 20F). Put covers on loosely until the containers come to temperature equilibrium, and then tighten covers. Remove the containers from the oven at specified intervals. Change in appearance is used for judging compatibility.






RESULTS AND DISCUSSIONS








Chapter 3
Results and discussions
In the present study the extruded sheets which are used for blood bags having different plasticizer concentrations like 39, 40, 41, 42, 43, 44 and 42 (modified the compounding principle) phr are characterized by using various chemical and physical tests. Plastic containers used for the storage of blood and its components should be chosen so as to minimize the leaching of chemical constituents into the products. So the oxidizable constituents, ammonia content, acidity or alkalinity, evaporation residue, turbidity and degree of opalescence should be within the limits. Blood bags are sterilized under the temperature of 1210C and also during the time of separation of blood components, centrifugation is done within the blood bag, so sufficient strength is required, in order to analysis its mechanical test like tensile, hardness etc were done. Clarity is also an important parameter. As transparency of blood bags is as essential requirement as it enables the user to observe the unwanted happenings like coagulation of blood and blood components or growth of microorganisms in the fluid stored in. Thermal analysis of blood sheets were done by DSC. In order to find the chemical bond in PVC, DINCH and DINCH plasticizer PVC and also to find the interaction among the above FTIR is done. Gas permeability is essential so that the living cells of blood components such as red blood cells and platelets can exchange oxygen and carbon dioxide, so gas permeability studies is also done. Water vapour transmission rate is also has to be with in the limit.












3.1 Chemical Test
Plastic containers used for the storage of blood and its components should be chosen so as to minimize the leaching of chemical constituent into the products. So the oxidizable constituents, ammonia content, acidity or alkalinity, evaporation residue, turbidity and degree of opalescence should be within the limits.
a) Residue on ignition
According to the ISO standard 3826 the maximum permissible residue for plasticized PVC is 1mg/g.
Sample (phr) Residue on ignition (mg/g)
39 0.008
40 0.003
41 0.012
42 0.006
43 0.003
44 0.007
42(modified the compounding ) 0.008
Table 3.1 Residue on ignition

The residues obtained in the above combinations of DINCH plasticized PVC is within the limit.

b) Determination of alkalinity
After the addition of 2 drops of phenolphthalein solution, 10ml of the test fluid no red colour appeared, however, on addition of less than 0.4 ml (i.e. 0.2ml) caustic soda red coloration occur. Hence alkalinity is within the range.

c) Determination of acidity
After the addition of 2 drops of phenolphthalein solution, 10ml of the test fluid no red colour appeared, however, on addition of less than 0.4 ml (i.e. 0.2) caustic soda red coloration occur .And on the addition of HCL red colour disappeared. And after the addition of 5 drops of methyl red solution, orange red colour appeared. Hence acidity is within the limit.

d) Determination of ammonia in the extract
The solution prepared using the extract is not more intense yellow colour than the reference solution. Since the extract is less intense yellow colour than the reference solution the NH3 for sheets is within the limit of 0.8mg/l.

e) Determination of turbidity and degree of Opalescence of the extract
The extract is slightly opalescent but not pronounced than that of reference suspension 2 (Table 3.4: reference suspension). So the test for the turbidity and opalescence is passed.

f) Evaporation residue

According to the ISO 3826 the evaporation of residue should be within the limit 5mg or 50mg/l.
Sample (phr) Weight of residue for 100ml (mg/l)
39 3.2mg
40 3mg
41 3.5mg
42 3mg
43 4mg
44 3.5mg
42 (modified the compounding ) 4mg

Table 3.2: Evaporation residue
In this test all the samples shows the evaporation of residue within the limit.

g) Oxidizable constituent in the extract:
The limit of oxidizable constituents in the extract is 1.5ml. Oxidizable constituents found for all the samples of different compositions are within the limit 1.5ml.




Samples(Phr) Oxidizable Constituents(ml)
39 0.4
40 0.3
41 0.7
42 0.5
43 0.5
44 0.7
42 (modified the compounding) 0.6



h) UV absorbance
According to the ISO standard 3826
Samples (phr) UV absorbance in the range
230nm 360nm
39 0.0690 0.001
40 0.087 0.001
41 0.042 0.010
42 0.089 0.004
43 0.160 0.011
44 0.185 0.012
42 (modified the compounding) 0.120 0.006
Table 3.4: UV absorbance







i) Leaching studies
It has found that values of plasticizer leaching for each formulation is within the limit and leaching is less than that of DEHP plasticizer.

Samples(phr) Plasticizer leaching(mg/100ml)
39 1.36
40 1.41
41 1.64
42 1.79
43 1.80
44 1.87
42(modified the compounding) .7mg (one day)
Table 3.5: plasticizer leaching




j) FTIR
The FTIR spectrum of PVC shows a peak at 687.7 cm -1 show C-C1 stretching vibrations. In addition to this characteristic band structure, the major feature of the PVC IR spectrum is CH2 scissors observed at 1425.5cm -1,the CH bending of the –CHC1- group at 1327.5cm-1 and 1245.5cm-1, the back bone –C-C- stretching [vCC] at 1096.4cm -1 , the CH2 rocking at 963.7cm -1 and the CH stretching of –CHC1- at 2917.2cm-1. And the IR spectrum of Di- isononyl-cyclohexane-1,2-dicarboxylate( DINCH) shows the peaks at C=O stretching at 1729.3cm-1 ,C-O stretching of ester group at 1244.1 cm-1 and CH2 at stretching 2925.5 cm-1 and 2954.8cm-1. CH bending in cyclohexane at 1454.9cm-1 and CH2 scissoring at 991cm-1 . And from the spectrum of DINCH plasticized PVC we can analyze that there is no shift for the above peaks mentioned. So there is no chemical interaction between the plasticizer and PVC




Fig3.1: FTIR Spectrum showing PVC, DINCH plasticizer and plasticized PVC



3.2 Test for plasticizer compatibility in PVC Compounds under Humid Conditions (D 2383)
This practice provides an accelerate method for determining the stability of PVC Compounds with respect to plasticizer compatibility under humid conditions the visual and tactile ratings are used for judging plasticizer compatibility and surface of sheet observed was dry hence there was no evidence on plasticizer extrudation. If there is any exudation shows the extraction of plasticizer on humid conditions.




3.3 Differential Scanning Calorimetry:
In differential scanning calorimetry (DSC), the thermal properties of a sample are compared against a standard reference material. In DSC glass transition temperature of various compositions like 39, 40, 41,42,43,44 and 42 (modified the compounding) phr etc. were analyzed.



Fig3.2: DSC graph

The glass transition temperature decreases as the plasticizer concentration increases. When the mixture of PVC and plasticizer heated, different transitions are observed. Glass transition depends on the final temperature reached, which corresponds to the fusion and gelation process. When the highest temperature reached by the sample is high, there appears on temperature, which corresponds, to the glass transition temperature of plasticized PVC. Experiments carried out by Gomez-Ribelles et al revealed that Tg of PVC is splited into two different glass transition temperature close to one another. But only one of them is interact with PVC.


Sample Glass Transition (Tg)
39 -14.75
40 -19.53
41 -20.65
42 -21.30
43 -22.69
44 -24.09
42(change the compounding principle) -21.06
Table 3.6: Glass transition temperature

When the plasticizer is added to the PVC, the glass temperature which is able to adsorb the plasticizer diminishes, while the Tg of other phase remain the same .the extent to which DSC. According measures the plasticizer decrease the glass transition temperature to the free volume theory the addition of plasticizer to the polymer creates a free volume. The free volume is low and the molecules cannot move past each other very easily. This makes the polymer rigid and hard. When the polymer is heated to above the glass transition temperature, tg, the thermal energy and molecular vibrations create additional free volume, which allows the polymer molecules to move past each other rapidly. This has the effect of making the polymer system more flexible and rubbery. Free volume can be increased through modifying the polymer backbone, such as by adding more side chains or end groups. When small molecules such as plasticizer are added, this also lowers the TG by separating the PVC molecules, adding free volume and making the PVC soft and rubbery. Molecules of PVC can then rapidly move past each other.

3.4 Water Absorption test
As per the ASTM D570 the water absorption is within the limit 0.07-0.75% for all the samples. Various polymeric materials are susceptible to water absorption during its life exposure. This may cause dimensional instability with property degradation and ultimately lead to failure. This test was to evaluate materials by exposing specimens to water for different time & temperature profiles. Testing is conducted on specimens that are submersed in water and a before & after weight change is documented. Depending on the application of the product, certain levels of moisture are accepted. The percent increase in weight of material after exposure to water under specified conditions. Water absorption can influence mechanical and length of exposure can affect the amount of water absorbed. As PVC doesn’t absorb water due to the strong interaction between Cl-H bonds. According too the free volume theory as the plasticizer is added to PVC there arise a free volume. This may be the reason of the absorption of water content.
Samples (phr) Water absorption ( % )
39 0.003
40 0.003
41 0.003
42 0.005
43 0.004
44 0.005
42(modified the compounding) 0.004
Table 3.7: Water absorption test

3.5 Tensile Test:
Strength refers to the ability of a structure to resist loads without failure. Failure may occur by rupture because of excessive stress or may take place owing to excessive deformation. Tensile properties include the resistance of materials to pulling or stretching forces. The amount of force required to break a material and the amount it extends before breaking are important properties. The tensile modulus is the ratio to elastic strain in tension. A high tensile modulus means that the material is rigid-more stress is required to produce a given amount of strain.


Fig 3.4: Force- Displacement curve

Samples(phr) Tensile modulus(N/mm2) Tensile strength(N/mm2) Tensile elongation (%)
39 9.7 14 >300
40 9.5 13.8 >300
41 9.2 13.7 >300
42 8.7 13 >300
43 7.3 12.87 >300
44 7.0 12 >300
42(modified the compounding ) 8.5 13.5 >300
Table 3.8: Tensile test

It shows that there is small increase in tensile modulus results that the material is rigid as the plasticizer concentration increases the tensile modulus decreases showing that its flexibility increases as the plasticizer loading increases.

3.6 Hardness test
Hardness value of the sample is given in the figure. From the figure we can see that the hardness decreases with the increase of plasticizer content. This is due to the increase in flexibility and softness.PVC, has a polyhalogenated chain with chlorine atoms covalently linked to atoms of carbon, providing thus many points of dipolar interaction along its chain with give rise to strong interchain interaction and consequent rigidity of the polymeric material.
Samples (phr) Hardness (Shore A)
39 76
40 74
41 72
42 70
43 68
44 64
42(modified the compounding) 70
Table 3.9: Hardness test
Plasticizing additives break interchain dipole interaction providing a material with mobility and flexibility characteristics of a polymer with less interchain interaction. Plasticizers are clear, organic liquid material that are added to PVC formulation to obtain flexible products. The use of plasticizer involves the introduction of a low molecular weight substance into the structure that act as a molecular lubricant, physically separating the chains and allowing them some mobility, thus giving the flexibility. The larger the volume of the plasticizer, greater the flexibility and softness. Therefore the hardness decreases as the flexibility increases.
3.7 Transparency
Transparency of blood bags is as essential requirement as it enables the user to observe the unwanted happenings like coagulation of blood and blood components or growth of microorganisms in the fluid stored in. Its transparency reduces potentially life- threatening mistakes with medicines and allows healthcare workers to see immediately if a fluid is running low. The blood bag should be sufficiently transparent or have sufficient contact clarity so that during typical use, a technician, nurse, physician or other person will be able to visibly identify the contents of the bag and identify pertinent blood characteristics including quality (particularly colour) and quantity.
Samples (phr) Absorbance(nm)
39 .373
40 .378
41 .380
42 .382
43 .385
44 .389
42(modified the compounding) .384
Table 3.10: Transmittance test

3.8 Water Permeability Testing
The technique to measure water vapour transmission was a modification of wet cup method described by ASTM 95-96. The mass of water loss from the dish found as a function of time and the water transmission rate was calculated from the steady state region. It is expressed as cc.mm/m2 time. Water vapour transmission is a measure of how much water vapour will pass through a material per unit area per unit time.
Water vapour transmission rate of the material for blood storage purpose should be minimal. Loss of water from the blood and blood components adversely affect the composition and thereby the stability of the body fluids inside the container.
Sample(phr) Water vapour transmission(g/m2/day)
39 0.120
40 0.127
41 0.140
42 0.137
43 0.141
44 0.151
42(modified the compounding) 0.140
42(DEHP) 0.263
Table 3.11: water vapor transmission test
3.9 Gas permeability studies
Gas permeability of the container used for blood and blood components are very important parameter. Gas permeability is essential so that the living cells of blood components such as red blood cells and platelets can exchange oxygen and carbon dioxide. This allows for the extended viability of the living blood component and longer storage times. Gas permeability was carried at a temperature of 230C with oxygen and carbon dioxide gases
Blood collected in bags containing buffered anticoagulants such as ACD (acid citrate dextrose) or CPD (citrate- phosphate dextrose). Platelet concentrates also contain glucose (dextrose) as consequences of the process by which they are collected. During the storage the platelet converts glucose to lactic acid and carbon dioxide, which lowers the PH.

Sample (phr) Gas permeability (ml/m2 per day)
O2 CO2
39 658 3357
40 735 3367
41 757 3387
42 770 3423
43 767 3443
44 780 3467
42(modified the compounding) 1250 4050
Table 3.12: Gas permeability studies

Murphy and Gardner measured CO2 and O2 pressures in various PVC bags containing platelet concentration and observed that the drop in pH was greater in thicker bags the walls of the bags. The pH of storage is critical. The pH falls during the storage due to the production of lactic acid and carbon dioxide. Platelets undergo disc- to-sphere transformation as the pH falls from its initial value of 7.0; they become swollen and irreversibly damaged at pH less than 6.2. This pH change limits the duration of storage. A high pH (>7.8) is also associated with loss of viability. Oxygen is known to suppress the conversion of glucose to lactic acid. So permeability of CO2 and O2 is important. In medical field the material, which is stored for the collection and storage of body fluids, should have more CO2 produced by platelets and other cells inside the container may dissolve in the fluid cause the fluid pH to drop and which in turn decreases the pH of the fluid stored in and may damage the platelets and other cells of the fluid. It is seen that the gas permeability increases as the plasticizer loading increases.


























4. CONCLUSION


After carrying out experimental study it was found that blood bags made up of PVC using DINCH plasticizer concentration 42phr (modified the compounding principle) shows experimental value within the permissible range as per the standards. The leaching value of the sample 42 phr (modified the compounding) is very less as compared to the DEHP Blood Bag. Chemical tests like determination of oxidizable constituents, determination of ammonia, determination of alkalinity, determination of acidity, determination of evaporation residue etc. shows all values within the permissible range. Physical tests like tensile strength, transparency, gas permeability values are within the permissible range.

Water absorption test shows that there is no significant change in water absorption value with change in phr of the plasticizer; all values are in permissible range.
A tensile result shows that there is change in the tensile strength, with increase in the concentration of plasticizer tensile strength, but all results are in the permissible range.
Gas permeability like oxygen and carbon dioxide shows all values in permissible range. From above results it is concluded that plasticizer DINCH has well- balanced technical profile and is a safe alternative for the DEHP/DOP for blood bag manufacturing.


















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