{{No footnotes, date=July 2019 Polyanhydrides are a class of

biodegradable Biodegradation is the breakdown of organic matter by microorganisms, such as bacteria and fungi. It is generally assumed to be a natural process, which differentiates it from composting. Composting is a human-driven process in which biodegradati ...

polymer A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...

s characterized by

anhydride An organic acid anhydride is an acid anhydride that is an organic compound. An acid anhydride is a compound that has two acyl groups bonded to the same oxygen atom. A common type of organic acid anhydride is a carboxylic anhydride, where the pa ...

bonds that connect

repeat unit In polymer chemistry, a repeat unit or repeating unit (or mer) is a part of a polymer whose repetition would produce the complete polymer chain (except for the end-groups) by linking the repeat units together successively along the chain, like the ...

s of the polymer

backbone chain In polymer science, the polymer chain or simply backbone of a polymer is the main chain of a polymer. Polymers are often classified according to the elements in the main chains. The character of the backbone, i.e. its flexibility, determines the ...

. Their main application is in the medical device and pharmaceutical industry.

In vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

, polyanhydrides degrade into non-toxic diacid

monomers In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification M ...

that can be metabolized and eliminated from the body. Owing to their safe degradation products, polyanhydrides are considered to be biocompatible.

Applications

The characteristic

bonds in polyanhydrides are water-labile (the polymer chain breaks apart at the anhydride bond). This results in two carboxylic acid groups which are easily

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

and

biocompatible Biocompatibility is related to the behavior of biomaterials in various contexts. The term refers to the ability of a material to perform with an appropriate host response in a specific situation. The ambiguity of the term reflects the ongoing de ...

Biodegradable Biodegradation is the breakdown of organic matter by microorganisms, such as bacteria and fungi. It is generally assumed to be a natural process, which differentiates it from composting. Composting is a human-driven process in which biodegradati ...

polymers A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic an ...

, such as polyanhydrides, are capable of releasing physically entrapped or encapsulated drugs by well-defined kinetics and are a growing area of medical research. Polyanhydrides have been investigated as an important material for the short-term release of drugs or bioactive agents. The rapid degradation and limited mechanical properties of polyanhydrides render them ideal as controlled

drug delivery Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect. Principles related to d ...

devices. One example, Gliad

is a device in clinical use for the treatment of

brain cancer A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondar ...

. This product is made of a polyanhydride wafer containing a chemotherapeutic agent. After removal of a

cancerous Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Poss ...

brain tumor A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and seconda ...

, the wafer is inserted into the brain releasing a

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

agent at a controlled rate proportional to the degradation rate of the

. The localized treatment of

protects the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

from high levels of

radiation In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a material medium. This includes: * ''electromagnetic radiation'', such as radio waves, microwaves, infrared, visi ...

. Other applications of polyanhydrides include the use of unsaturated polyanhydrides in bone replacement, as well as polyanhydride copolymers as vehicles for

vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...

delivery.

Classes

There are three main classes of polyanhydrides: aliphatic, unsaturated, and aromatic. These classes are determined by examining their R groups (the chemistry of the molecule between the

bonds).

Aliphatic In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, or ...

polyanhydrides consist of R groups containing

carbon Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with o ...

atoms bonded in straight or branched chains. This class of

is characterized by a crystalline structure, melting temperature range of 50–90 °C, and solubility in chlorinated hydrocarbons. They

degrade Degradation may refer to: Science * Degradation (geology), lowering of a fluvial surface by erosion * Degradation (telecommunications), of an electronic signal * Biodegradation of organic substances by living organisms * Environmental degradation ...

and are eliminated from the body within weeks of being introduced to the bodily environment. Unsaturated polyanhydrides consist of

organic Organic may refer to: * Organic, of or relating to an organism, a living entity * Organic, of or relating to an anatomical organ Chemistry * Organic matter, matter that has come from a once-living organism, is capable of decay or is the product ...

R groups with one or more double bonds (or

degrees of unsaturation In the analysis of the molecular formula of organic molecules, the degree of unsaturation (also known as the index of hydrogen deficiency (IHD), double bond equivalents, or unsaturation index) is a calculation that determines the total number of r ...

). This class of

has a highly crystalline structure and is insoluble in common organic solvents.

Aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

polyanhydrides consist of R groups containing a

benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...

(aromatic) ring. Properties of this class include a crystalline structure, insolubility in common organic solvents, and melting points greater than 100 °C. They are very

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...

and therefore degrade slowly when in the bodily environment. This slow

degradation Degradation may refer to: Science * Degradation (geology), lowering of a fluvial surface by erosion * Degradation (telecommunications), of an electronic signal * Biodegradation of organic substances by living organisms * Environmental degradation ...

rate makes

aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

polyanhydrides less suitable for drug delivery when used as homopolymers, but they can be copolymerized with the

aliphatic In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, or ...

class to achieve the desired degradation rate.

Synthesis and characterization

Polyanhydrides are synthesized using either melt condensation or solution polymerization. Depending on the synthesis method used, various characteristics of polyanhydrides can be altered to achieve the desired product. Characterization of polyanhydrides determines the structure, composition, molecular weight, and thermal properties of the molecule. These properties are determined by using various light-scattering and size-exclusion methods.

Polymerization

Polyanhydrides can be easily prepared by using available, low cost resources. The process can be varied to achieve desirable characteristics. Traditionally, polyanhydrides have been prepared by melt condensation polymerization, which results in high

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

polymers. Melt condensation polymerization involves reacting

dicarboxylic acid In organic chemistry, a dicarboxylic acid is an organic compound containing two carboxyl groups (). The general molecular formula for dicarboxylic acids can be written as , where R can be aliphatic or aromatic. In general, dicarboxylic acids show ...

monomers with excess

acetic anhydride Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula (CH3CO)2O. Commonly abbreviated Ac2O, it is the simplest isolable anhydride of a carboxylic acid and is widely used as a reagent in organic synthesis. It is a col ...

at a high temperature and under a vacuum to form the polymers.

Catalysts Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

may be used to achieve higher molecular weights and shorter reaction times. Generally, a one-step synthesis (method involving only one reaction) is used which does not require purification. There are many other methods used to synthesize polyanhydrides. Some of the other methods include: microwave heating, high-throughput synthesis (synthesis of polymers in parallel), ring opening polymerization (removal of cyclic monomers), interfacial condensation (high temperature reaction of two monomers), dehydrative coupling agents (removing the water group from two carboxyl groups), and solution polymerization (reacting in a solution).

Chemical structure and composition analysis

The

chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of at ...

and composition of polyanhydrides can be determined by H¹

NMR Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

spectroscopy Spectroscopy is the field of study that measures and interprets the electromagnetic spectra that result from the interaction between electromagnetic radiation and matter as a function of the wavelength or frequency of the radiation. Matter wa ...

. This will determine the class of polanhydride (aromatic, aliphatic, or unsaturated) as well as the structural features of the

. For example, the analysis of

nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

(

) peaks allows one to determine if a copolymer has a random or block-like structure.

Molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

and degradation rate can also determined by

Molecular weight analysis

Aside from using

to determine a polyanhydride’s molecular weight,

gel permeation chromatography Gel permeation chromatography (GPC) is a type of size-exclusion chromatography (SEC), that separates analytes on the basis of size, typically in organic solvents. The technique is often used for the analysis of polymers. As a technique, SEC was firs ...

(GPC), and

viscosity The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water. Viscosity quantifies the inte ...

measurements may also be used.

Thermal properties

Differential scanning calorimetry Differential scanning calorimetry (DSC) is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature. Both the sample and ref ...

(DSC) is used to determine the thermal properties of polyanhydrides. Glass transition temperature, melting temperature, and

heat of fusion In thermodynamics, the enthalpy of fusion of a substance, also known as (latent) heat of fusion, is the change in its enthalpy resulting from providing energy, typically heat, to a specific quantity of the substance to change its state from a so ...

can all be determined by DSC. Crystallinity of a polyanhydride can be determined using DSC,

Small angle X-ray scattering (SAXS) Small-angle X-ray scattering (SAXS) is a small-angle scattering technique by which nanoscale density differences in a sample can be quantified. This means that it can determine nanoparticle size distributions, resolve the size and shape of (monodis ...

Nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

(NMR), and

X-ray diffraction X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...

Degradation

The erosion and degradation of a

describe how the polymer physically loses mass (

s). The two common erosion mechanisms are surface and bulk erosion. Polyanhydrides are surface eroding polymers. Surface eroding polymers do not allow water to penetrate into the material. They erode layer by layer, like a lollipop. The

backbone with hydrolytically labile anhydride linkages allows

hydrolytic Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

degradation to be controlled by manipulating the

composition. This manipulation can occur by adding a

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are no ...

group to the polyanhydride to make a copolymer. Polyanhydride copolymers with

groups exhibit bulk eroding characteristics. Bulk eroding polymers take in water like a sponge (throughout the material) and erode inside and on the surface of the polymer. Drug release from bulk eroding

is difficult to characterize because the primary mode of release from these polymers is

diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...

. Unlike surface eroding polymers, bulk eroding polymers show a very weak relationship between the rate of polymer degradation and the rate of drug release. Therefore, the development of surface eroding polyanhydrides incorporated into the bulk eroding polymers is of increased importance.

Biocompatibility

Biocompatibility Biocompatibility is related to the behavior of biomaterials in various contexts. The term refers to the ability of a material to perform with an appropriate host response in a specific situation. The ambiguity of the term reflects the ongoing de ...

and

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

of a polymeric material is evaluated by examining

systemic Systemic fundamental to a predominant social, economic, or political practice. This refers to: In medicine In medicine, ''systemic'' means affecting the whole body, or at least multiple organ systems. It is in contrast with ''topical'' or ''loc ...

toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

responses, local tissue responses,

carcinogenic A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...

and

mutagenic In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in ...

responses, and

allergic Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

responses to the material's degradation products. Animal studies are conducted to test the polymer’s effect on each of these negative responses. Polyanhydrides and their degradation products have not been found to cause significant harmful responses and are considered to be

References

*Domb, A., Amselem, S., Langer, R., and Manair, M. “Chapter 3: Polyanhydrides as Carriers of Drugs.” Biomedical Polymers Designed –to –Degrade Systems. Hanser Publishers: Munich, Vienna, NY, 1994. *Kumar, N., Langer, R., and Domb, A. “Polyanhydrides: an overview.” Advanced Drug Delivery Reviews, 2002. *“Polyanhydride Synthesis Techniques.” Wyatt Technology Corp.

*Tamada, J. and Langer, R. “The development of polyanhydrides for drug delivery applications.” Journal of Biomaterials Science, Polymer Ed. Vol. 3, No. 4, pp. 315–353, 1992. *Torres, M. P.; Determan, A. S.; Malapragada, S. K.; Narasimhan, B. “Polyanhydrides.” Encyclopedia of Chemical Processing. 2006. *B.M. Vogel, S.K. Mallapragada, and B. Narasimhan, “Rapid Synthesis of Polyanhydrides By Microwave Polymerization”, Macromolecular Rapid Communications 25, 330-333, 2004. *B.M. Vogel, S.K. Mallapragada, “Synthesis of Novel Biodegradable Polyanhydrides Containing Aromatic and Glycol Functionality for Tailoring of Hydrophilicity in Controlled Drug Delivery Devices”, Biomaterials, 26, 721-728, 2004. *B.M. Vogel, Naomi Eidelman, S.K. Mallapragada and B. Narasimhan, “Parallel Synthesis and Dissolution Testing of Polyanhydride Random Copolymers”, ACS Combinatorial Science, Journal of Combinatorial Chemistry, 7, 921-928, 2005. *B.M. Vogel and S.K. Mallapragada, “The Synthesis of Polyanhydrides”, in Handbook of Biodegradable Materials and their Applications, edited by S.K. Mallapragada and Balaji Narasimhan, ASP Publishers, Vol. 1, 1-19, 2005. Biomaterials Biological engineering Polymers