- Email: [email protected]
Poly(vinylpyrrolidone)
9
Poly(vinylpyrrolidone)
Rajendra Awasthi1, Satish Manchanda2, Poppy Das3, Vinodhini Velu3, Himaja Malipeddi3, Kavita Pabreja4, Terezinha D.J.A. Pinto5, Gaurav Gupta6 and Kamal Dua7,8 1 NKBR College of Pharmacy and Research Centre, Meerut, India, 2Delhi Institute of Pharmaceutical Sciences and Research University, New Delhi, India, 3VIT University, Vellore, India, 4University of Newcastle, Newcastle, NSW, Australia, 5University of Sa˜o Paulo, Sa˜o Paulo, Brazil, 6School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, India, 7University of Technology Sydney, Sydney, NSW, Australia, 8 Shoolini University, Solan, India
9.1
Introduction
Poly(vinylpyrrolidone) or PVP (Fig. 9.1) is the first polymerized product of Nvinylpyrrolidone produced by a free radical mechanism. Low and medium grades of PVP forms pharmaceutical grade povidone powders. The US Food and Drug Administration has approved PVP for pharmaceutical applications and it is considered safe. During the Second World War, PVP was used as a blood plasma substitute. However, its oral administration has been withdrawn due to the accumulation of drugs within the body. Based on the degree of polymerization, it is synthesized in two different forms: 1. Soluble PVP (Povidone) Povidone is a polymerization product of N-vinylpyrrolidone in water or 2-propanol and was patented in 1939. Its molecular weight ranges from 8000 to 10000 daltons. It is one of the widely used pharmaceutical excipients and well known as a popular topical disinfectant called Povidone-iodine. 2. Insoluble PVP (Crospovidone) The molecular weight of Crospovidone is greater than 700,000 daltons. It is obtained by a physical cross-linking of PVP with a bifunctional monomer in the presence of alkali hydroxide at 100 C in water. Crospovidone is extensively used as an ideal disintegrant in tablet formulation and to hydrophylize insoluble constituents for selective adsorption and complex formation with a wide range of compounds (see also Fig. 9.2). H3C n N
CH3
O
Figure 9.1 Structure of poly(vinylpyrrolidone). Engineering of Biomaterials for Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-08-101750-0.00009-X © 2018 Elsevier Ltd. All rights reserved.
256
Engineering of Biomaterials for Drug Delivery Systems
Alk.hydroxide 100°C
N-Vinyl pyrrolidone
Bifunctional monomer
N-Vinyl pyrrolidone + Bifunctional monomer
Insoluble PVP or crospovidone
Figure 9.2 Flowchart presenting the production process of insoluble PVP or crospovidone. O
O
OH
HO
O
N
2H 2
Polymerization
OH
HO
H2
O O
NH3 H 2O
H N
O O
N
Figure 9.3 Synthesis of PVP by the reaction of acetylene with formaldehyde.
9.2
Synthesis of poly(vinylpyrrolidones)
Poly(vinylpyrrolidone) is synthesized via a free radical polymerization reaction. The reaction of acetylene with formaldehyde yields 1,4-butine diol (Fig. 9.3). The 1,4-butine diol is hydrogenated to butane diol which undergoes oxidative cyclization to yield butyrolactone. In the presence of ammonia, butyrolactone yields pyrrolidone and introduction of the vinyl group produces the vinylpyrrolidone substance (Fig. 9.3). Many other approaches have also been reported in respect to the polymerization of vinylpyrrolidone to a polyvinylpyrrolidone polymeric substance. Among these, the radical polymerization approach is reported to be significant method with a greatest degree of polymerization [1].
Poly(vinylpyrrolidone)
257
Step-I H 2O 2
Heat
Step-II
O OH
OH
OH
H HO H
H
N
H
H N O
H Step-III O N
H
O OH H
H
N
O H
H H
H
N H
O
H H HO H
N H
Figure 9.4 Synthesis of PVP by radical polymerization reaction.
The reaction mixture consisting of a monomeric substance (vinylpyrrolidone), free radical initiator (Azobisbutyronitrile), solvent (dioxane), and an inhibitor (2,2,6,6-tetramethylpiperidyl-1-oxyl) [2,3]. Polymerization using hydrogen peroxide as an initiator in aqueous media is commonly recommended to generate polymers (Fig. 9.4). The hydroxy radicals produced from the initiator molecule form the end group of the polymer. The molecular weight of polymer can be controlled by varying concentrations of hydrogen peroxide unit. The formation of pyrrolidone impurity is the major limitation of this method [4]. When a polymerization reaction is carried out using organic peroxides such as di-tertiary-butyl peroxide or dicumyl peroxide in organic solvents like alcohols, or toluene, it is the solvent radicals that acts as an initiator of polymerization reaction. These solvent radicals are produced through the hydrogen abstraction by the alkoxy radicals formed from the peroxides [1]. The poly(vinylpyrrolidone) produced in organic solutions were found to be more stable and no pyrrolidone impurity formation was observed as in case of polymerization performed using aqueous solvents with H2O2 as an initiator (Fig. 9.5). Keeping aside the advantages, preparation of poly(vinylpyrrolidone) by the radical polymerization method remains challenging due to a number of limitations such as the production of broad molecular weight distribution and no well-defined functionally terminated poly(vinylpyrrolidones). To overcome these limitations, polymerization of N-vinylpyrrolidone by atom transfer radical polymerization (ATRP) was reported by Lu et al., in 2007. Herein, to perform (ATRP), methyl 2-chloropropionate was used as an initiator of polymerization using 5, 5, 7, 12, 12, 14hexamethyl-1, 4, 7, 11-tetra-azacyclo-tetradecane (Me6Cyclam) as a ligand in the presence of 1, 4-dioxane and i-PrOH. The copper chloride (I) and (II) were used as a catalyst in this reaction. In this method, the molecular weight of synthesized poly
258
Engineering of Biomaterials for Drug Delivery Systems
Heat
Step-I
R 1 OOR 2
Step-II
R 1O
ROH solvent
Step-III
RO
N H
R 1O
R 2O R 1 OH
RO
H RO
H H
Step-IV
O
N H RO
H H
O
N H
H H
O
N
O
H RO
H H
N H
H
O H
H H
Figure 9.5 Synthesis of PVP by polymerization reaction using organic peroxides.
(N-vinylpyrrolidone) increased rapidly at the beginning of the reaction but leveled off at about 8900 g/mol. The prepared polyvinylpyrrolidone had a polydispersity index between 1.2 and 1.38 [5].
9.3
O
N
Polymer characteristics with special emphasis on drug delivery
9.3.1 General properties of PVP PVP is high polarity/proton acceptor, amphiphilic, and linear nonionic polymer. It is compatible with a variety of resins and electrolytes. It is a physiologically inert material. It forms hard, transparent, glossy, oxygen-permeable, adhesive and cohesive film. It is hygroscopic in nature and not suitable for thermoplastic processing. It is soluble in water and other polar solvents, but insoluble in esters, ethers, ketones, and hydrocarbons. PVP forms cross-linked matrix after cross-linking reaction with a variety of cross-linking agents [6].
9.3.2 Physical properties of PVP PVP is a cross-linked homopolymer (formed by polymerizing a single monomer) of pure vinylpyrrolidone. It has a slightly foul smell. In solution, it has brilliant wetting properties and readily forms a film, which makes it a coating agent or an
Poly(vinylpyrrolidone)
259
additive for coatings. PVP is soluble in water and other polar solvents, e.g., various alcohols, such as methanol and ethanol, as well as in other exotic solvents such as the deep eutectic solvent formed by urea and choline chloride (Relin) [7]. Commercialized PVP is free flowing, white powder, or solids with its content in the mass fraction of 20%, 30%, 45% and 50% aqueous solution. PVP has moisture equilibrium of 1/3 of the relative humidity of the environment.
9.3.2.1 Molecular weight The molecular weight of PVP depends on the method used to synthesize the polymer. PVP has a molecular weight range from 2500 to 2,900,000 daltons. As, it is formed of a series of different chain length polymers, its molecular weight is expressed as an average of different molecular weights of various chain length units that comprise the polymer [8].
9.3.2.2 Viscosity The K-values assigned to different grades of PVP represent a function of the degree of polymerization, average molecular weight and intrinsic viscosity. The K-values derived from the viscosity measurements can be calculated using following formula: log
ηrel 75K02 5 1 K0 C 1 1 1:5K02
K 5 1000K0
(9.1) (9.2)
where ηrel is the viscosity of solution compared with solvent, C is the concentration in g/100 mL solution, and K is the 1000K0. The K-value calculated by Fikentscher’s equation to measure viscosity is accepted worldwide by pharmacopoeia and other authorities for PVP. Viscosity does not vary significantly over a wide range of pH, but increases in the presence of concentrated hydrochloric acid. The polymer precipitates in presence of strong caustic solutions; however, the precipitate can redissolve on dilution with water. The density of PVP polymer water solution changes slightly with an increase in polymer concentration. It is recommended to investigate the effect of concentration and temperature on the products comprising of PVP [9].
9.3.3 Chemical properties PVP stored at normal conditions, i.e., dry PVP is quite stable and does not easily undergo a chemical reaction. PVP solution that has undergone mildew treatment is also stable. When heated up to 150 C or mixed with ammonium persulfate to heat at 90 C for 30 minutes, PVP is exchanged and it becomes a water-insoluble compound. In the presence of a dichromate-oxidizing agent or an azo compound, when
260
Engineering of Biomaterials for Drug Delivery Systems
PVP solution is exposed to light, it becomes a gel. Heating of PVP solution in the presence of a strong base (such as trisodium phosphate or sodium silicate) leads to its precipitation. PVP can form complexes with different compounds. For example, the complexes of PVP with iodine are very stable and have a good bactericidal effect and reduced toxicity. The addition of copolymers of the polyacrylic acid, methyl vinyl ether, or tannic acid and maleic acid to the aqueous solution of PVP generates a complex that is insoluble in water, ketones, and alcohols. But, when treated with a base for neutralization, the polyacid can reverse the reaction. Complexity between PVP and drugs, toxins, or toxic chemicals can decrease their toxicity. Some dyes can also form a strong complex with PVP, which is the base for using PVP as a dye-bleaching agent. PVP complexes can be easily removed by filtration due to its insolubility.
9.3.3.1 Stability PVP powder can be stored under ordinary conditions without undergoing degradation and decomposition. However, as it is hygroscopic in nature, appropriate precautions must be taken to prevent moisture absorption. PVP films are chemically stable and moisture acts as a plasticizer. The water equilibrium content of PVP films or solid PVP varies linearly with respect to relative humidity. PVP is quite stable to heat, however; it should not be exposed to extreme temperatures. PVP remains stable on heating repeatedly at 110 130 C at short intervals. Nevertheless, when exposed to a temperature of 150 C, a decrease in water solubility and darkening in color was observed. Aqueous PVP is stable for a long time, but exposure to molds must be prevented. Suitable preservatives may be added to PVP films or solutions after appropriate testing. PVP may also be sterilized by steam if it does not affect its properties. The addition of small amounts of acids or bases to PVP can cause large changes in pH [6].
9.3.3.2 Solubility PVP is freely soluble in cold water and many organic solvents such as alcohols, amines, chloroform, ethylene dichloride, methylene chloride, and nitroparaffins. It is insoluble in ethers, esters, ketones, hydrocarbons, and some chlorinated hydrocarbons. Desiccated PVP, comprising of less than 0.5% water, is soluble in dioxanes and ketones. Anhydrous PVP is soluble in CHX2 type of propellants and in various other chlorofluoroalkanes in case alcohol is used as a cosolvent. Similarly, PVP can be dissolved in hydrocarbons to prepare dilute solutions by using cosolvents such as nonylphenol, butanol, or N-methyl-2-pyrrolidone [6].
9.3.3.3 Compatibility PVP exhibits a high degree of compatibility in film as well as solution form, with natural and synthetic resins, most inorganic salts and many other chemicals [6].
Poly(vinylpyrrolidone)
261
9.3.4 Biological properties 9.3.4.1 Complex formation PVP forms complexes with many substances resulting in either solubilization or precipitation. PVP can cross-link with polyacids such as tannic acid or polyacrylic acid to form complexes that are soluble in dilute alkali but are water- or alcoholinsoluble. Ammonium persulfate forms a gel with PVP in 30 minutes at a temperature of 90 C. These gels are considerably insoluble in large quantities of water or salt solutions and are thermoreversible. The same effect is observed when more alkaline sodium phosphates are used. When PVP gels are dried at mild conditions, their uniform structure and swelling capacity are retained. Pyrogallol and resorcinol precipitates PVP from aqueous solutions, however, such complexes can be redissolved in water. PVP is insoluble in the presence of diazo compounds, oxidizing agents, and actinic light. Treatment of PVP with a strong alkali at 100 C permanently insolubilizes it. Heating of PVP at 150 C leads to the cross-linking of PVP. PVP acts as a binding agent in tablets [10,11]. In comparison to other binders PVP produces harder granulates with low friability and good flowability [12]. It also increases the dissolution of the active ingredient, e.g., acetaminophen (paracetamol) tablets formulated with PVP as a binder released the drug much quickly than tablets prepared using hydroxypropyl cellulose or gelatin as a binder [13]. Many germicidal products such as bisphenols and chlorinated phenols, when combined with PVP, exhibit reduced toxicity and intensity of skin reactions while retaining their germicidal activity. Other chemicals such as nicotine, formamide, and potassium cyanide exhibited reduced oral toxicity in the presence of a PVP solution. PVP copolymers are also used to improve the bioavailability of poorly soluble drugs such as tolbutamide, indomethacin and nifedipine [14 17]. PVP also provides stability to the tablet formulations and it may be combined with other reagents to obtain soft clear gelatin capsules of insoluble drugs.
9.3.4.2 Film-forming property The unmodified dry films of PVP are transparent, clear, hard, and glossy in appearance. The use of different solvent systems such as ethanol, chloroform, water, and ethylene dichloride while casting the films does not affect the appearance of the film. The absorbed moisture by PVP acts as plasticizer. Several commercial modifiers are added to control the brittleness or tackiness and the hygroscopic nature of PVP. Shellac, cellulose acetate propionate, and carboxymethyl cellulose can decrease the tackiness, whereas diethyl alcohol, sorbitol, and glycerin increase the tackiness. Ten percent arylsulfonamide-formaldehyde resin makes the PVP film tack-free over all ranges of relative humidity [18,19].
9.3.4.3 Protective-colloid action The addition of small quantities of PVP efficiently stabilizes suspensions, emulsions, and dispersions. PVP can also protect the lyophobic colloids, which do not
262
Engineering of Biomaterials for Drug Delivery Systems
possess significant affinity for the medium. PVP can absorb on the surface of the colloidal particles as a thin layer, which prevents contact, and overcomes the tendency to form a continuous phase. Low molecular weight PVPs use as an effective dispersant for low-bulk-density solids in aqueous media such as protective colloids for pigments in cosmetics and in detergent formulations to prevent redisposition of dirt on fibers. Higher molecular weight PVPs are used as a dispersant for organic pigments or latex polymers or titanium dioxide in emulsion paints and as a protective colloid in suspension polymerization of styrene [20,21].
9.4
Merits of poly(vinylpyrrolidones)
PVP is a versatile ingredient used in pharmaceutical and cosmetic industries. It is acquired by a multistep synthesis that ends with polymerization of vinylpyrrolidone in aqueous solution in the presence of hydrogen peroxide [1]. An extensive assortment of molecular weights, from a small number of thousand to a few million Daltons, can be achieved by scheming the degree of polymerization. PVP is extensively used in biomedical applications as a plasma substitute, binders in pharmaceutical tablets, hydrogels for wound dressings, and disinfectants. Its hygroscopic characters, film formation, and adhesion to diverse materials have made PVP broadly used in pharmaceuticals, cosmetics, and industrial production. The interactions between the carbonyl groups of PVP and the hydroxyl group of polyphenols are well recognized. Due to these interactions PVP is used to segregate polyphenols and as a colloidal stabilizer in beers by careful removal of tannoid polyphenols [22,23]. PVP formulations have been employed to fabricate preferred solution viscosity, permitting the deposition of a homogeneous coating thickness of a photoresist in the manufacture of high resolution display screens [24]. Various merits of PVP are described next.
9.4.1 Nontoxic As PVP is widely used in the pharmaceutical and food industries, it is necessary to know whether it is safe enough for the human health. PVP is commonly used to improve the storage qualities of beers. In 1961, a study was carried out to specify the gastrointestinal absorption of PVP. In this study, it was observed that in the object consuming beer, PVP of low average molecular weight was perfused into the blood stream and chiefly excreted in the urine within 24 hours. In addition, there was no indication of decomposition of PVP in the body when injected. To ensure the absorption of PVP, a single oral dose of beer (150 mL) admixture with 2 g of PVP was given to female subjects. The urine samples were collected for 4 days and analyzed at 24-hour interval. No PVP was detected in the urine samples [25]. No evidence of ocular irritation, skin sensitization, or skin irritation of PVP iodine solution was observed in experimental animals at 10% PVP concentration. These findings were considered to support the safety of the PVP for human use. Undiluted
Poly(vinylpyrrolidone)
263
PVP K-30 has been reported safe for dermal applications in clinical tests. PVP was observed genotoxic in certain studies. However, it showed negative results in the majority of studies [26]. This is the reason why it is being extensively used in the pharmaceutical, cosmetics, and food industries without any substitute.
9.4.2 Solubility enhancement In general, the lower the solubility, the lower the bioavailability. This is influenced by several additional factors. Solubility is considered an important parameter for formulation development. Researchers are regularly searching for new ways to improve the bioavailability by increasing the solubility. PVP has been utilized for enhancing the solubility of the drugs by the technique of solid dispersions [27,28]. In a study, Mahapatra et al. reported PVP as a better agent for solubility enhancement of valsartan, than β-cyclodextrin and hydroxypropyl β-cyclodextrin [29]. Koh et al. prepared solid dispersions to enhance the dissolution rate of efavirenz. Formulations with only polyvinylpyrrolidone showed the best dissolution profile [30]. PVP has been reported to enhance the solubility of curcumin by 880-fold in solid dispersion prepared by coevaporation of curcumin and PVP K-30 ethanol [31]. Improved solubility of flavonoids using PVP has been reported due to the presence of carbonyl groups of PVP and hydroxyl groups of flavanone aglycones (naringin and hesperidin). These interactions prevent the crystallization of both flavanone aglycones in the PVP matrix [32].
9.4.3 Stabilizer Suspensions are the biphasic dosage form and to date, no perfect suspension has been formulated that is devoid of stability issue. Every suspension formulation suffers from stability issues due to sedimentation and cake formation. A wide range of suspending agents is available and is being used in the pharmaceutical industry where PVP has its own standing. The literature shows a number of studies reported by the scientists to show the effect of PVP on the suspension stability. One of these kinds of studies was undertaken by Huertas et al. where they studied the influence of PVP adsorption on the silica suspension stability. The effects of silica content, polymer addition, and suspension dilution with water were examined. The turbidimetry method was applied to examine the stability of investigated systems as a function of time. It was shown that the suspension without polymer was characterized by the smallest stability, whereas the systems containing PVP (before and after dilution) are successively stable. The specific conformation of PVP chains on the solid surface is responsible for the stabilization flocculation properties of PVP in the colloidal suspension [33].
9.4.4 Intracytoplasmic sperm injection The technique of intracytoplasmic sperm injection (ICSI) is becoming more popular than in vitro fertilization (IVF). Due to the distinct features of PVP, it has been
264
Engineering of Biomaterials for Drug Delivery Systems
used successfully for ICSI in order to boost the viscosity of sperm solution, thereby assisting the management and immobilization of individual sperm in both domestic animal and human situations [34].
9.4.5 Ophthalmic suitability In ophthalmic solutions, PVP is used as a demulcent or moisturizer and is usually present at approximately 1% concentration in an aqueous matrix, which also includes additional excipients and active pharmaceutical components. It has been shown in combination with polyethylene glycol 400 and dextran 70 to be effective for the momentary relief of minor irritations, for protection of the eye in opposition to further irritation from the wind or sun, and relief from eye dryness [35].
9.4.6 Molding agent PVP as a surfactant has been used to prepare and shape controlled noble metal nanoparticles. It can avoid the aggregation of particles and uphold an identical colloidal dispersion as a stabilizing agent. Also, PVP is used as a shape-control agent or “crystal-habit modifier,” supporting growth onto precise crystal faces while preventing growth onto others. Therefore, the addition of different amounts of PVP can lead to a wide range of sizes and shapes of the resulting particles helpful when designing various drug delivery micro- or nanocarriers [36].
9.4.7 Application in cosmetics PVP is a versatile ingredient used in the cosmetics and beauty industry as a binder, film former, emulsion stabilizer, suspending agent, and hair fixative, and is seen primarily in products such as mascara, eyeliner, hair conditioners, hair sprays, shampoos, and other hair care products. PVP also has the ability to dry and form a thin coating on the skin, nails, or hair, and when it is seen as an ingredient in hair products, it is used to hold hairstyles in place by preventing the hair’s ability to absorb moisture. It is also used in contact lens solution, and as the thickening agent in whitening toothpastes and tooth whitening gels.
9.4.8 Binder PVP is also utilized as a binding agent during the process of tablet formulation and coating [37]. In general, physiochemical characteristics of drugs, binders, and other excipients may have a great influence on the binding efficiency. Also, the binder solution has a higher surface tension producing denser granules with larger mean particle size [38].
Poly(vinylpyrrolidone)
9.5
265
Disadvantages of poly(vinylpyrrolidones)
Potential disadvantages of PVP are classified into following categories:
9.5.1 Allergic reaction PVP is a synthetic polymer with a MW 10 700 kDa. The povidone iodine preparation contains K-30, of which the MW is about 40 kDa. The viscosity is strongly dependent on the molecular weight of the PVP fraction. By giving the K-value, a more precise specification of type of PVP is provided. It is chemically neutral and cannot be broken down further by enzymes. It has been suggested that low MW PVPs of approximately 10 kDa activate suppressor T cells, which inhibit antibody production by B cells. Bigger molecules of PVP (40 kDa and over) induce significant antibody formation in mice. Thus, PVPs may be able to sensitize individuals [39]. PVP acts as an allergen in the presence of serum. Although PVP is thought to be very safe, and anaphylactic reactions to PVP are very rare, once anaphylaxis develops it is severe and life threatening [40,41].
9.5.2 Intracytoplasmatic injection of sperm The numbers of ICSI treatments have been increasing more than conventional IVF treatments in Europe over the last few years [42]. The exposure of sperm to PVP has been found to cause submicroscopic changes in sperm structure; damage has been observed in the sperm nucleus, both in terms of shape and in the texture of chromatin, which was frequently decondensed. PVP-induced nuclear and membrane damage may have been due to the breakdown of sperm membranes. These studies suggest that PVP induces nuclear damage in the sperm leading to subsequent chromosomal aberration. Furthermore, PVP delayed the onset of calcium oscillations and sperm decondensation within the oocyte. Consequently, it is likely that exposure of sperm to PVP may suppress fertilization and embryonic development [43].
9.5.3 Nonbiodegradability Due to its physical, chemical, and biological properties (bio- and hemocompatible, physiologically inactive), PVP finds applications in a range of technological processes. Due to its resistance and zero toxicity to organisms, the compound is mainly used in the pharmaceutical and food industries within the system of E-numbers, utilized in food supplements, pills, and sweeteners. After ingestion, the substance passes through the organism unchanged; consequently, it enters the systems of municipal wastewater treatment plants (WWTP) without decomposing biologically during the waste treatment process. The literature study shows that the ultimate fate of PVP within a WWTP and subsequently in the environment has not been widely explored, so, reiterating presumptions that PVP does not pose an environmental problem is not really an option. PVP contains a lactam ring in its structure, γ-lactam, a substance that may be subject to attack by γ-lactamase (an enzyme).
266
Engineering of Biomaterials for Drug Delivery Systems
Therefore, from both a theoretical and practical perspective, it would be of interest to use microorganisms producing the aforementioned γ-lactamase as a cornerstone for biologically decomposing PVP [44].
9.5.4 Hygroscopicity PVP possesses many of the desired characteristics of a polymer to be used in film coating; however, because it is hygroscopic, in a humid atmosphere the film coat may be tacky and cause the tablets to adhere. It is reported that this disadvantage could be overcome by the addition of acetylated monoglycerides to the coating solution [45].
9.5.5 Particle growth inhibitor The concentration of PVP is a very important factor. PVP is not only a dispersant, but also an inhibitor of the particle and crystallite growth. Monodispersed nanoparticles of average size of 130 nm could be obtained with an intermediate PVP concentration and molecular weight of 100 g/L and 10,000 g/mol, respectively. The MW of PVP does not affect the growth of particle and crystalline in low concentrations. Using PVP with different molecular weights and in different concentrations, it was found that the thickness of the PVP shell should be at least 3 5 nm to achieve monodispersion; when the PVP shell was thinner the nanoparticle aggregated, beyond this thickness, nanoparticle aggregated with entanglement of the excess PVP [46].
9.6
Application of PVP in drug delivery
PVP has been used in various pharmaceutical formulations due to its following applications as shown in Table 9.1 [47]. Table 9.1 Applications of PVP in various pharmaceutical formulations Function
Pharmaceutical form
Binder Improved bioavailability Film-forming agent Solubilizing agent Taste masking Lyophilizing agent Stabilizer Stabilizer Hydrophilizer Adhesive Toxicity reducer
Tablets, capsules, granules Tablets, pellets, suppositories, transdermal systems Tablets, ophthalmic solutions Oral, parenteral, and topical solutions Oral solutions, chewing tablets Injectables, oral lyophilisates Suspensions, dry syrups Enzymes in diagnostics, different forms Sustained release forms of suspensions Transdermal systems, adhesive gels Injectables, oral preparations
Poly(vinylpyrrolidone)
9.7
267
Challenges of poly(vinylpyrrolidones) for applications in pharmaceutical formulations
Additional to its merits, the use of PVP also has disadvantages which may result in scientists facing problems in the pharmaceutical industry, especially in the case of its hygroscopic behavior. Due to this undesirable inheritance at 70% RH PVP films become tacky and at 50% RH they contain 18% moisture. One of the other challenges posed by PVP is its gelation when the solution is exposed to sunlight in the presence of oxidizing agents [48]. Nonbiodegradable behavior of PVP and rare PVP allergic reactions also require the attention of pharmaceutical scientists. It simply passes through the kidney when it is administered orally. It is not metabolized by the body, which may lead to retention of high molecular components within the body after parenteral administration [49,50]. Crospovidone may cause pulmonary vascular injury [51].
9.8
Patents based on poly(vinylpyrrolidones) for pharmaceutical applications
Scientists have utilized the numerous beneficial properties of PVP, resulting in some patents that have been procured. A few of these are discussed below:
9.8.1 Preparation of PVP iodine (US 4200710 A) Isen and O’driscoll invented the process for preparation of the reaction product of PVP and iodine (PVP iodine). The product was claimed to have germicidal, bactericidal, fungicidal and disinfectant properties [52].
9.8.2 Material to form a hydrogel (US 20150224222 A1) In 1978, Teng and Schmer were granted a patent for their invention to the development of a film or sponge which can be utilized for an adhesion barrier or hemostatic device. The developed film or sponge could be provided as a soft film or sponge in the dried state. The product can form water or blood absorbing hydrogel [53].
9.8.3 Fabrication of soft plastic contact lens blank (US3700761A) Isen and O’driscoll developed a method related to shaping and polymerizing a monomer polymer dispersion by casting in a mold and continuing the polymerization after removal from the mold at low (40 60 C) and medium (90 120 C) temperatures. The dispersion consisted of polymerized vinylpyrrolidone and monomethacrylate ester of propylene glycol, ethylene glycol, dipropylene glycol, and diethylene glycol. Stepwise postpolymerization after free radical initiation is the major benefit of this invention [54].
268
Engineering of Biomaterials for Drug Delivery Systems
9.8.4 Antithrombogenic PVP-heparin polymer (US4239664A) The patent disclosed covalently bound poly-N-vinylpyrrolidone-heparins synthesized on the basis of a novel concept that heparin molecules can be modified to have new desirable qualities by binding heparin covalently to an appropriate polymer carrier which has the desired characteristics. Heparin has a short half-life in vivo and it is insoluble in organic solvents. PVP-heparin complex retain the anticoagulant activities of heparin and it is soluble in organic solvents. This compound has a longer half-life in vivo [55].
9.8.5 Cross-linked PVP-I2 foam product (US5672634A) A patent was granted to Tseng and Wolf in 1996 for their invention disclosing crosslinked PVP-I2 foam product. The product was synthesized using shaped cross-linked PVP hydrogel by aqueous polymerization of vinylpyrrolidone monomer in the presence of a cross-linker (1-vinyl-3-ethylidene pyrrolidone), and an initiator (Lupersol 11 or Lupersol 554) at 70 110 C for 3 hours. The rubbery hydrogel product was washed with a large volume of water to remove residual vinylpyrrolidone monomer and water-soluble noncross-linked PVP. The preshaped hydrogel was further subjected to freeze drying to remove excess amounts of water and to form a rigid foamed polymer. The product was conditioned with moisture and acid and iodinated with solid iodine crystals at 45 C for 3 12 hours. Further, the additional conditioning was undertaken at 90 C for 6 12 hours. The final cross-linked PVP-I2 foam contained 0.1% 2% cross-linker and 16 18% w/w of inorganic I2 [56].
9.8.6 Pharmaceutical tablet with PVP having an enhanced drug dissolution rate (US5262171A) This invention reported enhanced dissolution rate of active pharmaceutical ingredient from the tablets using different grades of noncross linked PVP (K-30 to K-120 PVP) as a binding agent. For the synthesis of PVP, the vinyl pyrrolidone monomer was polymerized in the presence of an initiator (low energy peroxyester free radical initiators, such as t-amylperoxypivalate, an azo initiator, or a redox initiator which can perform at low temperatures) which produced a linear PVP polymerization (a poor hydrogen abstractor of PVP polymer backbones). The residual initiator level in the synthesized PVP was reduced to less than 500 ppm, which prevented the further possibility of cross-linking of the PVP during storage of the tablets [57].
9.8.7 Enhanced SPF UV-sunscreen/tricontanyl PVP photoprotecting (sprayable) formulations (US6436376B1) A patent was granted to Hansenne and Rick in 2002 for their invention disclosing topically applicable cosmetic/dermatological compositions for both effective and SPF-enhanced UV-photoprotection of human skin, hair, and/or scalp. The delivery system was packaged as topical spray systems containing UV-photoprotecting UVA and/or UV-B, sunscreen (avobenzone), and a copolymer tricontanyl PVP [58].
Poly(vinylpyrrolidone)
9.9
269
Research overview and future recommendations
PVP has found its extensive use in the food and pharmaceutical industry. Also, it has been widely used in the cosmetics industry. Being a nontoxic ingredient it is used for solubility enhancement of poorly water-soluble drugs, emulsion, and suspension stabilizer, in ICSI to regulate the motility and handling of sperms, for preparing photoresist screens, and in ophthalmic formulations for wetting the eyes. Wherever PVP is used, it has shown its promising performance, whether it is in water filtration system, extraction, or as excipient. Various researchers have utilized different properties of PVP and invented some patentable claims. However, still there is a scope to explore and advance more applications of PVP due to its uncountable properties. At the same time, one can also find out methods to combat its disadvantages.
9.10
Conclusions
Research is focused on finding ways of improving therapeutic efficacy of therapeutics by modifying the chemistry of existing drug molecules, modifying the formulation approaches, polymeric systems. The drawbacks associated with modifying drug chemistry or modifying the formulation approaches can be overcome by utilizing polymers synthesized specifically to solve the problems. Special attention has been given to the use of polyvinylpyrrolidone in pharmaceutical formulations due to its unique physicochemical properties, good solubility in water and many organic solvents, its chemical stability, its affinity to complex with hydrophobic and hydrophilic substances, nontoxic, nonsensitizer or irritant and its biodegradable character. Based on the available literature evidence, PVP is considered as a safe excipient for pharmaceutical applications.
References [1] Haaf F, Sanner A, Straub F. Polymers of N-vinylpyrrolidone: synthesis characterisation and uses. Polym J 1985;17(1):143 52. [2] Kudyshkin VO, Abdurakhmanova TR, Ruban IN, Voropaeva NL, Rashidova SS. Synthesis of polyvinylpyrrolidone under secondary inhibition conditions. Russ J Appl Chem 2002;75(6):1032 3. [3] Green chemistry in teaching laboratory: microwave induced reactions, Available from: ,https://web.njit.edu/Bmitra/green_chemistry/EXP_2.htm. [accessed on 16.07.17]. [4] Kern W, Cherdron H. 4th ed. Houben weyl methoden der organischen chemie, 14. Stuttgart: Georg Thieme Verlag; 1961. p. 1106. [5] Lu X, Gong S, Meng L, Li C, Yang S, Zhang L. Controllable synthesis of Poly (N-vinylpyrrolidone) and its block copolymers by atom transfer radical polymerization. Polymers 2007;48:2835 42. [6] Burnette LW. A review of the physiological properties of PVP. Proc Sci Sect TGA 1962;38:1 4.
270
Engineering of Biomaterials for Drug Delivery Systems
[7] Sapir L, Stanley CB, Harries D. Properties of polyvinylpyrrolidone in a deep eutectic solvent. J Phys Chem A 2016;120:3253 9. [8] Miller LE, Hamm FA. Macromolecular properties of polyvinylpyrrolidone: molecular weight distribution. J Phys Chem 1953;57:110 22. [9] Wohlfarth C. Thermodynamic properties of polymer solutions. Landolt-Bo¨rnstein, New Series, Group VIII, vol. 6D. Berlin, Germany: Springer Verlag; 2010. [10] Lehrman GP, Skauers DM. A comparative study of polyvinylpyrrolidone and other binding agents in tablet formulations. Drug Stand 1958;26:170 5. [11] Chowhan ZT. Role of binders in moisture-induced hardness increase in compressed tablets and its effect on in vitro disintegration and dissolution. J Pharm Sci 1980;69:1 4. [12] Chowhan ZT, Amaro AA, Ong JTH. Punch geometry and formulation considerations in reducing tablet friability and their effect on in vitro dissolution. J Pharm Sci 1992; 81:290 4. [13] Jun YB, Min BH, Kim SI, Kim YIJ. Preparation and evaluation of acetaminophen tablets. Kor Pharm Sci 1989;19:123 8. [14] Jijun F, Lishuang X, Xiaoli W, Shu Z, Xiaoguang T, Xingna Z, et al. Nimodipine (NM) tablets with high dissolution containing nm solid dispersions prepared by hotmelt extrusion. Drug Dev Ind Pharm 2011;37:934 44. [15] Chokshi RJ, Sandhu HK, Iyer RM, Shah NH, Malick WA, Zia H. Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion process as a means to manufacture solid dispersion/solution. J Pharm Sci 2005;94:2463 74. [16] Dua K, Pabreja K, Ramana MV. Preparation, characterization and in vitro evaluation of aceclofenac solid dispersions. ARS Pharm 2010;51:57 76. [17] Dua K, Pabreja K, Ramana MV, Bukhari NI. Preparation, characterization, and in vitro evaluation of aceclofenac PVP-solid dispersions. J Dispers Sci Technol 2011;32: 1151 7. [18] He H, Yang R, Tang X. In vitro and in vivo evaluation of fenofibrate solid dispersion prepared by hot-melt extrusion. Drug Dev Ind Pharm 2010;36:681 7. [19] Forster A, Hempenstall J, Rades T. Characterization of glass solutions of poorly watersoluble drugs produced by melt extrusion with hydrophilic amorphous polymers. J Pharm Pharmacol 2001;53:303 15. [20] Jachowicz R. Dissolution rates of partially water soluble drugs from solid dispersion systems. II. Phenytoin. Int J Pharm 1987;35:7 12. [21] White RK. Pharmaceutical compositions containing polyvinylpyrrolidone and a tri-ester and a process of manufacture thereof. Patent WO/1994/025008; November 10, 1994. [22] Magalhaes PJ, Vieira JS, Gonc LM, Pacheco JG, Guido LF, Barros AA. Isolation of phenolic compounds from hop extracts using polyvinylpolypyrrolidone: characterization by high-performance liquid chromatography diode array detection electrospray tandem mass spectrometry. J Chromatogr A 2010;1217:3258 68. [23] Leiper KA, Stewart GG, Mckeown IP, Nock T, Thompson MJ, Brew JI. Optimising beer stabilisation by the selective removal of tannoids and sensitive proteins. J Inst Brew 2005;111(2):118 27. [24] Swei J, Talbot JB. Viscosity correlation for aqueous polyvinylpyrrolidone (PVP) solutions. J Appl Polym Sci 2003;90(4):1153 5. [25] Angervall BL, Berntsson S. Oral toxicity of polyvinyl pyrrolidone products of low average molecular weight. J Inst Brew 1961;67(4):335 6.
Poly(vinylpyrrolidone)
271
[26] Nair B. Final report on the safety assessment of polyvinylpyrrolidone (PVP). Int J Toxicol 1998;17(4):95 130. [27] Choi J, Lee S, Jang WS, Byeon JC, Park J. Tadalafil solid dispersion formulations based on PVP/VA S-630: improving oral bioavailability in rats. Eur J Pharm Sci 2017; 30(106):152 8. [28] Ghanavati R, Taheri A, Homayouni A. Anomalous dissolution behavior of celecoxib in PVP/Isomalt solid dispersions prepared using spray drier. Mater Sci Eng C 2017; 72:501 11. [29] Mahapatra AK, Murthy PN, Biswal S, Mahapatra APK, Pradhan SP. Dissolution enhancement and physicochemical characterization of valsartan in solid dispersions with β-CD, HP β-CD, and PVP K-30. Dissolution Technol 2011;2:39 45. [30] Koh PT, Chuah JN, Talekar M, Gorajana A, Garg S. Formulation development and dissolution rate enhancement of efavirenz by solid dispersion systems. Indian J Pharm Sci 2013;75(3):291 301. [31] Xu DH, Wang S, Mei XT, Luo XJ, Xu SB. Studies on solubility enhancement of curcumin by Polyvinylpyrrolidione K30. J Chin Med Mater 2008;31(3):438 42. [32] Kanaze FI, Kokkalou E, Niopas I, Georgarakis M, Stergiou A, Bikiaris D. Dissolution enhancement of flavonoids by solid dispersion in PVP and PEG matrixes: a comparative study. J Appl Polym Sci 2006;102:460 71. [33] Huertas SP, Terpilowski K, Wi´sniewska M, Vladimir Z. Influence of polyvinylpyrrolidone adsorption on stability of silica aqueous suspension effects of polymer. Physicochem Probl Miner Process 2017;53(1):121 35. [34] Van Steirteghem AC, Nagy Z, Joris H, Liu J, Staessen C, Smitz J, et al. High fertilization and implantation rates after intracytoplasmic sperm injection. Hum Reprod 1993; 8(7):1061 6. [35] Urban J, Snow NH, Tavlarakis P, Urban JJ, Snow N. Determination of Total Polyvinylpyrrolidone (PVP) in ophthalmic solutions by size exclusion chromatography with ultraviolet-visible detection. J Chromatogr Sci 2011;49(6):457 62. [36] Wu X, Zhao Y, Yang C, He G. PVP-assisted synthesis of shape-controlled CuFeS2 nanocrystals for Li-ion batteries. J Mater Sci 2015;50(12):4250 7. [37] Yang M, Xie S, Li Q, Wang Y, Chang X, Shan L, et al. Effects of polyvinylpyrrolidone both as a binder and pore-former on the release of sparingly water-soluble topiramate from ethylcellulose coated pellets. Int J Pharm 2014;465(1 2):187 96. [38] Parikh DM. Handbook of pharmaceutical granulation technology. USA: Informa Healthcare; 2010. [39] Adachi A, Fukunaga A, Hayashi K, Kunisada M, Horikawa T. Anaphylaxis to polyvinylpyrrolidone after vaginal application of povidone-iodine. Contact Dermatitis 2003;48(3):133 6. [40] Yoshida K, Sakurai Y, Kawahara S, Takeda T, Ishikawa T, Murakami T, et al. Novel insights from clinical practice anaphylaxis to polyvinylpyrrolidone in povidone-iodine for impetigo contagiosum in a boy with atopic dermatitis. Int Arch Allergy Immunol 2008;146:169 73. [41] Reyazulla MA, Gopinath AL, Vaibhav N, Raut RP. An unusual complication of late onset allergic contact dermatitis to povidone iodine in oral & maxillofacial surgery a report of 2 cases. Eur Ann Allergy Clin Immunol 2014;6:157 9. [42] de Mouzon J, Goossens V, Bhattacharya S, Castilla JA, Ferraretti AP, Korsak V, et al. Assisted reproductive technology in Europe, 2006: results generated from European registers by ESHRE. Hum Reprod 2010;25(8):1851 62.
272
Engineering of Biomaterials for Drug Delivery Systems
[43] Kato Y, Nagao Y. Effect of polyvinylpyrrolidone on sperm function and early embryonic development following intracytoplasmic sperm injection in human assisted reproduction. Reprod Med Biol 2012;11(4):165 76. [44] Julinova M, Kupec J, Slavik R, Vaskova M. Initiating biodegradation of polyvinylpyrrolidone in an aqueous aerobic environment: technical note. Ecol Chem Eng S 2013; 20(1):199 208. [45] Alam AS, Parrott EL. Effect of adjuvants on tackiness of polyvinylpyrrolidone film coating. J Pharm Sci 1972;61(2):265 8. [46] Li J, Inukai K, Takahashi Y, Tsuruta A, Shin W. Effect of PVP on the synthesis of high-dispersion core shell barium-titanate polyvinylpyrrolidone nanoparticles. Integr Med Res 2017;1 10. [47] Buhler V. Polyvinylpyrrolidone excipients for pharmaceuticals: povidone, crospovidone and povidone. 1st ed. Berlin: Springer; 2005. [48] Schwarz W. A critical review of the kinetics and toxicology of polyvinylpyrrolidone (povidone). Boca Raton, FL: CRC Press; 1990. [49] Buhler V. Kollidon Polyvinylpyrrolidone Excipients for the Pharmaceutical Industry. 9th ed. Ludwigshafen: BASF The Chemical Company; 2008. [50] Folttmann BH, Quadir A. Excipients in pharmaceuticals: an overview. Drug Deliv Technol 2008;8:22 7. [51] Ganesan S, Felo J, Saldana M, Kalasinsky VF, Lewin-Smith MR, Tomashefski JF. Embolized crospovidone (poly[N-vinyl-2-pyrrolidone]) in the lungs of intravenous drug users. Mod Pathol 2003;16:286 92. [52] Denzinger W, Schenck HU, Schwarz W. Preparation of polyvinylpyrrolidone-iodine. US 4200710 A; 1979. [53] Koyama Y, Ito T. Material to form a hydrogel. US Patent US20150224222 A1; August 13, 2015. [54] Isen AA, O’driscoll KF. Fabrication of soft plastic contact lens blank. US3700761A; November 28, 1969. [55] Teng LN, Schmer G. Anti-thrombogenic PVP-heparin polymer. US4239664A; October 31, 1978. [56] Tseng SY, Wolf PF. Crosslinked PVP-I2 foam product. US5672634A; December 23, 1996. [57] Login RB, Tazi M, Chuang JC, Haldar RK, Jaiswal D, Wu CS. Pharmaceutical tablet with PVP having enhanced drug dissolution rate. US5262171A; November 25, 1991. [58] Hansenne I, Rick DW. Enhanced SPF UV-sunscreen/tricontanyl PVP photoprotecting (sprayable) formulations. US6436376B1; August 20, 2002.
Poly(vinylpyrrolidone)
Rajendra Awasthi1, Satish Manchanda2, Poppy Das3, Vinodhini Velu3, Himaja Malipeddi3, Kavita Pabreja4, Terezinha D.J.A. Pinto5, Gaurav Gupta6 and Kamal Dua7,8 1 NKBR College of Pharmacy and Research Centre, Meerut, India, 2Delhi Institute of Pharmaceutical Sciences and Research University, New Delhi, India, 3VIT University, Vellore, India, 4University of Newcastle, Newcastle, NSW, Australia, 5University of Sa˜o Paulo, Sa˜o Paulo, Brazil, 6School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, India, 7University of Technology Sydney, Sydney, NSW, Australia, 8 Shoolini University, Solan, India
9.1
Introduction
Poly(vinylpyrrolidone) or PVP (Fig. 9.1) is the first polymerized product of Nvinylpyrrolidone produced by a free radical mechanism. Low and medium grades of PVP forms pharmaceutical grade povidone powders. The US Food and Drug Administration has approved PVP for pharmaceutical applications and it is considered safe. During the Second World War, PVP was used as a blood plasma substitute. However, its oral administration has been withdrawn due to the accumulation of drugs within the body. Based on the degree of polymerization, it is synthesized in two different forms: 1. Soluble PVP (Povidone) Povidone is a polymerization product of N-vinylpyrrolidone in water or 2-propanol and was patented in 1939. Its molecular weight ranges from 8000 to 10000 daltons. It is one of the widely used pharmaceutical excipients and well known as a popular topical disinfectant called Povidone-iodine. 2. Insoluble PVP (Crospovidone) The molecular weight of Crospovidone is greater than 700,000 daltons. It is obtained by a physical cross-linking of PVP with a bifunctional monomer in the presence of alkali hydroxide at 100 C in water. Crospovidone is extensively used as an ideal disintegrant in tablet formulation and to hydrophylize insoluble constituents for selective adsorption and complex formation with a wide range of compounds (see also Fig. 9.2). H3C n N
CH3
O
Figure 9.1 Structure of poly(vinylpyrrolidone). Engineering of Biomaterials for Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-08-101750-0.00009-X © 2018 Elsevier Ltd. All rights reserved.
256
Engineering of Biomaterials for Drug Delivery Systems
Alk.hydroxide 100°C
N-Vinyl pyrrolidone
Bifunctional monomer
N-Vinyl pyrrolidone + Bifunctional monomer
Insoluble PVP or crospovidone
Figure 9.2 Flowchart presenting the production process of insoluble PVP or crospovidone. O
O
OH
HO
O
N
2H 2
Polymerization
OH
HO
H2
O O
NH3 H 2O
H N
O O
N
Figure 9.3 Synthesis of PVP by the reaction of acetylene with formaldehyde.
9.2
Synthesis of poly(vinylpyrrolidones)
Poly(vinylpyrrolidone) is synthesized via a free radical polymerization reaction. The reaction of acetylene with formaldehyde yields 1,4-butine diol (Fig. 9.3). The 1,4-butine diol is hydrogenated to butane diol which undergoes oxidative cyclization to yield butyrolactone. In the presence of ammonia, butyrolactone yields pyrrolidone and introduction of the vinyl group produces the vinylpyrrolidone substance (Fig. 9.3). Many other approaches have also been reported in respect to the polymerization of vinylpyrrolidone to a polyvinylpyrrolidone polymeric substance. Among these, the radical polymerization approach is reported to be significant method with a greatest degree of polymerization [1].
Poly(vinylpyrrolidone)
257
Step-I H 2O 2
Heat
Step-II
O OH
OH
OH
H HO H
H
N
H
H N O
H Step-III O N
H
O OH H
H
N
O H
H H
H
N H
O
H H HO H
N H
Figure 9.4 Synthesis of PVP by radical polymerization reaction.
The reaction mixture consisting of a monomeric substance (vinylpyrrolidone), free radical initiator (Azobisbutyronitrile), solvent (dioxane), and an inhibitor (2,2,6,6-tetramethylpiperidyl-1-oxyl) [2,3]. Polymerization using hydrogen peroxide as an initiator in aqueous media is commonly recommended to generate polymers (Fig. 9.4). The hydroxy radicals produced from the initiator molecule form the end group of the polymer. The molecular weight of polymer can be controlled by varying concentrations of hydrogen peroxide unit. The formation of pyrrolidone impurity is the major limitation of this method [4]. When a polymerization reaction is carried out using organic peroxides such as di-tertiary-butyl peroxide or dicumyl peroxide in organic solvents like alcohols, or toluene, it is the solvent radicals that acts as an initiator of polymerization reaction. These solvent radicals are produced through the hydrogen abstraction by the alkoxy radicals formed from the peroxides [1]. The poly(vinylpyrrolidone) produced in organic solutions were found to be more stable and no pyrrolidone impurity formation was observed as in case of polymerization performed using aqueous solvents with H2O2 as an initiator (Fig. 9.5). Keeping aside the advantages, preparation of poly(vinylpyrrolidone) by the radical polymerization method remains challenging due to a number of limitations such as the production of broad molecular weight distribution and no well-defined functionally terminated poly(vinylpyrrolidones). To overcome these limitations, polymerization of N-vinylpyrrolidone by atom transfer radical polymerization (ATRP) was reported by Lu et al., in 2007. Herein, to perform (ATRP), methyl 2-chloropropionate was used as an initiator of polymerization using 5, 5, 7, 12, 12, 14hexamethyl-1, 4, 7, 11-tetra-azacyclo-tetradecane (Me6Cyclam) as a ligand in the presence of 1, 4-dioxane and i-PrOH. The copper chloride (I) and (II) were used as a catalyst in this reaction. In this method, the molecular weight of synthesized poly
258
Engineering of Biomaterials for Drug Delivery Systems
Heat
Step-I
R 1 OOR 2
Step-II
R 1O
ROH solvent
Step-III
RO
N H
R 1O
R 2O R 1 OH
RO
H RO
H H
Step-IV
O
N H RO
H H
O
N H
H H
O
N
O
H RO
H H
N H
H
O H
H H
Figure 9.5 Synthesis of PVP by polymerization reaction using organic peroxides.
(N-vinylpyrrolidone) increased rapidly at the beginning of the reaction but leveled off at about 8900 g/mol. The prepared polyvinylpyrrolidone had a polydispersity index between 1.2 and 1.38 [5].
9.3
O
N
Polymer characteristics with special emphasis on drug delivery
9.3.1 General properties of PVP PVP is high polarity/proton acceptor, amphiphilic, and linear nonionic polymer. It is compatible with a variety of resins and electrolytes. It is a physiologically inert material. It forms hard, transparent, glossy, oxygen-permeable, adhesive and cohesive film. It is hygroscopic in nature and not suitable for thermoplastic processing. It is soluble in water and other polar solvents, but insoluble in esters, ethers, ketones, and hydrocarbons. PVP forms cross-linked matrix after cross-linking reaction with a variety of cross-linking agents [6].
9.3.2 Physical properties of PVP PVP is a cross-linked homopolymer (formed by polymerizing a single monomer) of pure vinylpyrrolidone. It has a slightly foul smell. In solution, it has brilliant wetting properties and readily forms a film, which makes it a coating agent or an
Poly(vinylpyrrolidone)
259
additive for coatings. PVP is soluble in water and other polar solvents, e.g., various alcohols, such as methanol and ethanol, as well as in other exotic solvents such as the deep eutectic solvent formed by urea and choline chloride (Relin) [7]. Commercialized PVP is free flowing, white powder, or solids with its content in the mass fraction of 20%, 30%, 45% and 50% aqueous solution. PVP has moisture equilibrium of 1/3 of the relative humidity of the environment.
9.3.2.1 Molecular weight The molecular weight of PVP depends on the method used to synthesize the polymer. PVP has a molecular weight range from 2500 to 2,900,000 daltons. As, it is formed of a series of different chain length polymers, its molecular weight is expressed as an average of different molecular weights of various chain length units that comprise the polymer [8].
9.3.2.2 Viscosity The K-values assigned to different grades of PVP represent a function of the degree of polymerization, average molecular weight and intrinsic viscosity. The K-values derived from the viscosity measurements can be calculated using following formula: log
ηrel 75K02 5 1 K0 C 1 1 1:5K02
K 5 1000K0
(9.1) (9.2)
where ηrel is the viscosity of solution compared with solvent, C is the concentration in g/100 mL solution, and K is the 1000K0. The K-value calculated by Fikentscher’s equation to measure viscosity is accepted worldwide by pharmacopoeia and other authorities for PVP. Viscosity does not vary significantly over a wide range of pH, but increases in the presence of concentrated hydrochloric acid. The polymer precipitates in presence of strong caustic solutions; however, the precipitate can redissolve on dilution with water. The density of PVP polymer water solution changes slightly with an increase in polymer concentration. It is recommended to investigate the effect of concentration and temperature on the products comprising of PVP [9].
9.3.3 Chemical properties PVP stored at normal conditions, i.e., dry PVP is quite stable and does not easily undergo a chemical reaction. PVP solution that has undergone mildew treatment is also stable. When heated up to 150 C or mixed with ammonium persulfate to heat at 90 C for 30 minutes, PVP is exchanged and it becomes a water-insoluble compound. In the presence of a dichromate-oxidizing agent or an azo compound, when
260
Engineering of Biomaterials for Drug Delivery Systems
PVP solution is exposed to light, it becomes a gel. Heating of PVP solution in the presence of a strong base (such as trisodium phosphate or sodium silicate) leads to its precipitation. PVP can form complexes with different compounds. For example, the complexes of PVP with iodine are very stable and have a good bactericidal effect and reduced toxicity. The addition of copolymers of the polyacrylic acid, methyl vinyl ether, or tannic acid and maleic acid to the aqueous solution of PVP generates a complex that is insoluble in water, ketones, and alcohols. But, when treated with a base for neutralization, the polyacid can reverse the reaction. Complexity between PVP and drugs, toxins, or toxic chemicals can decrease their toxicity. Some dyes can also form a strong complex with PVP, which is the base for using PVP as a dye-bleaching agent. PVP complexes can be easily removed by filtration due to its insolubility.
9.3.3.1 Stability PVP powder can be stored under ordinary conditions without undergoing degradation and decomposition. However, as it is hygroscopic in nature, appropriate precautions must be taken to prevent moisture absorption. PVP films are chemically stable and moisture acts as a plasticizer. The water equilibrium content of PVP films or solid PVP varies linearly with respect to relative humidity. PVP is quite stable to heat, however; it should not be exposed to extreme temperatures. PVP remains stable on heating repeatedly at 110 130 C at short intervals. Nevertheless, when exposed to a temperature of 150 C, a decrease in water solubility and darkening in color was observed. Aqueous PVP is stable for a long time, but exposure to molds must be prevented. Suitable preservatives may be added to PVP films or solutions after appropriate testing. PVP may also be sterilized by steam if it does not affect its properties. The addition of small amounts of acids or bases to PVP can cause large changes in pH [6].
9.3.3.2 Solubility PVP is freely soluble in cold water and many organic solvents such as alcohols, amines, chloroform, ethylene dichloride, methylene chloride, and nitroparaffins. It is insoluble in ethers, esters, ketones, hydrocarbons, and some chlorinated hydrocarbons. Desiccated PVP, comprising of less than 0.5% water, is soluble in dioxanes and ketones. Anhydrous PVP is soluble in CHX2 type of propellants and in various other chlorofluoroalkanes in case alcohol is used as a cosolvent. Similarly, PVP can be dissolved in hydrocarbons to prepare dilute solutions by using cosolvents such as nonylphenol, butanol, or N-methyl-2-pyrrolidone [6].
9.3.3.3 Compatibility PVP exhibits a high degree of compatibility in film as well as solution form, with natural and synthetic resins, most inorganic salts and many other chemicals [6].
Poly(vinylpyrrolidone)
261
9.3.4 Biological properties 9.3.4.1 Complex formation PVP forms complexes with many substances resulting in either solubilization or precipitation. PVP can cross-link with polyacids such as tannic acid or polyacrylic acid to form complexes that are soluble in dilute alkali but are water- or alcoholinsoluble. Ammonium persulfate forms a gel with PVP in 30 minutes at a temperature of 90 C. These gels are considerably insoluble in large quantities of water or salt solutions and are thermoreversible. The same effect is observed when more alkaline sodium phosphates are used. When PVP gels are dried at mild conditions, their uniform structure and swelling capacity are retained. Pyrogallol and resorcinol precipitates PVP from aqueous solutions, however, such complexes can be redissolved in water. PVP is insoluble in the presence of diazo compounds, oxidizing agents, and actinic light. Treatment of PVP with a strong alkali at 100 C permanently insolubilizes it. Heating of PVP at 150 C leads to the cross-linking of PVP. PVP acts as a binding agent in tablets [10,11]. In comparison to other binders PVP produces harder granulates with low friability and good flowability [12]. It also increases the dissolution of the active ingredient, e.g., acetaminophen (paracetamol) tablets formulated with PVP as a binder released the drug much quickly than tablets prepared using hydroxypropyl cellulose or gelatin as a binder [13]. Many germicidal products such as bisphenols and chlorinated phenols, when combined with PVP, exhibit reduced toxicity and intensity of skin reactions while retaining their germicidal activity. Other chemicals such as nicotine, formamide, and potassium cyanide exhibited reduced oral toxicity in the presence of a PVP solution. PVP copolymers are also used to improve the bioavailability of poorly soluble drugs such as tolbutamide, indomethacin and nifedipine [14 17]. PVP also provides stability to the tablet formulations and it may be combined with other reagents to obtain soft clear gelatin capsules of insoluble drugs.
9.3.4.2 Film-forming property The unmodified dry films of PVP are transparent, clear, hard, and glossy in appearance. The use of different solvent systems such as ethanol, chloroform, water, and ethylene dichloride while casting the films does not affect the appearance of the film. The absorbed moisture by PVP acts as plasticizer. Several commercial modifiers are added to control the brittleness or tackiness and the hygroscopic nature of PVP. Shellac, cellulose acetate propionate, and carboxymethyl cellulose can decrease the tackiness, whereas diethyl alcohol, sorbitol, and glycerin increase the tackiness. Ten percent arylsulfonamide-formaldehyde resin makes the PVP film tack-free over all ranges of relative humidity [18,19].
9.3.4.3 Protective-colloid action The addition of small quantities of PVP efficiently stabilizes suspensions, emulsions, and dispersions. PVP can also protect the lyophobic colloids, which do not
262
Engineering of Biomaterials for Drug Delivery Systems
possess significant affinity for the medium. PVP can absorb on the surface of the colloidal particles as a thin layer, which prevents contact, and overcomes the tendency to form a continuous phase. Low molecular weight PVPs use as an effective dispersant for low-bulk-density solids in aqueous media such as protective colloids for pigments in cosmetics and in detergent formulations to prevent redisposition of dirt on fibers. Higher molecular weight PVPs are used as a dispersant for organic pigments or latex polymers or titanium dioxide in emulsion paints and as a protective colloid in suspension polymerization of styrene [20,21].
9.4
Merits of poly(vinylpyrrolidones)
PVP is a versatile ingredient used in pharmaceutical and cosmetic industries. It is acquired by a multistep synthesis that ends with polymerization of vinylpyrrolidone in aqueous solution in the presence of hydrogen peroxide [1]. An extensive assortment of molecular weights, from a small number of thousand to a few million Daltons, can be achieved by scheming the degree of polymerization. PVP is extensively used in biomedical applications as a plasma substitute, binders in pharmaceutical tablets, hydrogels for wound dressings, and disinfectants. Its hygroscopic characters, film formation, and adhesion to diverse materials have made PVP broadly used in pharmaceuticals, cosmetics, and industrial production. The interactions between the carbonyl groups of PVP and the hydroxyl group of polyphenols are well recognized. Due to these interactions PVP is used to segregate polyphenols and as a colloidal stabilizer in beers by careful removal of tannoid polyphenols [22,23]. PVP formulations have been employed to fabricate preferred solution viscosity, permitting the deposition of a homogeneous coating thickness of a photoresist in the manufacture of high resolution display screens [24]. Various merits of PVP are described next.
9.4.1 Nontoxic As PVP is widely used in the pharmaceutical and food industries, it is necessary to know whether it is safe enough for the human health. PVP is commonly used to improve the storage qualities of beers. In 1961, a study was carried out to specify the gastrointestinal absorption of PVP. In this study, it was observed that in the object consuming beer, PVP of low average molecular weight was perfused into the blood stream and chiefly excreted in the urine within 24 hours. In addition, there was no indication of decomposition of PVP in the body when injected. To ensure the absorption of PVP, a single oral dose of beer (150 mL) admixture with 2 g of PVP was given to female subjects. The urine samples were collected for 4 days and analyzed at 24-hour interval. No PVP was detected in the urine samples [25]. No evidence of ocular irritation, skin sensitization, or skin irritation of PVP iodine solution was observed in experimental animals at 10% PVP concentration. These findings were considered to support the safety of the PVP for human use. Undiluted
Poly(vinylpyrrolidone)
263
PVP K-30 has been reported safe for dermal applications in clinical tests. PVP was observed genotoxic in certain studies. However, it showed negative results in the majority of studies [26]. This is the reason why it is being extensively used in the pharmaceutical, cosmetics, and food industries without any substitute.
9.4.2 Solubility enhancement In general, the lower the solubility, the lower the bioavailability. This is influenced by several additional factors. Solubility is considered an important parameter for formulation development. Researchers are regularly searching for new ways to improve the bioavailability by increasing the solubility. PVP has been utilized for enhancing the solubility of the drugs by the technique of solid dispersions [27,28]. In a study, Mahapatra et al. reported PVP as a better agent for solubility enhancement of valsartan, than β-cyclodextrin and hydroxypropyl β-cyclodextrin [29]. Koh et al. prepared solid dispersions to enhance the dissolution rate of efavirenz. Formulations with only polyvinylpyrrolidone showed the best dissolution profile [30]. PVP has been reported to enhance the solubility of curcumin by 880-fold in solid dispersion prepared by coevaporation of curcumin and PVP K-30 ethanol [31]. Improved solubility of flavonoids using PVP has been reported due to the presence of carbonyl groups of PVP and hydroxyl groups of flavanone aglycones (naringin and hesperidin). These interactions prevent the crystallization of both flavanone aglycones in the PVP matrix [32].
9.4.3 Stabilizer Suspensions are the biphasic dosage form and to date, no perfect suspension has been formulated that is devoid of stability issue. Every suspension formulation suffers from stability issues due to sedimentation and cake formation. A wide range of suspending agents is available and is being used in the pharmaceutical industry where PVP has its own standing. The literature shows a number of studies reported by the scientists to show the effect of PVP on the suspension stability. One of these kinds of studies was undertaken by Huertas et al. where they studied the influence of PVP adsorption on the silica suspension stability. The effects of silica content, polymer addition, and suspension dilution with water were examined. The turbidimetry method was applied to examine the stability of investigated systems as a function of time. It was shown that the suspension without polymer was characterized by the smallest stability, whereas the systems containing PVP (before and after dilution) are successively stable. The specific conformation of PVP chains on the solid surface is responsible for the stabilization flocculation properties of PVP in the colloidal suspension [33].
9.4.4 Intracytoplasmic sperm injection The technique of intracytoplasmic sperm injection (ICSI) is becoming more popular than in vitro fertilization (IVF). Due to the distinct features of PVP, it has been
264
Engineering of Biomaterials for Drug Delivery Systems
used successfully for ICSI in order to boost the viscosity of sperm solution, thereby assisting the management and immobilization of individual sperm in both domestic animal and human situations [34].
9.4.5 Ophthalmic suitability In ophthalmic solutions, PVP is used as a demulcent or moisturizer and is usually present at approximately 1% concentration in an aqueous matrix, which also includes additional excipients and active pharmaceutical components. It has been shown in combination with polyethylene glycol 400 and dextran 70 to be effective for the momentary relief of minor irritations, for protection of the eye in opposition to further irritation from the wind or sun, and relief from eye dryness [35].
9.4.6 Molding agent PVP as a surfactant has been used to prepare and shape controlled noble metal nanoparticles. It can avoid the aggregation of particles and uphold an identical colloidal dispersion as a stabilizing agent. Also, PVP is used as a shape-control agent or “crystal-habit modifier,” supporting growth onto precise crystal faces while preventing growth onto others. Therefore, the addition of different amounts of PVP can lead to a wide range of sizes and shapes of the resulting particles helpful when designing various drug delivery micro- or nanocarriers [36].
9.4.7 Application in cosmetics PVP is a versatile ingredient used in the cosmetics and beauty industry as a binder, film former, emulsion stabilizer, suspending agent, and hair fixative, and is seen primarily in products such as mascara, eyeliner, hair conditioners, hair sprays, shampoos, and other hair care products. PVP also has the ability to dry and form a thin coating on the skin, nails, or hair, and when it is seen as an ingredient in hair products, it is used to hold hairstyles in place by preventing the hair’s ability to absorb moisture. It is also used in contact lens solution, and as the thickening agent in whitening toothpastes and tooth whitening gels.
9.4.8 Binder PVP is also utilized as a binding agent during the process of tablet formulation and coating [37]. In general, physiochemical characteristics of drugs, binders, and other excipients may have a great influence on the binding efficiency. Also, the binder solution has a higher surface tension producing denser granules with larger mean particle size [38].
Poly(vinylpyrrolidone)
9.5
265
Disadvantages of poly(vinylpyrrolidones)
Potential disadvantages of PVP are classified into following categories:
9.5.1 Allergic reaction PVP is a synthetic polymer with a MW 10 700 kDa. The povidone iodine preparation contains K-30, of which the MW is about 40 kDa. The viscosity is strongly dependent on the molecular weight of the PVP fraction. By giving the K-value, a more precise specification of type of PVP is provided. It is chemically neutral and cannot be broken down further by enzymes. It has been suggested that low MW PVPs of approximately 10 kDa activate suppressor T cells, which inhibit antibody production by B cells. Bigger molecules of PVP (40 kDa and over) induce significant antibody formation in mice. Thus, PVPs may be able to sensitize individuals [39]. PVP acts as an allergen in the presence of serum. Although PVP is thought to be very safe, and anaphylactic reactions to PVP are very rare, once anaphylaxis develops it is severe and life threatening [40,41].
9.5.2 Intracytoplasmatic injection of sperm The numbers of ICSI treatments have been increasing more than conventional IVF treatments in Europe over the last few years [42]. The exposure of sperm to PVP has been found to cause submicroscopic changes in sperm structure; damage has been observed in the sperm nucleus, both in terms of shape and in the texture of chromatin, which was frequently decondensed. PVP-induced nuclear and membrane damage may have been due to the breakdown of sperm membranes. These studies suggest that PVP induces nuclear damage in the sperm leading to subsequent chromosomal aberration. Furthermore, PVP delayed the onset of calcium oscillations and sperm decondensation within the oocyte. Consequently, it is likely that exposure of sperm to PVP may suppress fertilization and embryonic development [43].
9.5.3 Nonbiodegradability Due to its physical, chemical, and biological properties (bio- and hemocompatible, physiologically inactive), PVP finds applications in a range of technological processes. Due to its resistance and zero toxicity to organisms, the compound is mainly used in the pharmaceutical and food industries within the system of E-numbers, utilized in food supplements, pills, and sweeteners. After ingestion, the substance passes through the organism unchanged; consequently, it enters the systems of municipal wastewater treatment plants (WWTP) without decomposing biologically during the waste treatment process. The literature study shows that the ultimate fate of PVP within a WWTP and subsequently in the environment has not been widely explored, so, reiterating presumptions that PVP does not pose an environmental problem is not really an option. PVP contains a lactam ring in its structure, γ-lactam, a substance that may be subject to attack by γ-lactamase (an enzyme).
266
Engineering of Biomaterials for Drug Delivery Systems
Therefore, from both a theoretical and practical perspective, it would be of interest to use microorganisms producing the aforementioned γ-lactamase as a cornerstone for biologically decomposing PVP [44].
9.5.4 Hygroscopicity PVP possesses many of the desired characteristics of a polymer to be used in film coating; however, because it is hygroscopic, in a humid atmosphere the film coat may be tacky and cause the tablets to adhere. It is reported that this disadvantage could be overcome by the addition of acetylated monoglycerides to the coating solution [45].
9.5.5 Particle growth inhibitor The concentration of PVP is a very important factor. PVP is not only a dispersant, but also an inhibitor of the particle and crystallite growth. Monodispersed nanoparticles of average size of 130 nm could be obtained with an intermediate PVP concentration and molecular weight of 100 g/L and 10,000 g/mol, respectively. The MW of PVP does not affect the growth of particle and crystalline in low concentrations. Using PVP with different molecular weights and in different concentrations, it was found that the thickness of the PVP shell should be at least 3 5 nm to achieve monodispersion; when the PVP shell was thinner the nanoparticle aggregated, beyond this thickness, nanoparticle aggregated with entanglement of the excess PVP [46].
9.6
Application of PVP in drug delivery
PVP has been used in various pharmaceutical formulations due to its following applications as shown in Table 9.1 [47]. Table 9.1 Applications of PVP in various pharmaceutical formulations Function
Pharmaceutical form
Binder Improved bioavailability Film-forming agent Solubilizing agent Taste masking Lyophilizing agent Stabilizer Stabilizer Hydrophilizer Adhesive Toxicity reducer
Tablets, capsules, granules Tablets, pellets, suppositories, transdermal systems Tablets, ophthalmic solutions Oral, parenteral, and topical solutions Oral solutions, chewing tablets Injectables, oral lyophilisates Suspensions, dry syrups Enzymes in diagnostics, different forms Sustained release forms of suspensions Transdermal systems, adhesive gels Injectables, oral preparations
Poly(vinylpyrrolidone)
9.7
267
Challenges of poly(vinylpyrrolidones) for applications in pharmaceutical formulations
Additional to its merits, the use of PVP also has disadvantages which may result in scientists facing problems in the pharmaceutical industry, especially in the case of its hygroscopic behavior. Due to this undesirable inheritance at 70% RH PVP films become tacky and at 50% RH they contain 18% moisture. One of the other challenges posed by PVP is its gelation when the solution is exposed to sunlight in the presence of oxidizing agents [48]. Nonbiodegradable behavior of PVP and rare PVP allergic reactions also require the attention of pharmaceutical scientists. It simply passes through the kidney when it is administered orally. It is not metabolized by the body, which may lead to retention of high molecular components within the body after parenteral administration [49,50]. Crospovidone may cause pulmonary vascular injury [51].
9.8
Patents based on poly(vinylpyrrolidones) for pharmaceutical applications
Scientists have utilized the numerous beneficial properties of PVP, resulting in some patents that have been procured. A few of these are discussed below:
9.8.1 Preparation of PVP iodine (US 4200710 A) Isen and O’driscoll invented the process for preparation of the reaction product of PVP and iodine (PVP iodine). The product was claimed to have germicidal, bactericidal, fungicidal and disinfectant properties [52].
9.8.2 Material to form a hydrogel (US 20150224222 A1) In 1978, Teng and Schmer were granted a patent for their invention to the development of a film or sponge which can be utilized for an adhesion barrier or hemostatic device. The developed film or sponge could be provided as a soft film or sponge in the dried state. The product can form water or blood absorbing hydrogel [53].
9.8.3 Fabrication of soft plastic contact lens blank (US3700761A) Isen and O’driscoll developed a method related to shaping and polymerizing a monomer polymer dispersion by casting in a mold and continuing the polymerization after removal from the mold at low (40 60 C) and medium (90 120 C) temperatures. The dispersion consisted of polymerized vinylpyrrolidone and monomethacrylate ester of propylene glycol, ethylene glycol, dipropylene glycol, and diethylene glycol. Stepwise postpolymerization after free radical initiation is the major benefit of this invention [54].
268
Engineering of Biomaterials for Drug Delivery Systems
9.8.4 Antithrombogenic PVP-heparin polymer (US4239664A) The patent disclosed covalently bound poly-N-vinylpyrrolidone-heparins synthesized on the basis of a novel concept that heparin molecules can be modified to have new desirable qualities by binding heparin covalently to an appropriate polymer carrier which has the desired characteristics. Heparin has a short half-life in vivo and it is insoluble in organic solvents. PVP-heparin complex retain the anticoagulant activities of heparin and it is soluble in organic solvents. This compound has a longer half-life in vivo [55].
9.8.5 Cross-linked PVP-I2 foam product (US5672634A) A patent was granted to Tseng and Wolf in 1996 for their invention disclosing crosslinked PVP-I2 foam product. The product was synthesized using shaped cross-linked PVP hydrogel by aqueous polymerization of vinylpyrrolidone monomer in the presence of a cross-linker (1-vinyl-3-ethylidene pyrrolidone), and an initiator (Lupersol 11 or Lupersol 554) at 70 110 C for 3 hours. The rubbery hydrogel product was washed with a large volume of water to remove residual vinylpyrrolidone monomer and water-soluble noncross-linked PVP. The preshaped hydrogel was further subjected to freeze drying to remove excess amounts of water and to form a rigid foamed polymer. The product was conditioned with moisture and acid and iodinated with solid iodine crystals at 45 C for 3 12 hours. Further, the additional conditioning was undertaken at 90 C for 6 12 hours. The final cross-linked PVP-I2 foam contained 0.1% 2% cross-linker and 16 18% w/w of inorganic I2 [56].
9.8.6 Pharmaceutical tablet with PVP having an enhanced drug dissolution rate (US5262171A) This invention reported enhanced dissolution rate of active pharmaceutical ingredient from the tablets using different grades of noncross linked PVP (K-30 to K-120 PVP) as a binding agent. For the synthesis of PVP, the vinyl pyrrolidone monomer was polymerized in the presence of an initiator (low energy peroxyester free radical initiators, such as t-amylperoxypivalate, an azo initiator, or a redox initiator which can perform at low temperatures) which produced a linear PVP polymerization (a poor hydrogen abstractor of PVP polymer backbones). The residual initiator level in the synthesized PVP was reduced to less than 500 ppm, which prevented the further possibility of cross-linking of the PVP during storage of the tablets [57].
9.8.7 Enhanced SPF UV-sunscreen/tricontanyl PVP photoprotecting (sprayable) formulations (US6436376B1) A patent was granted to Hansenne and Rick in 2002 for their invention disclosing topically applicable cosmetic/dermatological compositions for both effective and SPF-enhanced UV-photoprotection of human skin, hair, and/or scalp. The delivery system was packaged as topical spray systems containing UV-photoprotecting UVA and/or UV-B, sunscreen (avobenzone), and a copolymer tricontanyl PVP [58].
Poly(vinylpyrrolidone)
9.9
269
Research overview and future recommendations
PVP has found its extensive use in the food and pharmaceutical industry. Also, it has been widely used in the cosmetics industry. Being a nontoxic ingredient it is used for solubility enhancement of poorly water-soluble drugs, emulsion, and suspension stabilizer, in ICSI to regulate the motility and handling of sperms, for preparing photoresist screens, and in ophthalmic formulations for wetting the eyes. Wherever PVP is used, it has shown its promising performance, whether it is in water filtration system, extraction, or as excipient. Various researchers have utilized different properties of PVP and invented some patentable claims. However, still there is a scope to explore and advance more applications of PVP due to its uncountable properties. At the same time, one can also find out methods to combat its disadvantages.
9.10
Conclusions
Research is focused on finding ways of improving therapeutic efficacy of therapeutics by modifying the chemistry of existing drug molecules, modifying the formulation approaches, polymeric systems. The drawbacks associated with modifying drug chemistry or modifying the formulation approaches can be overcome by utilizing polymers synthesized specifically to solve the problems. Special attention has been given to the use of polyvinylpyrrolidone in pharmaceutical formulations due to its unique physicochemical properties, good solubility in water and many organic solvents, its chemical stability, its affinity to complex with hydrophobic and hydrophilic substances, nontoxic, nonsensitizer or irritant and its biodegradable character. Based on the available literature evidence, PVP is considered as a safe excipient for pharmaceutical applications.
References [1] Haaf F, Sanner A, Straub F. Polymers of N-vinylpyrrolidone: synthesis characterisation and uses. Polym J 1985;17(1):143 52. [2] Kudyshkin VO, Abdurakhmanova TR, Ruban IN, Voropaeva NL, Rashidova SS. Synthesis of polyvinylpyrrolidone under secondary inhibition conditions. Russ J Appl Chem 2002;75(6):1032 3. [3] Green chemistry in teaching laboratory: microwave induced reactions, Available from: ,https://web.njit.edu/Bmitra/green_chemistry/EXP_2.htm. [accessed on 16.07.17]. [4] Kern W, Cherdron H. 4th ed. Houben weyl methoden der organischen chemie, 14. Stuttgart: Georg Thieme Verlag; 1961. p. 1106. [5] Lu X, Gong S, Meng L, Li C, Yang S, Zhang L. Controllable synthesis of Poly (N-vinylpyrrolidone) and its block copolymers by atom transfer radical polymerization. Polymers 2007;48:2835 42. [6] Burnette LW. A review of the physiological properties of PVP. Proc Sci Sect TGA 1962;38:1 4.
270
Engineering of Biomaterials for Drug Delivery Systems
[7] Sapir L, Stanley CB, Harries D. Properties of polyvinylpyrrolidone in a deep eutectic solvent. J Phys Chem A 2016;120:3253 9. [8] Miller LE, Hamm FA. Macromolecular properties of polyvinylpyrrolidone: molecular weight distribution. J Phys Chem 1953;57:110 22. [9] Wohlfarth C. Thermodynamic properties of polymer solutions. Landolt-Bo¨rnstein, New Series, Group VIII, vol. 6D. Berlin, Germany: Springer Verlag; 2010. [10] Lehrman GP, Skauers DM. A comparative study of polyvinylpyrrolidone and other binding agents in tablet formulations. Drug Stand 1958;26:170 5. [11] Chowhan ZT. Role of binders in moisture-induced hardness increase in compressed tablets and its effect on in vitro disintegration and dissolution. J Pharm Sci 1980;69:1 4. [12] Chowhan ZT, Amaro AA, Ong JTH. Punch geometry and formulation considerations in reducing tablet friability and their effect on in vitro dissolution. J Pharm Sci 1992; 81:290 4. [13] Jun YB, Min BH, Kim SI, Kim YIJ. Preparation and evaluation of acetaminophen tablets. Kor Pharm Sci 1989;19:123 8. [14] Jijun F, Lishuang X, Xiaoli W, Shu Z, Xiaoguang T, Xingna Z, et al. Nimodipine (NM) tablets with high dissolution containing nm solid dispersions prepared by hotmelt extrusion. Drug Dev Ind Pharm 2011;37:934 44. [15] Chokshi RJ, Sandhu HK, Iyer RM, Shah NH, Malick WA, Zia H. Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion process as a means to manufacture solid dispersion/solution. J Pharm Sci 2005;94:2463 74. [16] Dua K, Pabreja K, Ramana MV. Preparation, characterization and in vitro evaluation of aceclofenac solid dispersions. ARS Pharm 2010;51:57 76. [17] Dua K, Pabreja K, Ramana MV, Bukhari NI. Preparation, characterization, and in vitro evaluation of aceclofenac PVP-solid dispersions. J Dispers Sci Technol 2011;32: 1151 7. [18] He H, Yang R, Tang X. In vitro and in vivo evaluation of fenofibrate solid dispersion prepared by hot-melt extrusion. Drug Dev Ind Pharm 2010;36:681 7. [19] Forster A, Hempenstall J, Rades T. Characterization of glass solutions of poorly watersoluble drugs produced by melt extrusion with hydrophilic amorphous polymers. J Pharm Pharmacol 2001;53:303 15. [20] Jachowicz R. Dissolution rates of partially water soluble drugs from solid dispersion systems. II. Phenytoin. Int J Pharm 1987;35:7 12. [21] White RK. Pharmaceutical compositions containing polyvinylpyrrolidone and a tri-ester and a process of manufacture thereof. Patent WO/1994/025008; November 10, 1994. [22] Magalhaes PJ, Vieira JS, Gonc LM, Pacheco JG, Guido LF, Barros AA. Isolation of phenolic compounds from hop extracts using polyvinylpolypyrrolidone: characterization by high-performance liquid chromatography diode array detection electrospray tandem mass spectrometry. J Chromatogr A 2010;1217:3258 68. [23] Leiper KA, Stewart GG, Mckeown IP, Nock T, Thompson MJ, Brew JI. Optimising beer stabilisation by the selective removal of tannoids and sensitive proteins. J Inst Brew 2005;111(2):118 27. [24] Swei J, Talbot JB. Viscosity correlation for aqueous polyvinylpyrrolidone (PVP) solutions. J Appl Polym Sci 2003;90(4):1153 5. [25] Angervall BL, Berntsson S. Oral toxicity of polyvinyl pyrrolidone products of low average molecular weight. J Inst Brew 1961;67(4):335 6.
Poly(vinylpyrrolidone)
271
[26] Nair B. Final report on the safety assessment of polyvinylpyrrolidone (PVP). Int J Toxicol 1998;17(4):95 130. [27] Choi J, Lee S, Jang WS, Byeon JC, Park J. Tadalafil solid dispersion formulations based on PVP/VA S-630: improving oral bioavailability in rats. Eur J Pharm Sci 2017; 30(106):152 8. [28] Ghanavati R, Taheri A, Homayouni A. Anomalous dissolution behavior of celecoxib in PVP/Isomalt solid dispersions prepared using spray drier. Mater Sci Eng C 2017; 72:501 11. [29] Mahapatra AK, Murthy PN, Biswal S, Mahapatra APK, Pradhan SP. Dissolution enhancement and physicochemical characterization of valsartan in solid dispersions with β-CD, HP β-CD, and PVP K-30. Dissolution Technol 2011;2:39 45. [30] Koh PT, Chuah JN, Talekar M, Gorajana A, Garg S. Formulation development and dissolution rate enhancement of efavirenz by solid dispersion systems. Indian J Pharm Sci 2013;75(3):291 301. [31] Xu DH, Wang S, Mei XT, Luo XJ, Xu SB. Studies on solubility enhancement of curcumin by Polyvinylpyrrolidione K30. J Chin Med Mater 2008;31(3):438 42. [32] Kanaze FI, Kokkalou E, Niopas I, Georgarakis M, Stergiou A, Bikiaris D. Dissolution enhancement of flavonoids by solid dispersion in PVP and PEG matrixes: a comparative study. J Appl Polym Sci 2006;102:460 71. [33] Huertas SP, Terpilowski K, Wi´sniewska M, Vladimir Z. Influence of polyvinylpyrrolidone adsorption on stability of silica aqueous suspension effects of polymer. Physicochem Probl Miner Process 2017;53(1):121 35. [34] Van Steirteghem AC, Nagy Z, Joris H, Liu J, Staessen C, Smitz J, et al. High fertilization and implantation rates after intracytoplasmic sperm injection. Hum Reprod 1993; 8(7):1061 6. [35] Urban J, Snow NH, Tavlarakis P, Urban JJ, Snow N. Determination of Total Polyvinylpyrrolidone (PVP) in ophthalmic solutions by size exclusion chromatography with ultraviolet-visible detection. J Chromatogr Sci 2011;49(6):457 62. [36] Wu X, Zhao Y, Yang C, He G. PVP-assisted synthesis of shape-controlled CuFeS2 nanocrystals for Li-ion batteries. J Mater Sci 2015;50(12):4250 7. [37] Yang M, Xie S, Li Q, Wang Y, Chang X, Shan L, et al. Effects of polyvinylpyrrolidone both as a binder and pore-former on the release of sparingly water-soluble topiramate from ethylcellulose coated pellets. Int J Pharm 2014;465(1 2):187 96. [38] Parikh DM. Handbook of pharmaceutical granulation technology. USA: Informa Healthcare; 2010. [39] Adachi A, Fukunaga A, Hayashi K, Kunisada M, Horikawa T. Anaphylaxis to polyvinylpyrrolidone after vaginal application of povidone-iodine. Contact Dermatitis 2003;48(3):133 6. [40] Yoshida K, Sakurai Y, Kawahara S, Takeda T, Ishikawa T, Murakami T, et al. Novel insights from clinical practice anaphylaxis to polyvinylpyrrolidone in povidone-iodine for impetigo contagiosum in a boy with atopic dermatitis. Int Arch Allergy Immunol 2008;146:169 73. [41] Reyazulla MA, Gopinath AL, Vaibhav N, Raut RP. An unusual complication of late onset allergic contact dermatitis to povidone iodine in oral & maxillofacial surgery a report of 2 cases. Eur Ann Allergy Clin Immunol 2014;6:157 9. [42] de Mouzon J, Goossens V, Bhattacharya S, Castilla JA, Ferraretti AP, Korsak V, et al. Assisted reproductive technology in Europe, 2006: results generated from European registers by ESHRE. Hum Reprod 2010;25(8):1851 62.
272
Engineering of Biomaterials for Drug Delivery Systems
[43] Kato Y, Nagao Y. Effect of polyvinylpyrrolidone on sperm function and early embryonic development following intracytoplasmic sperm injection in human assisted reproduction. Reprod Med Biol 2012;11(4):165 76. [44] Julinova M, Kupec J, Slavik R, Vaskova M. Initiating biodegradation of polyvinylpyrrolidone in an aqueous aerobic environment: technical note. Ecol Chem Eng S 2013; 20(1):199 208. [45] Alam AS, Parrott EL. Effect of adjuvants on tackiness of polyvinylpyrrolidone film coating. J Pharm Sci 1972;61(2):265 8. [46] Li J, Inukai K, Takahashi Y, Tsuruta A, Shin W. Effect of PVP on the synthesis of high-dispersion core shell barium-titanate polyvinylpyrrolidone nanoparticles. Integr Med Res 2017;1 10. [47] Buhler V. Polyvinylpyrrolidone excipients for pharmaceuticals: povidone, crospovidone and povidone. 1st ed. Berlin: Springer; 2005. [48] Schwarz W. A critical review of the kinetics and toxicology of polyvinylpyrrolidone (povidone). Boca Raton, FL: CRC Press; 1990. [49] Buhler V. Kollidon Polyvinylpyrrolidone Excipients for the Pharmaceutical Industry. 9th ed. Ludwigshafen: BASF The Chemical Company; 2008. [50] Folttmann BH, Quadir A. Excipients in pharmaceuticals: an overview. Drug Deliv Technol 2008;8:22 7. [51] Ganesan S, Felo J, Saldana M, Kalasinsky VF, Lewin-Smith MR, Tomashefski JF. Embolized crospovidone (poly[N-vinyl-2-pyrrolidone]) in the lungs of intravenous drug users. Mod Pathol 2003;16:286 92. [52] Denzinger W, Schenck HU, Schwarz W. Preparation of polyvinylpyrrolidone-iodine. US 4200710 A; 1979. [53] Koyama Y, Ito T. Material to form a hydrogel. US Patent US20150224222 A1; August 13, 2015. [54] Isen AA, O’driscoll KF. Fabrication of soft plastic contact lens blank. US3700761A; November 28, 1969. [55] Teng LN, Schmer G. Anti-thrombogenic PVP-heparin polymer. US4239664A; October 31, 1978. [56] Tseng SY, Wolf PF. Crosslinked PVP-I2 foam product. US5672634A; December 23, 1996. [57] Login RB, Tazi M, Chuang JC, Haldar RK, Jaiswal D, Wu CS. Pharmaceutical tablet with PVP having enhanced drug dissolution rate. US5262171A; November 25, 1991. [58] Hansenne I, Rick DW. Enhanced SPF UV-sunscreen/tricontanyl PVP photoprotecting (sprayable) formulations. US6436376B1; August 20, 2002.