Prolonging effects of polyvinyl alcohol on drug release Chimica Techno Acta ARTICLE published by Ural Federal University 2022, vol. 9(2), No. 20229206 eISSN 2411-1414; chimicatechnoacta.ru DOI: 10.15826/chimtech.2022.9.2.06 1 of 8 Prolonging effects of polyvinyl alcohol on drug release Anzhela S. Shurshina * , Roman Yu. Lazdin , Elena M. Zakharova, Anastasiya S. Titlova, Elena I. Kulish Bashkir State University, Ufa 450076, Russia * Corresponding author: anzhela_murzagil@mail.ru This paper belongs to a Regular Issue. © 2022, the Authors. This article is published open access under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Abstract Polymers are currently of interest as drug delivery systems. The use of polymeric forms of medicinal substances will eliminate or reduce the disadvantages of traditional drugs. The purpose of this work was to assess the ability to prolong the action of polyvinyl alcohol in rela- tion to the drug release when going from dilute to more concentrated solutions. It was established that an increase in the viscosity of the polymer in solution caused by an increase in its concentration results not only in a slowdown in the diffusion of drugs from the polymer solution, but also in a significant decrease in the amount of drugs firmly fixed on the polymer matrix. Since it is the adduct of the poly- vinyl alcohol-drug interaction that provides the slow release of the drug from the polymer solution, a decrease in its amount leads to the fact that no enhancement of the prolonging action is observed. It is claimed that when moving from solutions to polymer films, the rate of drug release is also determined by the structure of the polymer matrix. The lower the density of the polymer film, the greater the diffusion coefficient of the drug release from the film. Thus, in the course of evaluating the ability to prolong the action of polyvinyl al- cohol, it was shown that using some prolongation techniques, it is possible to achieve targeted regulation of the rate of drug release from polymer dosage forms. Keywords polyvinyl alcohol prolongation drug delivery polymer film Received: 11.04.22 Revised: 04.05.22 Accepted: 05.05.22 Available online: 11.05.22 1. Introduction Almost all currently known dosage forms are produced using pharmaceutical aids. Until recently, the require- ments of pharmacological and chemical inertness have been imposed on pharmaceutical aids [1–3]. However, it turned out that with their help it is possible to significant- ly influence the pharmacological activity of drugs and reg- ulate the parameters of pharmacokinetics and pharmaco- dynamics [4–6]. For example, dimethyl sulfoxide added to eye drops accelerates the penetration of antibiotics into the eye tissue [7, 8]. The use of methylcellulose allows the drugs to be retained in tissues for a long time, prolonging their action [9]. Pharmaceutical aids affect not only the therapeutic ef- ficacy of drugs, but also the physicochemical characteris- tics of dosage forms during their manufacture and storage. For example, the introduction of up to 1% polyvinylpyrrol- idone into the composition of nitroglycerin tablets signifi- cantly reduces their porosity and, as a consequence, re- duces the ability of nitroglycerin to evaporate [10]. As a result, the shelf life of the tablets in open packages in- creases from 2 weeks to several months. PVA nanofibers produced by o/w emulsion electrospinning were demon- strated to be suitable solid dispersion systems enabling robust controlled release of poorly water-soluble drugs in work [11]. One of the largest groups of pharmaceutical aids used are polymers, which mainly function as prolongates [12–14]. The use of prolonged dosage forms is caused by negative phenomena arising from the rapid clearance of drugs from the body. In this case, there is a need for fre- quent administration of drugs, which often leads to a sharp fluctuation in their concentration in the body and, in turn, causes toxicity, allergic reactions, irritation, etc. [6]. Rapid clearance of drugs from the body, in addition, caus- es the appearance of the forms of microorganisms re- sistant to these substances. http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2022.9.2.06 mailto:anzhela_murzagil@mail.ru http://creativecommons.org/licenses/by/4.0/ https://orcid.org/0000-0001-6737-7265 https://orcid.org/0000-0003-4774-9994 https://orcid.org/0000-0002-6240-0718 https://crossmark.crossref.org/dialog/?doi=https://doi.org/10.15826/chimtech.2022.9.2.06&domain=pdf&date_stamp=2022-5-11 Chimica Techno Acta 2022, vol. 9(2), No. 20229206 ARTICLE 2 of 8 One of the promising polymers for medicine, in gen- eral, and the technology of dosage forms, in particular, is polyvinyl alcohol (PVA) [15–17]. PVA is a biodegradable semicrystalline synthetic polymer that has been used for biomedical applications for several years [18]. Crystalline structures can be controlled by modifying the chemical composition of OH groups [19]. For example, in the phar- maceutical area, PVA has been widely used to prepare sol- id dispersions to improve the solubility of drugs [18, 20]. On the basis of PVS, nanoparticles are also created that provide prolonged release of medicinal substances [21]. The effects of PVA on the release behavior of polymer na- noparticles from nanocomposite particles using amino acids were investigated [22]. PVA cross-linked micro- spheres are used in oral precision relief systems [23, 24]. Hydrogel composites based on PVS are of interest [25, 26]. In the work [25] Lomefloxacin drug was loaded into the hydrogels and its release profile was studied. The two most important factors affect the ability to prolong drug release. First, it is the high viscosity of PVA solutions, which provide a slow diffusion of drugs. Second, it is the ability of PVA functional groups to form complex compounds with drugs through hydrogen bonds [27–29]. In this case, it is a priori assumed that if in dilute solu- tions PVA is capable of interacting with drugs, then this fact will provide a high level of prolongation in the transi- tion from liquid to soft dosage forms. However, an in- crease in the concentration of polymer in solution is ac- companied not only by an increase in viscosity, which could contribute to the prolongation, but also by the struc- turing of the polymer. In its turn, the structure formation is accompanied by the aggregation of macromolecules and a hereto related decrease in the availability of polymer units for interaction with drugs [30], which makes the prolongation effect not so prominent. In this regard, the purpose of this work was to assess the ability to prolong the action of PVA in relation to the drug release when going from dilute to more concentrated solutions. Three compounds of different chemical nature and mechanism of action–lidocaine (LD), cefazoline (CFZ) and dioxidine (DO)–which are presumably capable of forming complex compounds with PVA and are promising for creating liquid and soft dosage forms for the treatment of burns, purulent wounds of various etiologies, were tak- en as drugs. 2. Experimental 2.1. Materials A sample of PVA grade 11/2 and M = 35 kDa produced by OOO “Reakhim”, sodium salt of cefazolin (CFZ) produced by OJSC Biosintez (Penza, Russia), lidocaine hydrochloride (LD) – PJSC Biokhimik (Saransk, Russia), dioxidin (DO) – OJSC Novosibkhimpharm "(Novosibirsk, Russia) were tak- en for the study. The drugs were used without any addi- tional purification. 2.2. Equipment UV-spectra were recorded on an UV-2600 Shimadzu spec- trophotometer in bidistilled water solution at 298 K, wavelengths ranged from 190 to 500 nm (slit width 1.0 nm, medium scanning rate), with a quartz cuvette of 1 cm thickness. IR- spectra were recorded on an IR Affinity-1S Shimad- zu spectrophotometer with attachments for attenuated total internal reflection (ATIR). Rheological studies were carried out on a Haake Mars III modular dynamic rheometer at 298 K in the mode of continuous shear deformation in the range of shear rates from 0.1 to 100 s–1. The physicomechanical properties were investigated on a Shimadzu AGS-X tensile testing machine (Shimadzu, Ja- pan). DSC curves were recorded on a NETZSCH-Gerätebau instrument (Germany) with a heating rate of 10°C/min. 2.3. Study of interaction of polyvinyl alcohol with drugs To study the interaction of PVA with drugs, the UV spectra of individual compounds, as well as their mixtures, were investigated on a UV-2600 spectrophotometer. The con- centration of PVA solutions used in the study was 10–4–10–3 mol/l, CFZ and DO – 10–4 mol/l, LD – 10–3 mol/l. The composition and the stability constant of the re- sulting complexes were determined by the method of mo- lar ratios [31, 32]. 2.4. Film preparation The films were obtained by pouring a PVA solution onto the degreased surface of a Petri dish glass. The films were dried in two stages: first, in the open air, until the film was formed, and then in a vacuum cabinet at 30 °C until constant weight was obtained. The PVA concentration in the solution varied from 1 to 10%. In the case of prepara- tion of drug-filled films, the drug dissolved in a small amount of water (2 ml) was added with stirring to the PVA solution immediately before the formation of the films. The drug content in the film was 0.01–0.1 mol/mol of the polymer. 2.5. Rheological investigations Rheological investigations of PVA solutions, as well as their mixtures with drugs, were carried out on a Haake Mars III modular dynamic rheometer. 2.6. In vitro drug release The drug loaded solution of PVA was added to dialysis membrane cellophane bags. The bags were immersed in a flask containing 150 ml of PVA solution of the same con- centration as placed in the cellophane bags with a shaking speed of 100 r/min. The experiment was carried out in a thermostat at a temperature of 298 K. At specific time in- tervals, 1 ml of the solution was removed from the medi- Chimica Techno Acta 2022, vol. 9(2), No. 20229206 ARTICLE 3 of 8 um and replaced with fresh solution. The drug concentra- tion was determined by spectrophotometry in the UV re- gion at a wavelength corresponding to the drug absorption maximum. PVA solution was used as a reference solution. The diffusion coefficient of the drug through a semi- permeable membrane was determined based on the Crank approach [33] by the formula: 𝐺s 𝐺∞ ⁄ = [ 16𝐷s𝑡 π𝐿2 ] 0.5 , (1) where Gs is the concentration of the desorbed substance at time t, G∞ is the value of Gs at t→∞, L is the semi- permeable membrane thickness. The amount of the drug that passed through the mem- brane by the time t (Gs) was estimated from the calibra- tion curve. The moment when a constant drug concentra- tion (G∞) was established in the solution was considered the moment when equilibrium was established. 2.7. In vitro drug release from polymer films The kinetics of the drug release from the films into the aqueous medium at 298 K was studied by UV spectropho- tometry of aqueous solutions in the region of the drug ab- sorption maximum. Diffusion coefficients were calculated using equation (1). In this case, L was understood to be the thickness of the film. 2.8. Determination of density of polymer films The density of PVA and PVA-drug films was determined by the pycnometric method according to the standard proce- dure. 3. Results and discussion 3.1. Characterization of complexes polyvinyl alcohol-drugs The prolonging effect of polymers is, in fact, largely de- termined by their ability to form strong compounds such as complexes or salts with drugs. UV-spectroscopic study of dilute PVA solutions in the presence of the studied me- dicinal substances confirms the existing interaction be- tween them. Thus, absorption maxima in UV spectra of CFZ and LD in the aqueous solution are observed at 272 nm (CFZ) and 262 nm (LD). There are three absorp- tion maxima in the UV spectra of DO – at 235, 266, and 280 nm. When the equivalent amount of PVA not absorbed in the UV region at a concentration of 10−4–10−2 mol/l is added to the solution, the intensity of the absorption peak changes, while the absorption maximum shifts by about 3–5 nm bathochromically (Figure 1). The phenomena observed indicate the effect of the pol- ymer on the electronic system of the drugs and the for- mation of the interaction adducts. By the difference in the values of the wavelengths Δλ corresponding to the absorp- tion maximum of the complex and the individual drug, it is possible to estimate the binding energy in the complex compound by the Planck formula: ∆𝐸 = ℎ𝑐 ∆𝜆 , (2) where ΔE is the binding energy, h is Planck's constant, c is the speed of light. Figure 1 UV spectra of drug (1), PVA (2), and PVA-drug (3) for CFZ (a), LD (b) and DO (c). The value of the binding energy in the complexes of PVA with the drugs studied, estimated from the shift of absorption maxima in UV spectra, is about 10–15 kJ/mol. Chimica Techno Acta 2022, vol. 9(2), No. 20229206 ARTICLE 4 of 8 The small values of the bond energies suggest that com- plex formation occurs via hydrogen bonds. The composi- tion of the reaction adducts obtained for all studied sys- tems, determined by the method of isomolar series and the method of molar ratios, is equal to 1. The values of the stability constant for PVA-drug systems are 5.7·103, 6.5·103 and 5.1·103 l/mol when using DO, CFZ and LD, re- spectively. Thus, the adducts of the PVA-drug interaction in an ex- tremely dilute solution can be characterized as compounds with medium stability. 3.2. In vitro drug release The presence of interaction in the PVA-drug system, in principle, is capable of providing a certain level of drug action prolongation due to the attachment to the polymer chain. Indeed, as can be seen from curve 1 in Figure 2, the release of the drug (in this case, CFZ) from a dilute PVA solution occurs rather slowly. However, the situation changes when going from ex- tremely dilute solutions to more concentrated ones. The kinetic curves of the release of CFZ from PVA solutions shown in Figure 2 can be divided into two ranges. In the first initial short range, the release of free CFZ, not fixed on the polymer chain, occurs through diffusion. In the sec- ond range, CFZ attached to the macromolecule is released slowly due to the disintegration of the PVA-CFZ complex. In this case, the kinetic curves reach the limit correspond- ing to the equilibrium drug yield. From the difference be- tween the optical density value corresponding to the equi- librium drug yield and the optical density corresponding to the amount of CFZ introduced into the solution, it is possible to determine the value of equilibrium βequ fixed on the macromolecular chain. Generally, the higher the PVA concentration in the solution, the lower the value of the amount of the drug βequ fixed on the polymer chain (Figure 3). This fact allows us to assume that with an in- crease in the viscosity of the PVA solution, the effect of prolongation can actually be leveled. Figure 2 Kinetic curves of the release of CFZ from a PVA solution with a concentration of 4·10–3 (1), 4·10–1 (2), 1 (3) and 4 (4) g/dl. The content of CFZ in the solution is 10–4 mol/l. The dotted line shows the optical density value corresponding to the amount of CFZ introduced into the solution. Figure 3 Dependence of the amount of CFZ (1), DO (2) and LD (3) firmly attached to the polymer chain on the concentration of PVA in solution. For all the drugs studied, the nature of the dependence of βequ on the concentration is the same. There is a concen- tration range within which the amount of drug firmly held by macrochains is maximal and practically does not de- pend on the concentration of PVA. With an increase in the concentration of PVA in the solution, the values of βequ begin to decrease up to a minimum value, reaching the limit at a PVA concentration of the order of 8–10 g/dl. A decrease in the amount of the drug retained by macro- molecules is likely to be associated with a decrease in the availability of polymer units for interaction with drugs due to changes in the supramolecular state of the polymer that occur with an increase in the PVA content in the solu- tion. 3.3. Rheological investigations of polymer solutions The data of rheological measurements unambiguously indicate that an increase in the concentration of polymer in the solution is accompanied by an increase in viscosi- ty. Moreover, this increase in viscosity is not monotonic. Figure 4 clearly distinguishes three regions. Region I is the so-called region of dilute solutions, in which macro- molecules do not interact with each other. The viscosity in this area increases with increasing concentration ac- cording to the linear law η~С1 [34–36]. Region II is the region of concentrated solutions with a fully formed fluc- tuation network of entanglements of macromolecules. In this region, the viscosity increases with an increase in concentration according to the power law η~Сn, where n~5. The intermediate region of semi-diluted solutions is characterized by an intensive rearrangement of the su- pramolecular structure and the formation of a fluctua- tion network [37, 38]. Despite the fact that the addition of drugs at a concen- tration of up to 0.5 mol/l does not change the viscosity either in dilute or in more concentrated solutions (Fig- ure 4), the changes in the structural-physical state of PVA in solution are directly reflected in the character of the Chimica Techno Acta 2022, vol. 9(2), No. 20229206 ARTICLE 5 of 8 interaction of PVA with the drugs analyzed in the work (Figure 3). And, since from the structural-physical point of view PVA solutions are not equivalent, the value of βequ also changes unequally. Solutions with a PVA concentra- tion of less than 0.5 g/dl are the solutions of non- interacting macromolecules that are maximally available for interaction with a drug. It is in this region that βequ reaches its highest values, which remain constant while the solution is diluted. PVA solutions with a concentration of about 10 g/dl and more represent a continuous fluctua- tion network, in which the availability of PVA links for interaction with a drug is minimal. In this region, the val- ues of βequ are the lowest. The intermediate region of semi-diluted solutions is characterized by significant changes in the values of βequ. Consequently, an increase in the viscosity of the polymer in the solution caused by an increase in its concentration leads to a decrease in the fraction of the drug that is firmly attached to the polymer chain. In the case when the amount of a strongly attached drug is not large, there is a rapid release of a part of the drug that is not associated with the polymer chain but the remaining part of the drug, which is attached to the chain, is released at a rate corresponding to the rate of decompo- sition of the PVA-drug adduct. As can be seen from the data in Table 1, the rate of the drug release increases with an increase in the PVA concen- tration in the solution, since as the content of PVA in the solution increases, the amount of the free drug increases. The values of the diffusion coefficient undergo similar changes. If with an increase in the concentration of PVA in solution the value of βequ tended to zero, in concentrated solutions the yield of the drug would only be determined by the concentration of the free drug not bound by the polymer chain. In this case, during the transition from liquid to soft dosage forms of protective film coatings the prolongation effect due to the formation of the PVA-drug adduct would be virtually absent. However, since the val- ue of βequ goes to the non-zero limit, the drug yield from concentrated solutions is determined by two factors – the amount of the free drug and the stability constant of the PVA-drug complex. Thus, the effect of prolonging the action of PVA does not increase with an increase in its content in the solution. An increase in the viscosity of the polymer in solution, caused by an increase in its concentration, leads not only to a slowdown in the diffusion of the drug from the poly- mer solution, but also to a significant decrease in the amount of drugs firmly fixed on the polymer matrix. Since it is the PVA-drug interaction adduct that provides the slow release of the drug from the polymer solution, a de- crease in its amount leads to the fact that no enhancement of the prolonging action is observed. Table 2 presents the physicochemical and physicome- chanical characteristics of the PVA films obtained from solutions of various concentrations. Figure 4 Dependence of the dynamic viscosity of PVA on its con- centration in solution in logarithmic coordinates in the absence () and in the presence of DO (), LD (), CFZ () taken at a concentration of 0.1 mol/l. Table 1 Results of processing the kinetic curves of the drug re- lease from PVA solutions. Drug PVA concentra- tion in solu- tion, g/dl V, %/min Da·10 9, cm2/s CFZ 4·10–3 0.10 0.04 4·10–1 0.18 0.27 1.0 0.49 1.18 2.0 1.25 3.40 4.0 1.92 5.35 8.0 2.15 6.02 10.0 2.18 6.11 LD 4·10–3 0.13 0.11 4*10–1 0.19 0.30 1.0 0.67 1.70 2.0 1.75 4.86 4.0 1.98 5.53 8.0 2.26 6.35 10.0 2.28 6.40 DO 4·10–3 0.14 0.15 4·10–1 0.15 0.18 1.0 0.56 1.38 2.0 1.58 4.36 4.0 1.82 5.06 8.0 2.00 5.59 10.0 2.10 5.88 3.4. In vitro drug release from polymer films When film materials are obtained from PVA solutions, from the technological point of view it is much more con- venient to obtain them not from diluted but from more concentrated solutions. Consequently, the process of film formation will be carried out under conditions when the amount of the drug firmly fixed on the polymer matrix βequ, is small. This means that most of the drug will freely diffuse through the polymer film. So, the rate of this process will be determined not only by the value of βequ and Kest but also by the characteristics of the polymer film itself. In this regard, it becomes possi- ble to additionally regulate the rate of the drug release from the polymer film. Chimica Techno Acta 2022, vol. 9(2), No. 20229206 ARTICLE 6 of 8 Table 2 Characteristics of PVA films obtained from solutions of different concentrations. PVA concentration in the film, g/dl Tg, 0C T, 0C ∆H, J/g wcr, % αcr, % E, MPa σbreak, MPa lbreak, MPa 1 52 227 86.2 55.0 33.5 2404 57.8 86.3 2 44 226 85.4 54.5 33.0 3965 65.3 146.7 3 42 225 85.5 54.5 32.6 4672 87.4 150.6 5 40 224 84.7 54.0 32.4 5277 90.5 153.8 7 43 224 80.4 51.3 30.0 5513 88.5 110.0 10 45 223 71.8 45.8 28.3 4850 83.3 65.8 20 50 224 70.8 45.1 27.5 4167 73.4 50.1 wcr – from DSC data; αcr – from IR-spectra data. For example, by varying the concentration of the poly- mer in the initial solution films with different densities can be obtained. From the data shown in Table 3, it can be seen that the values of the density of the films obtained from the initial different concentration of the polymer in the solution (in the presence of the drug as well) pass through a mini- mum corresponding to the concentration value of 5 g/dl. It is important that, according to the change in density, the values of the drug release rate from the film and the diffu- sion coefficient also change. Table 3 Summary data on the results of processing the kinetic curves of drug release from the PVA films and data on the film density. Drug drug concen- tration, mol/mol PVA PVA con- centration in fillm, g/dl ρ, g/cm3 Da·10 9, cm2/s – – 1 1.142 – 2 1.120 – 5 1.050 – 10 1.156 – CFZ 0.01 1 – 1.11 2 – 2.72 5 – 3.22 10 – 1.98 0.10 1 1.159 1.14 2 1.134 2.80 5 1.072 3.41 10 1.167 1.92 LD 0.01 1 – 1.54 2 – 2.83 5 – 3.92 10 – 3.46 0.10 1 1.154 1.89 2 1.129 2.90 5 1.063 3.68 10 1.163 3.05 DO 0.01 1 – 1.24 2 – 1.98 5 – 2.90 10 – 2.81 0.10 1 1.150 1.27 2 1.125 1.32 5 1.057 1.41 10 1.160 0.98 Analysis of the data given in Table 3 unambiguously proves the fact that varying the polymer concentration in the initial solution is an additional factor regulating the rate of drug release. Previously, this kind of impact of the supramolecular organization of the polymer matrix on diffusion processes was discovered in the works [30, 39, 40] for the films of physiologically active polymers – chi- tosan polysaccharides, sodium salt of chitosan succina- mide and sodium salt of carboxymethylcellulose. It is noteworthy that the diffusion coefficients for the film samples for all considered cases are lower than those for solutions of the corresponding concentrations (Table 1). Obviously, a sharp increase in viscosity when going from solutions to solid film samples, in this case, has a decisive effect on the value of the diffusion coefficients. Thus, the assessment of the ability to prolong the ac- tion of one of the physiologically active polymers, polyvi- nyl alcohol, showed that using some prolongation techno- logical methods, involving the creation of compounds of medicinal and auxiliary substances, as well as an increase in the viscosity of the dispersion medium when the drugs are enclosed in film shells, it is possible to achieve direct regulation of the rate of release of medicinal drugs from polymer dosage forms. 4. Conclusions It was shown that mixing aqueous PVA solutions with the solutions of cefazolin, lidocaine, and dioxidine is accom- panied by the formation of reaction adducts which are complex compounds of medium stability formed by means of hydrogen bonds. It was found that the range of PVA concentrations in a solution of 0.5–10 g/dl is characterized by an intense rear- rangement of the supramolecular structure, which results in a significant decrease in the amount of the drug which can be firmly fixed on the macromolecular chain under the equilibrium conditions. As a result, no increase in the pro- longing effect of PVA with an increase in its content in the solution and a corresponding increase in viscosity is ob- served. It was proven that when going from solutions to poly- mer films, the yield of drugs is largely determined by the structure of the polymer matrix, in particular, by its densi- ty. The lower the density of the polymer film, the greater Chimica Techno Acta 2022, vol. 9(2), No. 20229206 ARTICLE 7 of 8 the diffusion coefficient of the drug release from the film. The diffusion coefficient values for the film samples for all considered cases are lower than those for the solutions of corresponding concentrations. Supplementary materials No supplementary data are available. Funding This research had no external funding. Acknowledgments None. Author contributions Conceptualization: K.E.I. Data curation: Sh.A.S Formal Analysis: T.A.S., L.R.Yu., Z.E.M. Investigation: Sh.A.S., L.R.Yu., Z.E.M. Methodology: K.E.I., Sh.A.S. Project administration: K.E.I. Validation: K.E.I. Visualization: L.R.Yu Writing – original draft: K.E.I., Sh.A.S., T.A.S. Writing – review & editing: Sh.A.S. Conflict of interest The authors declare no conflict of interest. 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