Pharmacophore an International Research Journal
Pharmacophore
Submit Manuscript
Open Access | Published: 2021 - Issue 1

STABILIZATION OF PHYSIOLOGICAL SALINE SOLUTIONS FOR INJECTION BY LOW-FREQUENCY ACOUSTIC TREATMENT

A. S. Magamadov1,  M.-I. V. Chuchaev1, D. R. Baragunova1, I. A. Sokurov1, A.V. Sklyuev2*, D. Berthold3, M.P, Marinicheva5, E.V. Svetlakova6, O.A. Baklanova4, A.E. Mishvelov7, S.N. Povetkin4

 

  1. North Ossetian State Medical Academy, Vladikavkaz, RNO-Alania, Russia
  2. Soil Respiration Ltd, Stavropol, Russia.
  3. EVN Inc., Vienna, Austria.
  4. North Caucasus Federal University, Stavropol, Russia.
  5. Saratov State Agrarian University named after N.I. Vavilov, Saratov, Russia.
  6. Stavropol State Agrarian University, Stavropol, Russia.
  7. Stavropol State Medical University, Stavropol, Russia

ABSTRACT

Despite the large range of ready-made medicines, the extemporal formulation has not lost its significance.  One of the most significant extemporal dosage forms in providing, including emergency medical care, is solutions for injection, which have technological features of manufacturing. The article presents the results of a study of the main properties of water during low-frequency acoustic treatment for the preparation of stable saline solutions. Methods of stabilization of solutions for injection were studied. The effect of low-frequency acoustic treatment on the physical and chemical properties of osmotic water has been experimentally confirmed. Using computed quantum and chemical modeling, the most probable forms of water nanoclusters formed during low-frequency acoustic treatment are determined. Prospects of using the low-frequency acoustic treatment in the Pharmaceutical Industry and pharmacies to stabilize saline solutions for injection are shown. Further research will be related to the treatment of real physiological solutions of drugs with different molecular weights.


Keywords: low-frequency acoustic treatment, saline solution, injection solution, stabilization, structured water, water nanoclusters


Introduction

Despite the large range of ready-made medicines, the extemporal formulation has not lost its significance [1]. This is due to the lack of industrial analogs for some medicines and unavailability of taking into account the individual characteristics of the patient such as body weight, the severity of the disease, and allergic reactions, etc. [2, 3].

One of the most significant extemporal dosage forms in providing, including emergency medical care, is solutions for injection, which have technological features of manufacturing. The advantage of solutions for injection as dosage forms is their high bioavailability, the accuracy of dosing, and the possibility of manufacturing in the form of an intra-apical billet [4, 5].

Despite the extensive range of injectable solutions produced at pharmaceutical enterprises, injectable solutions made in pharmacies are still in demand. [1, 6-10] The main reasons for demand are:

  • lack of industrial analogs
  • lower cost compared to analogs produced at pharmaceutical enterprises
  • possibility of manufacturing a dosage form of a given volume

However, there is also a serious disadvantage of using injectable solutions – they need stabilization [5, 11].

The stability of drugs means their ability to maintain the physical and chemical properties and pharmacological activity required by the Pharmacopoeia or technical documentation for a certain period of storage [12-14].

The study of stabilization of injectable solutions is an important technological task since about 90 % of medicinal substances require the use of stabilizers or special preparation conditions [15]. This is because solutions of medicinal substances undergo various changes during thermal sterilization. They can be caused by hydrolysis, oxidation-reduction, decarboxylation, polymerization, photochemical degradation, etc. [16-18, 30, 33].

To increase the stability of dosage forms for injection, stabilization is used by physical, chemical, and complex methods [19, 32, 34]. From the point of view of environmental friendliness and inertia, physical methods are the most promising [20-22, 31, 35].

Currently, the following physical methods are widely used:

- boiling water followed by rapid cooling;

- saturation of water for injection with carbon dioxide or inert gases;

- recrystallization of origin substances;

- adsorbents application.

Pharmacies usually use the first method. Using boiling and rapid cooling method the content of free oxygen in water decreases from 9 to 1.4 mg/l, which significantly reduces the intensity of redox processes in solutions, ensuring their stability [23, 24, 36]. The disadvantage of this method is the high energy consumption and duration of the process.

The method of saturating water for injection with carbon dioxide or inert gases is more effective than the boiling/cooling method since water saturated with these gases contains less oxygen than boiled water (0.18 mg/l). However, it is technically a more complicated method and requires special equipment [25, 26].

The method of recrystallization of origin substances is used to remove their impurities. It is advisable to use it for the purification of hexamethylenetetramine if the drug contains impurities of amines, ammonium salts, and para forms and does not meet the requirement "suitable for injection" [27].

Impurities contained in medicals can also be removed by adsorption from solutions of medicinal substances. Usually activated carbon grade A is used as an adsorbent. It serves as an adsorbent not only for low-molecular chemical impurities (for example calcium oxalate in calcium lactate) but also for high-molecular compounds, e.g. pyrogenic mixtures of polylipoproteins and lipopolysaccharides [28].

Thus, the main directional effect of physical methods for stabilizing physiological solutions for injection is to reduce the redox potential and active acidity. At the same time, other physical and chemical properties of water also change, which contribute to its structuring, formation of nanoclusters, and, consequently, stabilization.

Our preliminary research has shown that acoustic effects in the infrasound range can have a similar effect on water. In this regard, the purpose of this work was to study the effect of low-frequency acoustic treatment on the physical and chemical parameters of water.

 

Materials and Methods

Experimental studies were carried out on samples of osmotic water using an innovative acoustic water treatment equipment "ERADA" provided by "Soil Respiration" Ltd. (Stavropol, Russia). This company is engaged in the treatment of drinking water and acoustic stimulation of the growth of native soil microflora for better germination of crop seeds. The technology is developed by the company, and the processing parameters are "know-how", so it was decided not to disclose the parameters of the equipment and the radiation frequency.

The effect of infrasound radiation on the physical and chemical properties of water and its structure was studied in the laboratories of North Caucasus Federal University and Stavropol State Agrarian University. Samples of osmotic water treated with acoustic exposure from 0 to 60 minutes in 15-minute increments were examined.

Reagent grade chemicals and grade A glassware were used in the present study. The conductivity of distilled water used was less than 1 µS/cm.

 

pH determination

The active acidity of water was measured at room temperature using a pH meter-ionomer "Expert 001" with measurement accuracy ±0.05 (Avtomatika TH, Smolensk, Russia).

 

RedOx potential determination

The RedOx potential was measured at room temperature using a pH meter-ionomer "Expert 001" using an ERP-105 electrode with measurement accuracy ±0.01 mV (Avtomatika TH, Smolensk, Russia).

 

Investigation of specific electrical conductivity of water

The specific electrical conductivity was measured at room temperature with conductometer "Expert 002" with measurement accuracy ±0.1 µs/m (Automatika TH, Smolensk, Russia).

 

Measurement of the freezing point of water

The freezing temperature of samples was measured using an automatic cryoscope (Cryostar GmbH., Germany) with measurement accuracy ±0.0001 оС.

 

Measurement of the boiling point of water

The boiling point of the samples was measured using an induction furnace and a laboratory thermocouple TL-2 (Altavir LLC, Belgorod, Russia) with measurement accuracy ±0.05 оС

 

Computed quantum and chemical modeling of water

Quantum and chemical modeling were performed in the QChem program using the IQmol molecular editor. The simulation parameters were selected according to the method of Blinov et al. (2019) [29]: Energy mode – HF (Hartree-Fock), basis – 6-31G, convergence – 5, force field – Ghemical.

Results and Discussion

When studying water samples after low-frequency acoustic treatment, nonlinear dependences were obtained that confirm the reliable effect of treatment on the physical and chemical properties of water.

Results of the obtained pH of samples are shown in Figure 1.

 

Figure 1. Dependence of the pH of osmotic water samples on the acoustic treatment duration

 

In the analysis of Figure 1 data found that the most significant change of the active acidity observed in the 30-minute acoustic treatment, which is associated with an increase in the concentration of hydrogen ions [H+] and intensification of the process of dissociation of water molecules under the action of acoustic treatment.

Figure 2 shows the result of the RedOx measurement.

 

 

Figure 2. Dependence of the RedOx potential in samples of osmotic water on the acoustic treatment duration

Figure 2 shows that the greatest changes in the RedOx potential observed at a 30-minute acoustic treatment, which is associated with an increase in the concentration of particles (water molecules or clusters) with antioxidant properties that appear under the influence of acoustic treatment of water.

The dependence of specific electrical conductivity in samples of osmotic water on the time of acoustic treatment is shown in Figure 3.

 

Figure 3. Dependence of specific electrical conductivity in samples of osmotic water on the acoustic treatment duration

 

Analysis of Figure 3 data revealed that the greatest changes in the electrical conductivity are observed at the 30-minute acoustic treatment, which is associated with an increase in the concentration of charged pre dissolving particles (molecules or water clusters) formed by the action of acoustic treatment of samples.

The obtained dependences of the freezing point of the experimental samples are shown in Figure 4. The dependence of the boiling point of osmotic water on the time of acoustic treatment is shown in Figure 5.

 

Figure 4. Dependence of the osmotic water freezing point on the acoustic treatment duration

 

Figure 5. Dependence of the boiling point of osmotic water on the acoustic treatment duration

 

Analysis of Figure 5 data showed that the greatest temperature change of boiling and freezing is observed at 15 – 30 minute acoustic treatment, which also correlates with previous results and, apparently, due to the increase in the number of particles and supramolecular structures (clusters or aggregates of water), destruction of which in the process of evaporation and freezing requires a lot of energy.

According to the data obtained, it was found that during acoustic processing, clusters and supramolecular formations of water molecules are formed, reaching maximum values at 15-30 minutes. In this regard, computed quantum-chemical modeling of water nanoclusters that are most likely to be formed during low-frequency acoustic treatment was performed based on the analysis of the energy characteristics of water clusters (Table 1).

 

Table 1. Results of the study of energy characteristics of water clusters forming under low-frequency acoustic treatment

Cluster

Chemical energy, kJ/mol

Monomer

0,0000

Dimer

-65,8672

Trimer

-351,3552

Tetramer

-85,8265

Pentamer

-179,0214

Gexamer

-241,9691

Geptamer

-290,5196

 

Constructed models are represented in Figure 6.

 

 

 

 

a)

b)

c)

 

 

 

d)

e)

f)

Figure 6. 3D models of nanocluster of treated water.

a) dimer, b) trimer, c) tetramer,d) pentamer, e) gexamer, f) geptamer

 

As a result of computer quantum-chemical modeling, possible models of water clusters are shown and it is revealed that water clusters are stable formations from the energy point of view.

 

Conclusion

The experiment showed that low-frequency acoustic treatment of osmotic water helps to stabilize its pH and RedOx. The water structure changes during processing, forming stable nanoclusters and submolecular formations, the chemical binding energy of which is calculated by computer quantum chemical modeling. The results showed that an innovative method of low-frequency acoustic water treatment can be used to stabilize physiological solutions for injection. Further research will be related to the treatment of real physiological solutions of drugs with different molecular weights.

Acknowledgments: The authors express their gratitude to their colleague, inventor Eduard Merzakaev, for the development of the emitter used in this work

Conflict of interest: None

Financial support: None

Ethics statement: All submitted materials are carefully selected and peer-reviewed.

References

 

  1. Bledzhyants GA, Mishvelov AE, Nuzhnaya KV, Anfinogenova OI, Isakova JA, Melkonyan RS, et al. The Effectiveness of the Medical Decision-Making Support System "Electronic Clinical Pharmacologist" in the Management of Patients Therapeutic Profile. Pharmacophore. 2019;10(2):76-8
  2. Nuzhnaya KV, Mishvelov AE, Osadchiy SS, Tsoma MV, Slanova RH, ‎Kurbanova AM, et al. Computer Simulation and Navigation in Surgical ‎Operations‎. Pharmacophore. 2019;10(4):46-5
  3. Osipchuk GV, Povetkin SN, Nagdalian AA, Rodin IA, Rodin MI, Ziruk, IV, et al. The Issue of Therapy Postpartum Endometritis in Sows Using Environmentally Friendly Remedies, Pharmacophore. 2019;10(2): 82-84.
  4. Barabanov PV, Gerasimov AV, Blinov AV, Kravtsov AA, Kravtsov VA. Influence of nanosilver on the efficiency of Pisum sativum crops germination. Ecotoxicol Environ Saf. 2018;147:715-9. doi: 10.1016/j.ecoenv.2017.09.024
  5. Blinov AV, Kravtsov AA, Krandievskii SO, Timchenko V, Gvozdenko AA, Blinova A. Synthesis of MnO2 Nanoparticles Stabilized by Methionine. Russ J Gen Chem, 2020;90(2):283-6.
  6. Lopteva, MS, Povetkin SN, Pushkin SV, Nagdalian AA. 5% Suspension of Albendazole Echinacea Magenta (Echinacea Purpurea) Toxicometric Evaluation. Entomol Appl Sci Lett. 2018;5(4):30-4.
  7. Dubey J, Singh A. Green Synthesis of TiO2 Nanoparticles Using Extracts of Pomegranate Peels for Pharmaceutical Application. Int J Pharm Phytopharm Res. 2019;9(1):85-
  8. Bhusari S, Borse G, Rindhe M, Wakte P. Validated RP-HPLC for Simultaneous Estimation of Etoposide and Picroside-II in Patented Pharmaceutical Formulation and the Bulk. Int J Pharm Phytopharm Res. 2019;9(2):83-90.
  9. Surachman F.E, Muhtadi A. Integration of service quality and quality function deployment as an effort of pharmaceutical service improvement on outpatient in a referral Hospital, Karawang, Indonesia J Adv Pharm Edu Res. 2019;9(2):13-23.
  10. Haider S, Nisar QA, Baig F, Azeem M. Dark Side of Leadership: Employees' Job Stress & Deviant Behaviors in Pharmaceutical Industry. Int J Pharm Res Allied Sci. 2018;7(2):125-38.
  11. Nagdalian, AA, Oboturova, NP, Budkevich, RO, Selimov, MA, Demchenkov, EL. Study of the Influence of the Electrohydraulic Effect on the Structure and Mechanical Properties of Muscular Tissue Using Atomic-Force Microscopy. Res J Pharm Biol Chem Sci. 2016a;7(2):517-23.
  12. Areshidze DA, Mischenko DV, Makartseva LA, Rzhepakovsky IV, Nagdalian AA. Some functional measures of the organism of rats at modeling of ischemic heart disease in two different ways. Entomol Appl Sci Lett. 2018;5(4):2349-2864.
  13. Morozov VY, Kolesnikov RO, Chernikov AN, Skorykh LN, Dorozhkin VI. Effect from Aerosol Read-justment Air Environment on Productivity and Bio-chemical Blood Parameters of Young Sheep. Res J Pharm Biol Chem Sci. 2017;8(6):509-14.
  14. Saleeva IP, Morozov VY, Kolesnikov RO, Zhuravchuk EV, Chernikov AN. Disinfectants effect on microbial cell. Res J Pharm Biol Chem Sci. 2018;9(4):676-81.
  15. Nagdalian AA, Pushkin SV, Povetkin S, Nikolaevich K, Egorovna M, Marinicheva MP, et al. Migalomorphic Spiders Venom: Extraction and Investigation of Biological Activity. Entomol Appl Sci Lett. 2018 Jan 1;5(3):60-70.
  16. Selimov MA, Nagdalian AA, Povetkin SN, Statsenko EN, Kulumbekova IR, Kulumbekov GR, et al. Investigation of CdCl Influence on Red Blood Cell Morphology. Int J Pharm Phytopharmacological Res. 2019;9(5):8-13.
  17. Sizonenko MN, Timchenko LD, Rzhepakovskiy IV, DA SP AV, Nagdalian AA, Simonov AN, et al. The New Efficiency of the «Srmp»–Listerias Growth-Promoting Factor during Factory Cultivation”. Pharmacophore. 2019;10(2):85-8.
  18. Pushkin SV, Tsymbal BM, Nagdalian AA, Nuzhnaya KV, Sutaeva AN, Ramazanova SZ, et al. The Use of Model Groups of Necrobiont Beetles (Coleoptera) for the Diagnosis of Time and Place of Death. Entomol Appl Sci Lett. 2019;6(2):46-56.
  19. Nagdalyan AA, Oboturova AP, Povetkin SN, Ziruk IV, Egunova A, Simonov AN, et al. Adaptogens Instead Restricted Drugs Research for An Alternative Itemsto Doping In Sport. Res J Pharm Biol Chem Sci. 2018;9(2):1111-6.
  20. Nesterenko AA, Koshchaev AG, Keniiz NV, Shhalahov DS, Vilts KR. Development of device for electromagnetic treatment of raw meat and starter cultures. Res J Pharm Biol Chem Sci. 2017a;8(1):1080-5.
  21. Nesterenko AA, Koshchaev AG, Keniiz NV, Shhalahov DS, Vilts KR. Effect of low frequency electromagnetic treatment on raw meat. Res J Pharm Biol Chem Sci. 2017;8(1):1071-9.
  22. Nagdalyan AA, Selimov MA, Topchii MV, Oboturova NP, Gatina YS, Demchenkov EL. Ways to reduce the oxidative activity of raw meat after a treatment by pulsed discliarge technology. Res J Pharm Biol Chem Sci. 2016;7(3):1927-32.
  23. Keniiz NV, Koshchaev AG, Nesterenko AA, Omarov RS, Shlykov SN. Study the effect of cryoprotectants on the activity of yeast cells and the moisture state in dough. Res J Pharm Biol Chem Sci. 2018;9(6):1789-96.
  24. Kojima K. Biological evaluation and regulation of medical devices in Japan, Editor(s): Jean-Pierre Boutrand, In Woodhead Publishing Series in Biomaterials, Biocompatibility and Performance of Medical Devices, Wood head Publishing, 2012:404-48, https://doi.org/10.1533/9780857096456.4.404.
  25. Omarov RS, Shlykov SN, Nesterenko AA. Obtaining a biologically active food additive based on formed elements blood of farm animals. Res J Pharm Biol Chem Sci. 2018;9(6):1832-8.
  26. Moayed RZ, Izadi E, Heidari S. Stabilization of saline silty sand using lime and micro silica. J Cent South Univ. 2012 Oct 1;19(10):3006-11. https://doi.org/10.1007/s11771-012-1370-1  
  27. Hughes IE, Smith JA. The stability of noradrenaline in physiological saline solutions. J Pharm Pharmacol. 1978 Sep;30(1):124-6. 10.1111/j.2042-7158.1978.tb13179.x.
  28. Blinov AV, Yasnaya MA, Blinova AA, Shevchenko IM, Momot EV, Gvozdenko AA, et al. Computer quantum-chemical simulation of polymeric stabilization of silver nanoparticles. Physical and chemical aspects of the study of clusters nanostructures and nanomaterials. 2019;11:414-21.
  29. Cheboi PK, Siddiqui SA, Onyando J, Kiptum CK, Heinz V. Effect of Ploughing Techniques on Water Use and Yield of Rice in Maugo Small-Holder Irrigation Scheme, Kenya. Agri Engineering. 2021;3(1):110–117. https://doi.org/10.3390/agriengineering3010007
  30. Nagdalian AA, Rzhepakovsky IV, Siddiqui SA, Piskov SI, Oboturova NP, Timchenko LD, Lodygin A, Blinov AV, Ibrahim SA. Analysis of the Content of Mechanically Separated Poultry Meat in Sausage Using Computing Microtomography. Journal of Food Composition and Analysis. 2021; 100, 103918. https://doi.org/10.1016/j.jfca.2021.103918
  31. Siddiqui, SA, Ahmad, A. Dynamic analysis of an observation tower subjected to wind loads using ANSYS. In: Proceedings of the 2nd International Conference on Computation, Automation and Knowledge Management (ICCAKM) [conference proceedings on the Internet]; 2021 Jan 19-21; Dubai, United Arab Emirates. United Arab Emirates: IEEE; 2021 [cited 2021 Jan 19]. p. 6-11. Available from: IEEE Xplore
  32. Salins SS, Siddiqui SA, Reddy SVK, Kumar S. Parametric Analysis for Varying Packing Materials and Water Temperatures in a Humidifier. In: Proceedings of the 7th International Conference on Fluid Flow, Heat and Mass Transfer (FFHMT’20) [conference proceedings on the Internet]; 2020 Nov 15-17; Niagara Falls, Canada. Canada: FFHMT; 2020. p. 196(1)-196(11). Available from: FFHMT
  33. Siddiqui SA, Ahmad A. Implementation of Thin-Walled Approximation to Evaluate Properties of Complex Steel Sections Using C++. SN Computer Science [Internet]. 2020 Oct [cited 2020 Oct 16];1(342):1-11. Available from: https://link.springer.com/article/10.1007/s42979-020-00354-1 DOI: 10.1007/s42979-020-00354-1
  34. Siddiqui SA, Ahmad A. Implementation of Newton’s Algorithm Using FORTRAN. SN Computer Science [Internet]. 2020 Oct [cited 2020 Oct 17];1(348):1-8 Available from: https://link.springer.com/article/10.1007/s42979-020-00360-3#citeas DOI: 10.1007/s42979-020-00360-3
  35. Salins SS, Siddiqui SA, Reddy SVK, Kumar S. Experimental investigation on the performance parameters of a helical coil dehumidifier test rig. Energy Sources, Part A: Recovery, Utilization, and Environmental Effects [Internet]. 2021 Apr [cited 2021 Apr 9];43(1):35-53. Available from: https://www.tandfonline.com/doi/full/10.1080/15567036.2020.1814455 DOI: 10.1080/15567036.2020.1814455
  36. Ovchinnikova J A, Nesterenko A, Oboturova N, Baklanova O, Barybina L, Baklanov I, et al. Technological Aspects of the Use of Lentil Proteins in the Production of Raw Smoked Sausages. Int j pharm phytopharm res. 2020;10(6):246-251. https://doi.org/10.51847/kDAbNX7J2N
QR code:

Short Link:
Quick Access

Pharmacophore
ISSN: 2229-5402


Pharmacophore
© 2021 All rights reserved