STUDY OF THE STABILITY OF ORGANOLEPTIC AND STRUCTURAL-MECHANICAL INDICATORS OF SEMI-SOLID PREPARATIONS WITH METAL NANOPARTICLES

Aim. Research of the stability of organoleptic and rheological properties of semi-solid preparations with silver and gold nanoparticles.Methods. For the study of organoleptic parameters, a classic method for determining the stability with periodic control of dosage forms in two temperature regimens was used: 8-15 °C (cool place) and 15-25 °C (room temperature). To study the rheological characteristics of semi-solid preparations, a rotary viscometer with a system of coaxial cylinders was used.Results. We studied three medicinal forms based on silver nanoparticles - ointment, cream and gel, which can be promising for the use in dermatology, as well as two dosage forms based on nanoparticles of silver and gold for the use in dentistry and surgery for the treatment of infectious, purulent-inflammatory diseases of skin and mucous membranes of the oral cavity. Within 24 month of storage of dosage forms in a dark place in dark glass containers every 6 months the following parameters: homogeneity, odour, colour and pH were monitored. Rheological parameters were investigated after the preparation of dosage forms and after 24 months of storage. According to the rheological indicators rheograms of stream semi-solid preparations were constructed, and also indicators of mechanical stability were calculated. It was found that all samples are coagulation systems with a pseudoplastic flow type. The obtained rheograms contain loops of hysteresis, which characterize their certain degree of thixotropy.Conclusion. According to the results of studies the stability of organoleptic characteristics of semi-solid preparations at a storage temperature 8-15 0С in a place protected from light is established. According to the rheological properties, samples of studied semi-solid preparations have a good ability to apply on the skin and extrusion from tubes.


Introduction
Stability of quality indicators of drugs ensures the continuity of their therapeutic properties in the process of storage and use. Therefore, the study of stability should be the subject of special attention at the stage of pharmaceutical design of drugs [1,2].
The development of a new medicinal product should be based on general methodological approaches to pharmaceutical design, taking into account the requirements for the dosage form [3].
In the development of soft drugs, considerable attention should be paid to the study of the rheological properties of ointment and gel bases, since conducting such studies can control the quality of the drug by introducing additional auxiliary substances, changes in modes and methods of the process [4].

Formulation of the problem in a general way, the relevance of the theme and its connection with important scientific and practical issues
Important indicators of stability of soft drugs are organoleptic parameters: appearance, colour, odour, homogeneity and rheological properties: marginal shear stress (yield strength) and structural viscosity. From a practical point of view, the study of properties such as smearing and extrusion from tubes, which are determined by the degree of thixotropy of samples, is important.

Analysis of recent studies and publications in which a solution of the problem and which draws on the author
At the Department of Technology of medicine and biopharmacy of the Lviv National Medical University named after Danylo Halytsky, was conducted research on the pharmaceutical development of drugs in which metal nanoparticles are used as active pharmaceutical ingredients [5].
Based on the study of the peculiarities of the course of the pathological process in infectious, purulentinflammatory and burn skin diseases and the analysis of the results of microbiological studies, the composition of soft drugs with silver nanoparticles in various dosage forms (ointment, cream, gel) depending on the stage of the wound process was substantiated [6,7].
The combination of silver and gold nanoparticles proved to be effective in purulent inflammatory diseases of the maxillofacial area in an in vitro and in vivo experiment. The high antimicrobial, anti-inflammatory activity and ability of the studied nanoparticles to stimulate the reparative processes of soft tissues and bones was estab-lished [8]. On the basis of a colloidal solution of silver and gold nanoparticles, an ointment and gel have been developed for use in dentistry and surgery [9].
According to SPHU, soft drugs should be homogeneous in terms of weight and content, colour and odour in accordance with the specifications and have constant rheological characteristics throughout the shelf life [10].
In the design of soft drugs, Ukrainian scientists pay close attention to studying the structural and mechanical properties of these dosage forms [11,12].

Allocation of unsolved parts of the general problem, which is dedicated to the article
The main indicator of drug stability is the quantitative content of active pharmaceutical ingredients, but for soft drugs, organoleptic parameters such as appearance, colour, odour, homogeneity, and rheological properties that characterize the consumer's properties of the medicinal product are equally important indicators of stability, the ability to smear and extrude the tubes.

Formulation of goals (tasks) of Article
The aim of the work is to study the stability of organoleptic and rheological properties of soft drugs with silver and gold nanoparticles.

Statement of the basic material of the study (methods and objects) with the justification of the results
Regardless of dosage form and specific drug requirements, all methods of stability research are designed to determine the term for which the components of the drug and the finished product will be stable [13].
Three drugs based on silver nanoparticlesointment, cream and gel, which can be promising for use in dermatology, as well as two dosage forms based on nanoparticles of silver and gold for use in dentistry and surgery for the treatment of infectious, purulent, inflammatory diseases of the skin and mucous membranes of the oral cavity.
For the study of organoleptic parameters, a classic method for determining the stability with periodic control of dosage forms was used [14,15]. The study was performed on 3 series of drugs stored in dark glass containers at two temperature regimes: 8-15 °C (cool place) and 15-25 °C (room temperature) in a place protected from light.
The study of the rheological characteristics of drugs in soft dosage forms with nanoparticles of metals was carried out after the preparation of dosage forms and after 24 months of storage on a rotary viscometer Myr VR 3000, manufactured in Spain, using a system of coaxial cylinders.
Characteristics of the studied soft dosage forms with nanoparticles of metals are given in Table 1. Gel with nanoparticles of silver and gold During 24 months of storage, every 6 months, samples of drugs in soft dosage forms were monitored for the following parameters: homogeneity, odour, colour and pH. The results of the study of dosage forms are given in Table 2.
As a result of the research, it was found that drugs in soft dosage forms, which were stored at a temperature of 8-15 °С, were stable for the studied quality indices. In samples of gels, which were stored at a temperature of 15-25 °С, after 12-18 months of storage, stratification and liquefaction of gels were observed. These results indicate instability of gels during storage in such conditions. Study of the rheological properties of soft drugs was carried out according to the methodology, which was as follows: the weight of the sample was placed in the chamber and immersed in the spindle TR-11; after this, the spindle was forced to rotate, starting at low speeds, and fixed the viscometer's visibility. Rheological indicators of samples of soft drugs after manufacturing dosage forms and after 24 months practically did not differ. The rheograms of the flow of soft drugs are shown in Fig. 1-4.   As can be seen from Fig. 3  Also, indicators of mechanical stability were calculated as the ratio of the value of the strength to the fracture (τ1) and the value of the strength after the destruction (τ2) by the formula τ1 / τ2 (Table 3). Samples of drugs in soft dosage forms are characterized by the same ability to structure and have indicators of mechanical stability approaching 1. According to rheological behavior, the samples studied differ from each other depending on their composition. The presence of upward and downward curves on rheograms (hysteresis loops) indicates that the studied drugs in soft dosage forms have thixotropic properties, which characterizes the good ability to smear on the skin and the ability to extrude from tubes.

Conclusions from the conducted research and prospects for further development of this field
1. According to the results of the research the stability of organoleptic parameters of soft drugs at a storage temperature of 8-15 °С in a place protected from light was established.
2. According to the results of rheological studies, it was found that the samples of tested drugs in soft dosage forms have a good ability to smear on the skin and extrusion from tubes.