INTRODUCTION:

The solubility index is a key aspect of the physico-chemical parameters of a pharmaceutical substance, which determines the bioavailability profile in the development of a dosage form. Tamsulosin hydrochloride (TH) is a symptomatic drug for benign prostatic hyperplasia (BPH) and disorders of the urethra in men. In women, it is possible to use "off label" for urolithiasis¹. According to the chemical structure, TH is an organic compound of the sulfonamide class, which does not exhibit the characteristic antimicrobial action characteristic of this group.

The benzene ring forms the central part of the molecule, to which a sulfonamide group is attached. Unlike analogues, the molecule does not contain fragments of furan and quinazoline groups. The hydrophobic properties are due to the presence of an ester group (CH₃-CH₂-O) in combination with a tert-butylamine group ((CH₃)₃C-NH-), which increases the lipophilicity and volume of the molecule. At pH ≈ 7 in an aqueous medium, the solubility of the substance is less than 0.05 mg /ml, which makes it difficult to absorb it in the gastrointestinal tract (gastrointestinal tract). Two hydrophobic groups provide not only a selective mechanism for blocking α1A and α1D -adrenoreceptors of the smooth muscles of the neck of the bladder, the prostatic part of the urethra and the stroma of the prostate gland, but also a high penetrating ability through the phospholipid layers of cell membranes due to the significant lipophilicity of the molecule. The lipophilic properties of TH cause high oral bioavailability (per os), reaching about 90%². By relaxing smooth muscles, TH helps to increase the maximum outflow of urine and reduce the symptoms of BPH, without affecting systemic blood pressure. During treatment, it is well tolerated, there may be minor side effects such as dizziness, orthostatic hypotension, skin reactions that are less pronounced than those of analogues. The investigated pharmaceutical substance TH (Fig. 1) is a white crystalline powder with prismatic crystals without a pronounced odor. It has a high solubility in organic solvents, but in an aqueous medium the solubility is significantly lower due to molecular lipophilicity.

Figure 1: Structure of Tamsulosin hydrochloride, C20H28N2O5S *HCl, 2-Methoxy-5-[(2R)-2-{[2-(2- ethoxyphenoxy)ethyl]amino} propyl]benzene-sulfonamide hydrochloride, (444.97 g/mol).

A critical formulation challenge for TH involves improving both aqueous solubility and dissolution characteristics^3-5. The results of experimental data confirm the improvement of the therapeutic effect of medicinal substances in dosage forms in the form of solid dispersions (SD)⁶. SD represent systems composed of molecular mixtures of poorly water-soluble solid drug substances with an inert hydrophilic carrier, where the active ingredient exists in a highly dispersed state within the polymer matrix, forming «solid solutions» with variable compositions of molecular complexes^7-9. Then the solid phase is dissolved, as a rule, a colloidal solution of the active pharmaceutical substance is formed. In relatively rare cases, several complexes of the polymer matrix and the active substance are formed. Various polymers can be selected as a carrier matrix, but most often of a hydrophilic nature^10,11. The stability of SD systems is significantly compromised by two primary factors: excessive moisture exposure and temperatures exceeding the recommended range¹².

MATERIALS AND METHODS:

The substance TH RA Chem Pharma Limited, India meeting the requirements of regulatory documentation (FS 000827-040522, 2023, Tamsulosin hydrochloride), was used as the object of the study. In the synthesis of SD, a polymer - PVP with a molecular weight of 10,000g/mol (Germany, Merck) was used as a hydrophilic polymer matrix.

The technological process of obtaining SD. According to the literature data and accumulated experience, the method of «removal of volatile solvent» is the optimal method for obtaining SD with a hydrophilic matrix PVP-10000 ^13-19. A certain mass of polymer and TH was mixed with a minimum volume of 96% ethyl alcohol (h.d.a.), preheated to a temperature of 80±2°C. Further, the solvent was evaporated to a constant mass under vacuum. Used: UT-4301E water bath (P.R.C, Ulab company)) with a maintained temperature of 80±2°C and vacuum pump UED-Lab 115 (P.R.C.).^20,21.

Study of the kinetics of TH dissolution. They were investigated in accordance with the methodology presented in the sources²². The main problem of the experiment was the discrepancy between the chosen method of Russia State Pharmacopoeia XIV «Dissolution for solid dosage forms» 1.4.2.0014.15 due to the formation of an oversaturated TH solution. The SD synthesized as a result of the conducted studies are viscous and highly adhesive masses of a yellowish hue, prone to coagulation. Numerous studies show that conducting the «dissolution» test on equipment such as a «rotating basket» leads to similar results obtained using a modified technique. To evaluate the kinetics of dissolution of the tested samples, a magnetic stirrer with the functions of thermostating and heating RCT-BASIC (manufactured in Germany, IKA company) was used. The conditions for the kinetics of SD dissolution were selected based on the achievement of the maximum concentration of the dissolved substance TH in solution. The temperature of the aqueous medium (distilled water) is 37±1°C. The SD sample was added to 100ml of distilled water with constant stirring of the medium (200 revolutions/min). During the study of the kinetics of TH dissolution in water, samples were taken at set time intervals: 5, 10, 15 and 20 minutes, and after that at 30, 40, 50 and 60 minutes. The volume of each sample taken for analysis was 5ml. After each sampling, the dissolution medium was restored to the original volume of 100 ml using distilled water. Before measuring the optical density, the samples were filtered.

Filtration of the selected samples was carried out using Minisart® syringe nozzles (Germany, Sartorius), with a diameter of 0.45 microns filter pores and a filter material - nylon.

Research of TH concentration in the studied solutions research. To analyze the optical density of the samples, a UNICO-2800 spectrophotometer (USA, Unitedproducts and instruments) with complete quartz glass cuvettes (the thickness of the absorbing layer is 10 mm) was used. If necessary, the samples taken from the solutions were diluted with distilled water in the required number of times. After dilution, the optical density of the samples was determined at a wavelength corresponding to the maximum absorption of TH (278 ± 2 nm). The experimental results are presented in Table 1 and Figure 1.

Microcrystalloscopy. The study of microcrystals of TH substance was carried out according to the method described in²³ using a Levenhuk D50L NG microscope (China, Levenhuk, Ltd.) with a digital camera. The substance in the form of a powder was applied to a slide, mixed with one drop of petroleum jelly oil and microscopic examination of the drug was performed under a cover glass. During microscopic analysis of SD, several drops of a solution in 96% ethyl alcohol, including SD components (TH and PVP-10000) in the required ratios, were placed on a slide. The sample was then examined under a microscope after the final evaporation of ethyl alcohol. The polymer PVP-10000 was analyzed separately on a slide in an ethyl alcohol solution, after evaporation of alcohol and solidification of the PVP mass. Micrographs and additional parameters of microscopic examination are shown in Fig. 3

RESULTS AND DISCUSSION:

Hydrophilic polyvinylpyrrolidone polymers of different molecular weights (general monomeric formula H-(C6H9NO)n-H) represent the primary carrier system for SD, supplemented by various other water-soluble excipients²⁴. An aqueous solution from the polyvinylpyrrolidone matrix does not change the viscosity during various reactions of the medium. Upon hydrolysis of PVP to poly-N-vinyl-γ-aminobutyric acid, it exhibits a slightly acidic nature of the medium (pH≈5). During the phase transition of the solvent from PVP solutions to a vaporous state, a polymer film with a cracking pattern is formed. The polymers of the PVP group are absolutely non-toxic, have good adhesive and complexing properties. Given the set of properties of PVP-10000 and its effect on the technological characteristics of dosage forms such as tablets and granules (strength, for example), the selected range of ratios is the most optimal when administered in SD (TH: PVP) in solid dosage forms. When studying the kinetics of dissolution, the samples of TH and its SD substances were measured in excess relative to the solvent (distilled water). The relative error of the average concentrations is approximately 4.7%. The change in the solubility of TH was determined by comparing the concentration of TH in a saturated solution of its SD with a saturated concentration in a solution of the starting substance 60 minutes after the start of the dissolution process. By the end of the experiment, all solutions of the studied samples became visually cloudy. The initial substance of TH is characterized by a very slow dissolution rate (Fig. 2). The concentration of TH in a solution of its substance varies slightly during the experiment – from 2.19mg/ml (after 5 minutes) to 4.7mg/ml (after 60 minutes). Analysis of the dissolution dynamics shows that the formation of a SD using the hydrophilic polymer PVP-10000 significantly increases the solubility of the TH substance. The maximum increase in solubility is observed in SD (TH: PVP (1: 3) – by 3.1 times. SD of TH with PVP in 1:1 and 1:2 ratios also accelerate the dissolution of TH, increasing this indicator by 2.47 and 2.95 times, respectively. In most SD solutions, a supersaturation effect occurs: in the first 20 minutes, the concentration of TH quickly reaches its peak, amounting to 9.46–14.8mg/ml. At this stage, the rate of dissolution of TH from SD increases by ≈ 4.74 times. Due to recrystallization processes, the concentration level of TH in the SD solution decreases slightly, until after 20 minutes it is set at an almost constant level reflecting the new solubility of the substance. An increase in the amount of polymer in the SD to a ratio of 1:2 and 1:3 with the active component leads to an increase in the solubility and dissolution rate of TH in an aqueous medium. The TH: PVP-10000 (1:3) weight ratio is the best. It provides a maximum increase in both the dissolution rate and the solubility of TH from SD, and also enhances the effect of oversaturation of the solution.

Table 1: Dynamics of changes in time of concentration in solutions of TH and its SD with PVP-10000.

No.

Sample

Weight (g)

Average concentrations of TH (mg/ml) in solutions of the studied samples;n=5

Analysis time (min)

5,0

10,0

15,0

20,0

30,0

40,0

50,0

60,0

TH is a substance

2,2±

0.11

2.4±

0.12

2.94±

0.15

3.12±

0.16

3.66±

0.18

3.89±

0.19

4.38±

0.22

4.70±

0.24

TD TH:PVP-10000 (1:1)

2:2

6.86±

0.34

9.36±

0.47

8.95±

0.45

9.46±

0.47

10.24±

0.51

10.48±

0.52

10.72±

0.54

11.59±

0.58

TD TH:PVP-10000 (1:2)

2:4

11.05±

0.55

12.9±

0.65

13.73±

0.69

13.8±

0.69

13.81±

0.69

13.60±

0.68

14.10±

0.71

14.10±

0.71

TD TH:PVP-10000 (1:3)

2:6

13.8±

0.69

14.5±

0.73

14.8±

0.74

14.9±

0.75

14.92±

0.75

15.20±

0.76

14.44±

0.72

14.58±

0.73

Figure 2: Change in the concentration of solutions of TH and SD on with PVP-10000 over time: 1 – TH (substance); 2 – SD TH: PVP-10000 (1:1); 3 – SD TH: PVP-10000 (1:2) 4 – SD TH: PVP-10000 (1:3).

Fluctuations in the concentration of TH in solutions of SD are probably due to the interaction of antagonistic processes. An increase in concentration occurs due to the release of TH from the PVP matrix when SD is dissolved in an aqueous medium and partially in the form of a colloid. PVP includes hydrophobic molecules of the compound in water-soluble complexes performing the function of a solubilizer. Stabilizes the complex with high concentration and colloidal protection. However, when saturation of the solution is reached, the processes of TH recrystallization and coagulation are activated. The observed enhancement of solubility and bioavailability can be attributed to drug amorphization, improved wettability, and dissolution within the hydrophilic carrier matrix [25]. The balance of physico-chemical processes, which establishes a constant concentration of TH in a solution of SD, is a complex relationship that requires separate study.

Figure 3: Microcrystalloscopic analysis (magnification ×64): 1 – TH (substance); 2 – TD TH: PVP-10000 (1:3); 3 – PVP-10000 after solvent removal.

Microcrystalloscopy of TH substance (fig.3) - characteristic particles with a crystalline structure and a prismatic shape. Crystal fragments are transparent or white with a smooth surface, which indicates their purity and absence of impurities. The PVP-10000 carrier matrix is an amorphous mass of white color with inclusions of a dark shade. SD is characterized by the presence of at least two different phases forming a heterogeneous system. There are inclusions that are the result of the recrystallization of TH in PVP-10000, or its polymorphic modifications. Based on the experimental data obtained earlier, we believe that it is not always possible to use thermoanalytical methods in the analysis of TH SD with PVP-10000²⁶. The results of microcrystalloscopy suggest that the main factor in increasing the solubility of TH from SD is the loss of its crystal structure during the synthesis of SD. During the synthesis of SD (evaporation of the solvent using vacuum), TH is almost completely dissolved in the PVP-10000 matrix, forming a homogeneous composition in the solid state. When SD is dispersed in an aqueous medium, the matrix dissolves, releasing TH in colloidal form. Thus, the polymer provides a modified release of TH and maintains the stability of its concentration in the dosage form. A number of sources^27-32. They point to a factor that improves the dissolution of pharmaceutical substances from SD, the formation of colloidal solutions. To confirm the formation of a colloidal solution, the optical refractive properties of SD solutions and TH substance were investigated. After filtration, the studied solutions of the obtained SD create a Faraday-Tyndall cone, scattering blue light, which indicates the colloidal dispersed state of the TH substance present in them. (Fig. 4).

Figure 4: Results of studying the optical properties of SD solutions (TH: PVP-10000) (33.33% by weight): 1 – saturated SD solution, daytime illumination; 2 – SD solution, filtered (Minisart filter, pores 0.45 microns); 3 – SD solution, observation of the Faraday-Tyndall cone during dimming.

CONCLUSION:

The analysis of the presented experimental data shows that the acceleration of the dissolution of TH from its SD with the polymer PVP-10000, obtained by removing a common solvent (ethyl alcohol 96%), is associated with two main factors: a significant loss of crystallinity by TH (during the synthesis of its SD) and the process of solubilization of TH by polymer (during the dissolution of SD). In addition, during the dissolution of the SD, a colloidal solution of TH stabilized by PVP-10000 is formed. The optimal ratio of substances in SD (TH: PVP is not more than 1: 3 by weight. The results of the conducted research are planned to be used in the subsequent development of the technology and composition of «effervescent» granules and tablets of TH as well as intestinal-soluble capsules containing its SD with PVP-10000.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 30.06.2025 Revised on 01.10.2025

Accepted on 02.12.2025 Published on 16.03.2026

Available online from March 18, 2026

Research J. Pharmacy and Technology. 2026;19(3):1260-1264.

DOI: 10.52711/0974-360X.2026.00180

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