INTRODUCTION:

Oral drug administration is considered the most common and preferred route due to its advantages, including ease of administration, great stability, accurate dosage, and high patient compliance¹. However, a major challenge in the development of oral dosage forms is poor bioavailability, which is often associated with poor solubility and dissolution rate². The poor water solubility of many drugs is a major constraint to their successful market launch despite their potential pharmacokinetic activity³.

So poor solubility is a critical factor that can interfere with the composition of molecules in dosage forms, and poorly soluble drugs are usually administered at a much higher dose than the actual dose to achieve the desired plasma drug level, which results in increased production costs and in adverse reactions, and often causes an unstable pharmacological response⁴^,5. Thus, solubilization technologies that overcome this problem by increasing the solubility of such drugs and increasing their dissolution rate are becoming more and more important to the pharmaceutical industry⁶. To these technologies belong solid dispersions (SDs), which may be defined as molecular mixtures of a poorly water-soluble drug in an inert hydrophilic carrier, the properties of which determine the release profile of the drug from the mixture^7,8. The increased solubility and dissolution rate of drugs from SDs may be explained by the following^9,10,11:

· Improved wetting of the drug caused by the hydrophilic carrier;

· transforming the drug into an amorphous state;

· increase in particle porosity;

· increased surface area available for drug dissolution due to the small size of its particles.

Since dissolution of class II BCS drugs is the step that limits the rate of absorption and, therefore, the bioavailability^12,13, the correlation of in vivo results with dissolution tests is likely to be best for these drugs and, thus, most studies on SD technologies focus on this class of drugs¹⁴.

To this class belongs mefenamic acid (MA) [2- (2,3-dimethylphenyl) aminobenzoic acid], a widely used non-steroidal anti-inflammatory drug (NSAID). MA is practically insoluble in water and therefore has poor absorption and bioavailability from the gastrointestinal tract. However, its absorption rate can approach 100% at high membrane permeability¹⁵. Therefore, dissolution becomes the limiting step for absorption, and rapid release of mefenamic acid in the gastrointestinal tract after oral administration is desirable¹⁶.

Regarding the dissolution study, different studies used different media and compared the dissolution of MA from SD with the dissolution of pure MA in the same medium. For example, about 32% of MA (0.034g/l) was dissolved after 60 minutes in phosphate buffer (pH=7.4)¹⁷, and 9% (0.0270g/l) MA was dissolved after 120 minutes in artificial intestinal fluid (pH 6.8) in the absence of enzymes¹⁸.

The preparation of SDs with water-soluble polymers is one of important methods that may be applied to increase the solubility and dissolution rate of MA. In this work, we prepared MA in SDs using as carriers polyethylene glycol (PEG) 4000, polyvinylpyrrolidone (PVP) K30 and polysorbate 80.

MATERIALS AND METHODS:

Materials:

Mefenamic acid (Min Chem India), PEG 4000 , PVP K30, and polysorbate 80 (Salius Pharma Pvt Ltd/ India). All other chemicals were of analytical grade.

Preparation of solid dispersions:

SDs were prepared by kneading method¹⁹, where the carrier (s) was saturated with water to a paste. Then MA was added, and the resulting mixture was stirred for 15 minutes and dried in an oven at 100 ̊C. The dried mass was ground in a mortar and sieved through a sieve N. 60. Six formulations (D1-D6) were prepared according to the ratios indicated in the table 1. Physical mixture (PM1-PM6) with corresponding ratios were also prepared by just mixing MA and carrier (s).

Determination of drug content:

50mg was taken from each prepared formulation and dissolved in 5ml of ethanol 95%. Then the solution was diluted with a phosphate buffer (pH = 8) to 100ml in a volumetric flask. The resulted solution was filtrated, and the filtrate was analyzed, after appropriate dilution, by UV spectrophotometry (СФ-103 single-beam scanning spectrophotometer, Russia) at 285nm, in correspondence with the maximum absorption of MA in the dissolution medium. Then concentration was calculated using a pre-developed calibration curve.

Study of dissolution:

Dissolution study was carried out using paddle type (PTWS 120D, Germany) in 900ml of phosphate buffer (pH=8). Samples (5 ml each) were taken at 0, 15, 30, 45, 60, 90, 120min and replaced with the same volume of phosphate buffer to maintain a constant total volume of dissolution medium. The concentrations of MA in the selected samples were determined, after filtration and appropriate dilution, by measuring absorbance by UV spectrophotometry (λ= 285nm) and using the pre-developed calibration curve.

Mathematical modeling of release kinetics:

Experimental data of MA release from PMs and SDs in phosphate buffer were analyzed using the kinetic models of zero order, first order, model Hixson-Crowell, and model Higuchi. The correlation coefficient (r²) and rate constants (k) were calculated according to these models, and the model that best describes drug release was chosen according to the values of (r²)^20,21. In order to understand the mechanism of dissolution we used the Ritger-Peppas and Peppas-Salhin equations²².

Statistical analysis:

To determine the effect of used carriers on the dissolution rate of MA from prepared formulations, the Student test was performed, and the p-value was calculated, where the investigated factor is statistically significant if p≤0.05.

RESULTS AND DISCUSSION:

Determination of drug content:

The test of relative content of MA in all prepared formulations showed good results, that ranged from (99.1-101.2)% in PMs and (98.4-101.2)% in SDs (Table 1).

Table 1: Composition of the prepared formulations and the relative content of mefenamic acid in them

Batch	MA:PEG 4000:PVP K30: polysorbate 80	The relative content of MA %
PM1	1:1:0:0	101.1
D1	1:1:0:0	98.4
PM2	1:1:1:0	99.1
D2	1:1:1:0	101.2
PM3	1:1:0:1	101.2
D3	1:1:0:1	100.9
PM4	1:0:1:1	100.1
D4	1:0:1:1	99.7
PM5	1:1:1:1	99.7
D5	1:1:1:1	101
PM6	1:1:1:1.5	100.9
D6	1:1:1:1.5	100.1

Study of dissolution:

The dissolution study showed that MA released from SDs at a higher rate than from the corresponding PMs (P <0.05), which in turn showed a greater release rate than pure MA.

The increase in the dissolution rate of MA in PMs in comparison with pure MA may be associated with an improvement in the wettability of MA, which could be the result of the formation of a polymer film around its particles, resulting in a decrease in the hydrophobicity of their surfaces²³. In addition, the improvement in the dissolution kinetics of MA from SDs can be associated with a decrease in the size of crystals, the absence of aggregation of MA crystals, and its transformation from a crystalline to an amorphous/microcrystalline state²⁴.

These results can be seen starting with D1, which was prepared just with PEG 4000 at a ratio of 1:1, then the addition of PVP in D2 also improved (P<0.05) the dissolution (fig. 1).

Figure 1: The dissolution profiles of mefenamic acid from formulations prepared with PEG (and PVP)

PM1, D1= physical mixture, solid dispersion prepared in the ratio 1:1 (MA: PEG 4000); PM2, D2: =physical mixture, solid dispersion prepared in the ratio 1:1:1 (MA: PEG 4000: PVP K30).

The addition of polysorbate 80 to SD with PEG 4000 led to an increase (P <0.05) in dissolution rate (Fig. 2). This may be interpreted by a decrease in the tension on the solid surface of the drug, which increases the area available for dissolution, and increases wettability and solubility of the drug^25,26.

Figure 2: the effect of addition polysorbate 80 on the dissolution of mefenamic acid

PM1, D1= physical mixture, solid dispersion prepared in the ratio 1:1 (MA: PEG 4000); PM3, D3: physical mixture, solid dispersion prepared in the ratio 1:1:1 (MA: PEG 4000: polysorbate 80).

Comparison release profiles of D3 and D4 showed that PVP K30 improved (P <0.05) the release kinetics of MA more than PEG 4000 (fig.3), which is most likely associated with a stronger wetting and solubilizing effect of PVP K30 compared to PEG 4000, and with the relatively stronger interactions of MA with PVP than with PEG^27,28. Also, MA in SDs with a PVP matrix can be completely amorphous and partially amorphous in SDs with PEG, since PVP is an amorphous polymer, while PEG is semicrystalline^29,30. In addition, the preparation process may contribute to this dissolution rate difference, where the initial wetting of the PEG during the preparation of SDs may result in a much faster hydration of the gel layer³¹.

Figure 3: the effect of carrier type on the dissolution of mefenamic acid

PM3, D3: physical mixture, solid dispersion prepared in the ratio 1:1:1 (MA: PEG 4000: polysorbate 80); PM4, D4: physical mixture, solid dispersion prepared in the ratio 1:1:1 (MA: PVP K30: polysorbate 80).

The inclusion of surfactants in solid dispersions has a significant effect on the properties of the resulting particles. These effects include changes in dissolution rate, drug-polymer interactions, and particle morphology. The mechanism of these effects appears to be highly dependent on the method of preparation of drug-polymer mixtures²⁶. Increasing the ratio of polysorbate 80 (D5 and D6) increases (P<0.05) the dissolution rate of MA (Fig. 4), as polysorbate enhances the effect of one or more of the following factors^32,33:

· A decrease in the particle size of the drug;

· The solubilizing effect of the carrier;

· The absence of drug crystallites aggregation;

· An improvement in the wettability and dispersibility of the drug;

· Dissolution of the drug in the hydrophilic carrier;

· Drug transforming into amorphous state.

Figure 4: the effect of polysorbate 80 ratio on the dissolution of mefenamic acid

PM5, D5: physical mixture, solid dispersion prepared in the ratio 1:1:1:1 (MA: PEG 4000: PVP K30: polysorbate 80); PM6, D6: physical mixture, solid dispersion prepared in the ratio 1:1:1:1.5 (MA: PEG 4000: PVP K30: polysorbate 80).

It should be noted that the change in the solubility and dissolution rate of MA in PMs and SDs cannot be explained by the salting out effect of the phosphate buffer, since the concentration of its components in all cases remains constant and the ionic strength of the solution did not change.

Study of dissolution stages with different rates:

The type of kinetic dependences of MA dissolution in phosphate buffer indicates the presence of two time sections with different rates of mass transfer processes. The tangent of the slope of the initial section was used to determine the velocity (W1), which characterizes the fast period of dissolution. The velocity (W2) corresponding to the process of slow transition of MA into solution was determined in a similar way. Table 2 shows the obtained values of W1 and W2.

Table 2: Dissolution rates of mefenamic acid from physical mixtures and solid dispersions

Batch	W1 (min^-1)	W2 (min^-1)
PM1	1.46	0.022
D1	1.70	0.03
PM2	1.67	0.13
D2	2.15	0.09
PM3	1.64	0.14
D3	1.99	0.11
PM4	1.73	0.10
D4	2.10	0.11
PM5	2.14	0.17
D5	2.77	0.18
PM6	2.37	0.17
D6	2.55	0.18

The presence of two phases with different rates of dissolution MA in SDs prepared with PEG can be explained by the fact that the solvent molecules quickly penetrate into the diffusion layer surrounding drug particles, turning the drug into an amorphous structure, which accelerates dissolution³⁴, and as a result, the concentration of MA remaining in the SD decreases. This leads to a decrease in the dissolution rate at the second stage³⁵. Moreover, the hydrogen bond between the drug and hydrophilic groups of the polymer expands the polymer chain, increasing the viscosity, which leads to a decrease in the molecular mobility of the drug and a decrease in the dissolution rate in the second stage.

With regard to PVP, the presence of two stages of dissolution is likely due to different dissolution mechanisms. During the dissolution test, the PVP began to take up water in the pH=8 buffer, resulting in a less viscous gel. High dissolution rates at the initial stage are associated with both diffusion and degradation of the polymer matrix. When PVP dissolves rapidly, MA is exposed to the dissolution medium in the form of very fine particles for rapid dissolution³⁶. Since PVP is a highly soluble polymer, the initial high drug release and subsequent decrease may also be due to the fact that the initial rapid flow of the drug from the solid dispersion particles into the dissolution medium occurs at a high concentration, which rapidly decreases with time³⁷.

The addition of polysorbate increased the speed in the first and second stages. This is consistent with the above results of the effect of the carrier on the dissolution rate of the drug.

Based on the results of studying the stages of dissolution, it was also found that the dissolution is higher in SDs than in PMs with the same composition. This is facilitated by different wettability properties, which can be explained not only by the wetting properties of each component, as in physical mixtures, but also by the interaction between polymer and drug molecules. This interaction results in a rearrangement of the polymer orienting the hydrophilic groups towards the surface, making the surface more hydrophilic than any of its components³⁸.

Mathematical modeling of release kinetics:

The correlation coefficients (r²), calculated for different kinetic models, revealed that model Higuchi fits better (Table 3). So, it may be said that the release of MA is controlled by diffusion, i.e., MA is released by diffusion through the pathways that have formed in the matrix. Under the influence of an aqueous liquid, hydrophilic matrices absorb water, and the polymer begins to hydrate with the formation of a gel layer³⁹. Drug release is controlled by the diffusion barrier of the gel and/or surface erosion⁴⁰.

Over time, water penetrates deep into the core of the matrix, increasing the thickness of the gel layer. Simultaneously, the outer layers become hydrated and begin to dissolve or break down. As the concentration of the drug falls, the release rate of the drug begins to decrease. At the same time, an increase in the thickness of the barrier layer over time increases the length of the diffusion path, reducing the rate of drug release⁴¹.

Study of the release mechanism:

A comparison of the results obtained using the Ritger-Peppas and Peppas-Salhin models showed that they do not have significant differences (table 4). It should be noted that the Peppas-Salhin model is an extended version of the Ritger-Peppas model and takes into account the abnormal course of the drug mass transfer process in the case of a swelling hydrophilic matrix.

The application of the Ritger-Peppas model showed the possibility of excellent linearization of the obtained results. The calculated value of the parameter n (0.20–0.26) confirms the influence of drug diffusion, obeying Fick law, as well as swelling and degradation processes of the polymer matrix on the overall patterns of mass transfer of MA from SDs into an aqueous solution.

CONCLUSION:

In the course of this work, physical mixtures and solid dispersions based on mefenamic acid were obtained by kneading method and various proportions of polyethylene glycol (PEG4000), polyvinylpyrrolidone (PVP K30), and polysorbate 80. It turned out that the drug dissolution in vitro followed model Higuchi and the dissolution profile can be controlled by the type and the proportion of the hydrophilic carrier. The mathematical modeling of release kinetics showed that the drug release from prepared solid dispersions is well described by model Ritger-Peppas, which mainly considers the Fickian diffusion of drug, with the possible contribution of swelling and degradation of the polymeric matrix.

Table 3: Different release rate constants and correlation coefficients according to different kinetic models

Formulation code	Zero order		First order		Hixson Crowell		Higuchi
Formulation code	r²	K₀(mg/100mg/min)	r²	K₁(min^-1)	r²	K_HC(mg/ 100mg)^1/3/ min	r²	K_H₍mg/100mg/min^1/2)
PM1	0.60	0.29	0.65	0.004	0.64	0.005	0.93	3.95
D1	0.60	0.37	0.67	0.006	0.65	0.008	0.93	5.17
PM2	0.65	0.40	0.76	0.007	0.64	0.009	0.95	5.45
D2	0.64	0.49	0.77	0.009	0.72	0.012	0.94	6.68
PM3	0.74	0.40	0.75	0.006	0.72	0.009	0.95	5.46
D3	0.61	0.45	0.75	0.008	0.70	0.010	0.93	6.18
PM4	0.63	0.39	0.74	0.006	0.75	0.008	0.94	5.40
D4	0.60	0.47	0.75	0.009	0.70	0.011	0.93	6.50
PM5	0.65	0.51	0.83	0.011	0.77	0.013	0.95	6.88
D5	0.65	0.57	0.88	0.015	0.81	0.016	0.95	7.79
PM6	0.62	0.54	0.85	0.014	0.77	0.015	0.94	7.51
D6	0.60	0.61	0.96	0.027	0.86	0.023	0.93	8.54

Table 4: release rate constants and correlation coefficients according to the Ritger-Peppas and Peppas-Salhin equations

Formulation code	Ritger-Peppas			Peppas-Salhin
Formulation code	r²	K_RP(mg/100mg/min^-n)	n	r²	K₁ (mg/100mg/min^-^m)	K₂(mg/100mg/min^-^2m)
PM1	0.98	16.89	0.23	0.98	11.75	5.94
D1	0.98	19.86	0.23	0.98	12.15	8.59
PM2	0.99	18.40	0.25	0.99	10.65	8.65
D2	0.98	22.33	0.26	0.98	10.74	12.56
PM3	0.99	19.99	0.24	0.99	11.32	9.48
D3	0.99	25.20	0.22	0.99	11.99	13.99
PM4	0.99	19.29	0.24	0.99	11.32	9.48
D4	0.99	26.46	0.22	0.99	12.40	14.88
PM5	0.99	24.29	0.25	0.99	11.42	13.63
D5	0.99	27.22	0.25	0.98	8.89	13.20
PM6	0.99	30.22	0.22	0.99	16.00	15.25
D6	0.99	37.48	0.20	0.99	18.74	19.79

CONFLICT OF INTEREST:

The authors have no conflicts of interest.

AKNOWLEDEGMENT:

This paper has been supported by the RUDN University Strategic Academic Leadership Program.

REFERENCES:

1. Pradeep N. Sh. A Review: Increasing Solubility of Poorly Soluble Drugs, by Solid Dispersion Technique. Research J. Pharm. and Tech. 2011;4(12):1933-1940.

2. Arun J.K. Rajeshwar V. Shrivastava B. Bakshi V. Self Nano Emulsifying Drug Delivery System: A Novel Technique for Enhancement of Oral Bioavailability. Research J. Pharm. and Tech. 2020; 13(5): 2516-2521. doi: 10.5958/0974-360X.2020.00448.5

3. Hajare A. A. Kashid U.T. Walekar P. Hajare P. M. Enhancement of Dissolution Rate and Formulation Development of Efavirenz Capsule Employing Solid Dispersion Method. Research J. Pharm. and Tech. 2013; 6(1): 112-117.

4. Harshil M.P. Bhumi B.P. Chainesh N.Sh. Dhiren P.Sh. Nanosuspension Technologies for Delivery of Poorly Soluble Drugs- A Review. Research J. Pharm. and Tech. 2016; 9(5): 625-632. doi: 10.5958/0974-360X.2016.00120.7

5. Bhaduka G. Rajawat J.S. Formulation Development and Solubility Enhancement of Voriconazole by Solid Dispersion Technique. Research J. Pharm. and Tech. 2020; 13(10):4557-4564. doi: 10.5958/0974-360X.2020.00803.3

6. Shinkar D. M. Patil A. N. Saudagar R. B. Solubility and Dissolution Enhancement of Sulfasalazine by Solid Dispersion Technique. Research J. Pharm. and Tech. 2018; 11(4):1277-1282. doi: 10.5958/0974-360X.2018.00237.8

7. Manekar S. Bakal R. Charde M. Enhancement of Dissolution profile of poorly water soluble drug using Water Soluble Carriers. Asian Journal of Pharmaceutical Research. 2022; 12(2):137-2. doi: 10.52711/2231-5691.2022.00021

8. Choudhary H. Yadav B. Patel P. Das P. Pillai S. Formulation and Evaluation of Ramipril Fast Dissolving Tablet using Solid Dispersion. Research J. Pharm. and Tech. 2019; 12(8): 3764-3772. doi: 10.5958/0974-360X.2019.00645.0.

9. Bhore S.D. A Review on Solid Dispersion as a Technique for Enhancement of Bioavailability of Poorly Water Soluble Drugs. Research J. Pharm. and Tech. 2014; 7(12):1485-1491.

10. Surendra M. Venkateswara Rao T. Formulation and Evaluation of Ibuprofen Solid-Dispersions Prepared by Solvent Evaporation Technique. Research J. Science and Tech. 2012; 4(1): 22-27

11. Bhairav B. Bachhav J. Saudagar R. Review on Solubility Enhancement Techniques. Asian J. Pharm. Res. 2016; 6(3): 147-152. doi: 10.5958/2231-5691.2016.00025.3

12. Galam A. Shahi S. Deore S. Quraishi F. Solid Dispersion: Recapitulation. Asian J. Pharm. Tech. 2020; 10(2):107-117. doi: 10.5958/2231-5713.2020.00019.7.

13. Tawar M. Raut K. Chaudhari R. Jain N. Novel Methods to Enhance Solubility of Water Insoluble Drugs. Asian Journal of Research in Pharmaceutical Sciences. 2022; 12(2):151-156. doi: 10.52711/2231-5659.2022.00026

14. Kumar S. Singh P. Various techniques for solubility enhancement: An overview. The Pharma Innovation Journal. 2016; 5(1): 23-28.

15. Kothawade S. Ishware A. Darekar P. Lunkad A. Formulation and Evaluation of Sustained Release Matrix Tablet of Mefenamic Acid. Res. J. Pharm. Dosage Form. and Tech. 6(4):Oct.- Dec.2014; Page 249-252.

16. Srivastava R. Mishra MK. Patel AK. Singh A. Kushwaha K. An insight of non-steroidal anti-inflammatory drug mefenamic acid: A review. GSC Biological and Pharmaceutical Sciences. 2019; 7(2): 52-59.

17. Sambasiva Rao KRS, Nagabhushanam M V, K Chowdary PR. In vitro Dissolution Studies on Solid Dispersions of Mefenamic Acid. Indian J Pharm Sci. 2011;73(2):243-247.

18. Fülöp I. Gyéresi Á. Kiss L. Deli MA. Croitoru MD. Szabó-Révész P. Aigner Z. Preparation and investigation of mefenamic acid - polyethylene glycol - sucrose ester solid dispersions. Acta Pharm. 2015; 65(4): 453-62. doi: 10.1515/acph-2015-0035. PMID: 26677901.

19. Anupama S. Pramod K Sh. Jay G M. Rishabha M. Evaluation of enhancement of solubility of paracetamol by solid dispersion technique using different polymers concentration. Asian J of Pharm and Clinical Res. 2011; 4(1): 117-119.

20. Lijuan H. Zhang N. Yang G. Effects of Tween-80 on the Dissolution Properties of Daidzein Solid Dispersion in Vitro. Int J of Chem. 2011; 3(1): 68-73.

21. Allawadi D. Singh N. Singh S. Arora S. Solid dispersions: a review on drug delivery system and solubility enhancement. International Journal of Pharmaceutical Sciences and Research. 2013; 4(6): 2094-2105.

22. Mohamed R.I. Damodharan N. Mathematical Modelling of Dissolution Kinetics in Dosage forms. Research J. Pharm. and Tech. 2020; 13(3):1339-1345. doi: 10.5958/0974-360X.2020.00247.4.

23. Patel Anar J. Singh R. P. Patel Vaibhav, Goswami Shambaditya. Application of Mathematical Models in Drug Release Kinetics of Lagerstroemia Speciosa Extract-Phospholipid Complex. Research J. Pharm. and Tech. 2022; 15(3):1257-2. doi: 10.52711/0974-360X.2022.00210.

24. Alrouhayya R. Sheshko T.F. Markova E.B. Boldyrev V.S. Razvodova A.A. Cherednichenko A.G. Study of Dissolution Kinetics of Mefenamic Acid Solid Dispersion with Polyvinylpyrrolidone. Herald of the Bauman Moscow State Technical University, Series Natural Sciences. 2021; 6 ( 99 ): 79-95 ( in Russ.) . DOI : https://doi.org/10.18698/1812-3368-2021-6-79-95.

25. Jafar A. Majid S. Katayoun M-S. et al. The Effect of Tween 20, 60, and 80 on Dissolution Behavior of Sprionolactone in Solid Dispersions Prepared by PEG 6000. Adv Pharm Bulletin. 2015;5(3):435-441.

26. Al-Obaidia H. Lawrenceb J. Buckton G. Atypical effects of incorporated surfactants on stability and dissolution properties of amorphous polymeric dispersions. Journal of Pharmacy and Pharmacology. 2016; 68: 1373–1383.

27. Al-Kazemi R. Yacoub Al-Basarah Y. Nada A. Dissolution enhancement of atorvastatin calcium by cocrystallization. Advanced Pharmaceutical Bulletin. 2019; 9(4): 559-570.

28. Krishnaiah Y. Pharmaceutical Technologies for Enhancing Oral Bioavailability of Poorly Soluble Drugs. Journal of Bioequivalence and Bioavailability. 2010; 2(2): 28-36.

29. Guedes F. G. de Oliveira B. Hernandes M. De Simone C. Veiga F et al. Solid dispersions of imidazolidinedione by peg and pvp polymers with potential antischistosomal activities. AAPS Pharm Sci Tech. 2011; 12(1): 401–410.

30. Patel R. Patel M. Physicochemical Characterization and Dissolution Study of Solid Dispersions of Lovastatin With Polyethylene Glycol 4000 and Polyvinylpyrrolidone K30. Pharm Dev Technol. 2007; 12(1): 21-33.

31. Nellore RV. Rekhi GS. Hussain AS. et al. Development of metoprolol tartarate matrix tablet formulations for regulatory policy consideration. dissolution of the polymeric matrix. Desired zero-order release J Control Release. 1998; 50: 247-256.

32. Sharma M. Sharma R. Jain DK. Nanotechnology based approaches for enhancing oral bioavailability of poorly water soluble antihypertensive drugs. Scientifica (Cairo). 2016; 2016: 8525679. doi: 10.1155/2016/8525679. Epub 2016 Apr 30. PMID: 27239378; PMCID: PMC4867069.

33. Mahendra D. Chandrashekhara S. Nagesh C. Mitul P. Sandip P. Vivek M. Enhancement of Solubility of Trimethoprim IP by Using Different Surfactants. Research J. Pharma. Dosage Forms and Tech. 2012; 4(1): 48-51.

34. Desi Reddy R.B. Neelima Rani T. Sindhuri S.L. Bandhavi P. Anusha Rani T. Sowjanya Y. Formulation and In-vitro Evaluation of Simvastatin Solid Dispersions. Research J. Pharm. and Tech. 2012; 5(8): 1069-1071.

35. Kalpana P. Manish S. Dinesh Sh. Surendra J. Solid Dispersion: Approaches, Technology involved, Unmet need and Challenges. Drug Invention Toda. 2010; 2(7): 349-357.

36. Duraivel S. Venkateswarlu V. Kumar A. Gopinath H. Enhancement of Dissolution Rate of Cefpodoxime Proxetil by Using Solid Dispersion and Cogrinding Approaches. Research J. Pharm. and Tech. 2012; 5(12):1552-1562.

37. Hasnain MS, Nayak AK. Enhancement of ibuprofen by solid dispersion technique using PEG 6000-PVP K 30 combination carrier. Chemistry: Bulgarian J of Sci Education. 2012;21(1):118-132.

38. Dahlberg C. Millqvist-Fureby A. Schuleit M. Furo I. Polymer–drug interactions and wetting of solid dispersions. Eur J Pharm Sci. 2010; 39: 125–133.

39. Jambukiya V. Parmar R. Dudhrejiya A. Tank H. Limbachiya V. Enhancement of Solubility and Dissolution Rate of Poorly Water Soluble Drug by Using Modified Guar Gum. Asian J. Res. Pharm. Sci. 2013; 3(1): 25-30.

40. Singh JV. Singh SJ. Kumar Sh. Design, Formulation and in vitro Drug Release from Transdermal Patches containing Nebivolol Hydrochloride as Model Drug. Asian J. Pharm. Res. 2012; 2(4): 136-141.

41. Chithaluru K. Tadikonda R. VijethaJ Ch. Kandula K. Effect of Various Grades of Hydroxypropylmethylcellulose (HPMC) on Drug Release from Naproxen Sodium Matrix Tablets. Research J. Pharm. and Tech. 2011; 4(2): 223-229.

Received on 05.10.2022 Modified on 30.01.2023

Research J. Pharm. and Tech 2023; 16(12):5701-5706.

DOI: 10.52711/0974-360X.2023.00922