INTRODUCTION:

Controlled release systems have gained significance in recent years due to their ability to sustain the pharmacological effects of drugs over an extended period of time. Various methods can be employed to modify drug solubility in order to achieve controlled release. Some of these methods include crystal modifications, drug solubility modifications, chelation-induced products, pro-drugs, and probiotic use.¹ These methods provide a variety of options to alter drug solubility and produce controlled release, each with specific benefits and restrictions. The particular drug, its desired release profile, and the intended therapeutic use all influence the choice of an appropriate strategy. The solid dispersion method is a pharmaceutical technique for managing medication release. This technique has been frequently used to improve the bioavailability and dissolving characteristics of slightly water-soluble medicines. The fundamental idea is to distribute the medication within a water-soluble carrier to aid in its solubility and release.² ABT-963 using solid dispersion containing Pluronic F-68, loperamide in PEG6000 I, solid dispersion particles of tolbutamide prepared with fine hydrophilic and porous silica particles (Sylysia 350) by the spray-drying method, itraconazole and HPMC 2910, Eudragit E100, or a mixture of Eudragit E100-PVPVA64 produced by hot-stage extrusion are some examples of drugs.³ The solid dispersion approach can also be used to regulate the rate at which highly water-soluble medications release. By including oxprenolol hydrochloride in a water-insoluble carrier, such as ethyl cellulose, while encouraging the production and retention of the swelling phase of water-soluble hydroxypropyl cellulose (HPC), for instance, the release of the compound can be controlled. To provide regulated and prolonged drug release, sustained-release pharmaceutical forms can be created using water-insoluble carriers in solid dispersion formulations. The adaptability of the solid dispersion approach allows for the formulation of pharmaceuticals with various solubility profiles and the achievement of optimal release characteristics, thereby enhancing therapeutic efficacy and patient compliance.⁴ By creating and retaining the swollen phase of water-soluble hydroxyl propyl cellulose (HPC) in water-insoluble ethyl cellulose, it is possible to control the release rate of extremely water-soluble medications such as oxprenolol hydrochloride. Water-insoluble carriers are used to create sustained-release pharmaceutical formulations. Ethyl cellulose, cellulose acetate phthalate, waxes, and methacrylic acid copolymers are examples of these polymers.⁵ To provide regulated and prolonged drug release, sustained-release pharmaceutical forms can be created using water-insoluble carriers in solid dispersion formulations. The adaptability of the solid dispersion approach allows for the formulation of pharmaceuticals with various solubility profiles and the achievement of optimal release characteristics, thereby enhancing therapeutic efficacy and patient compliance. By creating and retaining the swollen phase of water-soluble hydroxypropyl cellulose (HPC) in water-insoluble ethyl cellulose, the release rate of extremely water-soluble medications such as oxpernolol hydrochloride can be controlled. Water-insoluble carriers are used to create sustained-release pharmaceutical forms. Ethyl cellulose, cellulose acetate phthalate, waxes, and methacrylic acid copolymers are some of these polymers. Different types of polymethacrylates (Eudragit) have also been considered as carriers for the production of sustained-release pharmaceuticals.⁶

Manufacturing methods for solid dispersion:

Preparation of Solid Dispersions.Various methods used for preparation of solid dispersion system.⁷

These methods are described below:

Medication and water-soluble carriers are prepared using the melting or fusing method, which involves heating the mixture directly until it melts.

Melting solvent method (melt evaporation):

To prepare solid dispersions, the drug must first be dissolved in an appropriate liquid solvent. The drug solution was then added directly to the polyethylene glycol melt and allowed to evaporate until a clear solvent-free film was left behind. The film was dried further to maintain its weight. Polyethylene glycol 6000 can integrate liquid chemicals up to a weight percentage of 5–10% (w/w) without significantly altering its solid properties.

Melt extrusion method:

Typically, a twin-screw extruder is used to process the drug/carrier mixture. The combination of medicine and carrier is homogenized, melted simultaneously, and then extruded to form tablets, granules, pellets, sheets, sticks, or solid dispersions. After that, the intermediates can be processed once more to create regular tablets.⁷

Solvent method:

Using this technique, a common solvent was used to dissolve the physical mixture of the drug and carrier. The solvent was evaporated until a clear, solvent-free film remained. To maintain its weight, the film is further dried. The primary benefit of the solvent approach is its ability to prevent drug or carrier thermal degradation due to the comparatively low temperatures needed for organic solvent to evaporate⁷.

MATERIAL METHOD:

Metoprolol succinate was supplied by INDICO Mumbai. Research Fine Lab Chem provided HPMC K100M, ethyl cellulose, magnesium stearate, dichloromethane (DCM), talc, and aerosols. Mumbai.

UV Spectra:

The UV spectrum of metoprolol succinate was determined using SICAN 2301 INKARP. A precise 100 mg dose of the medication was dissolved in an adequate amount of 6.8 phosphate buffer, resulting in a volume of 100 ml, which was referred to as the stock solution (1000 µg/ml).To get 10 µg/ml of concentration, 0.1 ml of aliquot were removed, and the volume was increased to 10 ml using 6.8 phosphate buffer. Figure 1 shows the spectrum that was collected after the resulting solution was scanned from 200 to 400 nm.^8,9

Differential Scanning Calorimetry (DSC):

Differential thermal analysis of the pure drug, Eudragits RLPO and RSPO, physical mixtures, and solid dispersions was carried out using a differential scanning calorimeter (Mettler DSC 20, Germany). The device was calibrated with indium as the reference material and 10 mg samples were placed in aluminum pans and heated at a scanning rate of 1°C/ min between 25 and 600 °C. The sensitivity of the device was 0.1^◦C.

Infrared (IR) Analysis:

The KBr pellet method was used to record IR spectra of the drug samples. In a porcelain mortar and pestle, the medication was titrated at a ratio of 1:100 with dry potassium bromide. Pellets were made in a KBr press at an 8-ton pressure. Using an IR 200 Thermo electron spectrometer, the pellet was scanned over a 4000-400 cm-1 range. The resulting spectra are shown in Fig. 2.

Preparation of solid dispersion:

Preliminary Trial Batches The solvent technique was used to create solid dispersions. Dichloromethane (DCM), which contains the medication in various ratios with HPMC K4M/ HPMC K15M/HPMC K100M, and Ethyl cellulose in ratios of 0.5:1,1:1 and 0.5:0.5:1. Drug release profiles were determined using the USP II rotating paddle method in a phosphate buffer solution (pH 6.8). DSC, IR, and microscopic observations were performed to evaluate the physical characteristics of solid dispersions.¹⁰

Solvent evaporation method:

To create a homogenous solution, the polymer and metoprolol succinate were first separated into separate solutions and then mixed in dichloromethane. To create a solid dispersion, the second stage involved mechanically stirring dichloromethane to evaporate it at room temperature. Ultimately, the solid dispersion was crushed and sent through sieve number twenty^.11

Table 1: Solid dispersion composition of preliminary trial batches by solvent evaporation method

Batch code	HPMCK 100 M	Ethyl cellulose	Metoprol succinate
F7	0.5gm	1.0gm	0.5gm
F8	0.5.0gm		1.0gm
F9	1.0gm		0.5gm
F10	0.5gm	0.5gm	0.5gm
F11	1.0gm		1.0gm
F12	1.0gm	1gm	0.5gm
F13	--	1gm	0.5gm

Optimization of solid dispersion:

Using dichloromethane as an organic solvent and the hydrophobic polymer ethyl cellulose, solid dispersion is optimized by the solvent evaporation method. Table 5 illustrates the different drug-to-ethyl cellulose ratios that are taken (1.5:0.5, 2.0:0.5, 2.5:0.5, 3.0:0.5)

Table 2: Trial batch with Ethyl cellulose

Batch code	Ethyl cellulose	Metoprolol succinate
EF1	1.5gm	0.5gm
EF2	2.0gm	0.5gm
EF3	2.5gm	0.5gm
EF4	3gm	0.5gm

Evaluation of solid dispersion:

The granules, or solid dispersion, from which the tablet is made, determine the tablet's quality. As a result, it is imperative to assess the solid dispersion and determine whether or not the requisite quality is there. The bulk density, tapped density, Hausner's ratio, angle of repose, and Carr's index (compressibility) were assessed for the solid dispersion of batches EF1, EF2, EF3, and EF4. Table 8 reports the solid dispersion parameters that were investigated.¹²

In-vitro drug release of solid dispersion:

The drug release rate from metopropol succinate solid dispersion (n = 3) was measured using a USP apparatus type II (Labindia, India). For the dissolving test, 900 milliliters of 6.8 phosphate buffers were used, and it was run for 8 hours at 37±0.5 C at 50rpm. A sample (5 ml) was taken out and replaced with an equal volume of completely fresh, dissolving liquid at certain intervals. The samples were filtered using a Whattman filter paper. The absorbance of the solutions was measured at 224 nm. Data on the cumulative drug release of metoprolol succinate are shown in Table 9. The drug release profiles of batches EF1 through EF4 are shown in Figure 8.¹³

RESULTS AND DISCUSSION:

The goal of the current work was to use various polymers to form a solid dispersion of metoprolol succinate using solvent evaporation for controlled release. Each formulation's physical and chemical properties were evaluated, along with the results of in vitro drug release experiments.

Melting point:

By using the capillary method, the average melting point of metoprolol succinate was found to be between136º-142ºC, which is in good agreement with the reported melting point.

UV Spectra:

Metoprolol succinate solution (50µg/ml) showed an absorption maximum wavelength at 224 nm in its UV spectrum, in accordance with the reported in fig 1.

Figure 1: UV spectra of metoprolol succinate

IR Spectra:

Metoprolol succinate's infrared spectra was captured between 400 and 4000 cm^-1.

The observed spectrum correlated with the reference shown in Figure 2 and Table 3.

Table 3: Infrared Spectral Assignments for metoprolol succinate

Sr. No	Energy (wave numbers cm^-1)		Assignment
Sr. No	Reported	Sample	Assignment
1	3300-3700	3672.47	Hydroxyl (-OH)
2	1000-1350	1159.22	C-N
3	2200-3000	2351.23	Alkyl (-CH₃)
4	1600-1700	1614.42	-COOH

Figure 2: Infrared Spectrum of metoprolol succinate

Melting point, UV, infrared, and DSC thermogram analysis were used to determine that the obtained sample of metoprolol succinate was of a satisfactory purity and quality. The sample was obtained for additional research.

DSC Spectra:

Metoprolol succinate's DSC thermogram revealed a single endothermic peak of fusion with a peak maximum of 138.2°C. This was consistent with what was reported. (Fig. 3)

Fig.3: DSC Thermogram of metoprolol succinate Obtained at Heating Rate of 10° C/min

Analytical Method Development:

Metoprolol succinate was estimated using the UV spectrophotometric technique. The greatest absorbance (λmax) in the UV spectrum was observed at 224.

Developed method was validated and validation parameters are listed in Table 5.

Table 4. Validation parameter

Parameter	Limit	Results
Accuracy	98 - 102	99.06% ±0.808
Repeatability	%RSD < 2	0.0851%
Intraday precision	%RSD < 2	0.0619%
Inter day precision	%RSD < 2	0.612%
Linearity and Range	R² > 0.9997 %RSD < 2	0.9999 10-50µ/ml
LOD	-	1.26µ/ml
LOQ	-	8.54µ/ml

From the above observation, it was revealed that the analytical method complies with the validation parameters.

Drug Excipients Compatibility:

Physical Compatibility In table 6, showed physical mixtures of drug and polymer, there was no physical change was observed.

Table 5. Excipient Compatibility Study

Sr No	Conditions	Time	Open\ Closed	Observations
1	121^o C	15 min	Closed	No colour change
2	Room temp	4 weeks	Closed/ open	No colour change
3	Refrigerator	4 weeks	Closed/ open	No colour change
4	40^o C/75%RH	4 weeks	open	No Colour change

DSC Studies-The endothermic peak at 147ºC can be attributed as melting point of Metoprolol succinate. The thermogram showed that the Metoprolol succinate, HPMC and Ethyl cellulose are compatible with each other.(fig 4)

Fig. 4. DSC Thermogram of Physical Mixture of metoprolol succinate + Ethyl cellulose

IR Studies:

We are therefore able to infer that drugs and polymers are compatible with each other because neither the masking of a single characteristic peak nor the existence of an extra peak in the drug spectra was present in any physical mixing of the two (Figure 5). The absorption of the –COOH group at 1612 cm-1 characterizes the infrared spectra of metoprolol succinate. This band in the drug's IR spectra (fig 5) has the same absorption pattern as the drug's pure form when combined with ethyl cellulose. Therefore, it may be concluded from the evidence mentioned that there is no physical contact between the medication and polymer, hence no changes are observed.

Fig 5.:IR spectrum of Metoprolol Succinate +Ethyl cellulose

FORMULATION STUDY:

Formulation F7 to F12 releases drug in first 6 hr. Formulation F13 Ethyl cellulose drug showed 71% drug release in the first 6 hr,due to the hydrophobic nature of ethyl cellulose.

Fig 6.:% Cumulative Drug Release of Batches F7 to F13

Optimization of solid dispersion:

Formulations EF1, and EF2 containing 1.5:0.5 and 2.0:0.5(polymer:drug) respectively, showed 90% drug release in 12hrs. Similarly Formulation EF3 and EF4 showed 100% Drug release in 24hrs.

Evaluation of solid dispersion:

Table 6. Drug content assay of EF1 to EF4 batch

Batch code	Assay % N=3	Solid dispersion for dissolution equivalent to 95 mg of MS
EF1	87±0.519	408
EF2	91±0.468	479
EF3	97±0.264	586
EF4	91±0.429	688

The drug content of batches EF1 to EF4 were found within limit

In-Vitro drug release

Figure 7: % Cumulative drug release of batch EF1 to EF4 up to 8 hrs

Formulations EF1, and EF2 containing 1.5:0.5 and 2.0:0.5(polymer:drug) respectively, showed 70% drug release in 8hrs. similarly Formulation EF3 and EF4 showed 45% drug release in 8 hrs. in fig 7 from formulation EF3 and EF4.

SUMMARY AND CONCLUSION:

Solid dispersion systems have a 40year history of enhancing drug dissolution and bioavailability. The recent emphasis on controlled- release forms underscores their potential for enhanced drug delivery. In conclusion, solid dispersions provide diverse opportunities for controlled drug release. Continued research is unlocking their potential for innovative dosage form development, contributing to advancements in pharmaceutical drug delivery. In conclusion, our study shows that employing a hydrophobic polymer matrix, we were able to effectively create a sustained-release vehicle for a very hydrophilic medication. In spite of this achievement, significant burst effects were observed at high drug concentrations Drug release was 90% in 12h for formulations EF1 and EF2, which included polymer-drug ratios of 1.5:0.5 and 2.0:0.5, respectively. Likewise, at 24h, formulations EF3 and EF4 demonstrated 100% drug release. The polymer combinations that were found to be most efficient in controlling the release of metoprolol were the 1.5:0.5 ratio of ethyl cellulose when using the solvent approach.

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Received on 16.06.2024 Revised on 17.10.2024

Accepted on 23.01.2025 Published on 12.06.2025

Available online from June 14, 2025

Research J. Pharmacy and Technology. 2025;18(6):2627-2632.

DOI: 10.52711/0974-360X.2025.00377

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