A Study of the effect of some Formulation and Preparation variables on Drug Release from Matrix Tablets

Ranim Alrouhayyah^1,2*, Nermin Dahma³, Irena G Bratchikova⁴

¹Department of General Pharmaceutical and Biomedical Technology, Institute of Medicine, Peoples’ Friendship University of Russia named after Patrice Lumumba (RUDN University),

6 Miklukho-Maklaya street, Moscow, 117198, Russian Federation.

²Department of Analytical and Food Chemistry, Faculty of Pharmacy, Damascus University, Damascus, Syria.

³The Federal State Autonomous Educational Institution of Higher Education “Belgorod National Research University”, 308015 Belgorod, Pobedy street, 85, Russian Federation.

⁴Physical and Colloidal Chemistry Department, Faculty of Science, Peoples’ Friendship University of Russia Named after Patrice Lumumba (RUDN University),

6 Miklukho-Maklaya street, Moscow, 117198, Russian Federation.

*Corresponding Author E-mail: ranimalrouhayya@yahoo.com

ABSTRACT:

This study aimed to evaluate the effect of some formulation and preparation variables (amount of hydrophobic polymer, amount and type of lubricant, compressive strength) on drug release from sustained- release domperidone matrix tablets prepared by wet granulation using ethylcellulose as a release-prolonging polymer. Drug release from the matrix tablets was studied in acidic medium (HCl 0.1 N) for the first 2 hours and then in phosphate buffer (pH=6.8) for the rest of the time (up to 24 hours), and the release kinetics were assessed using various mathematical models. It turned out that the total amount of drug released in acidic and phosphatic media decreases as the percentage of ethylcellulose or the compressive strength increases. Also, replacing a hydrophobic lubricant with a hydrophilic one or reducing the compressive strength increases the rate of dissolution. The release kinetics study showed that the drug was released from the prepared formulations according to Higuchi model, and the fit of the release data to Ritgger-Peppas model pointed to Fick's law of diffusion as the main release mechanism. The results of this study showed that ethylcellulose can be effectively used to prepare sustained-release domperidone matrix tablets, with the ability to prolong the release of the drug up to 24 hours by controlling not only the amount of polymer but also the compressive strength or lubricants.

KEYWORDS: Matrix tablets, ethylcellulose, sustained release, dissolution rate, release kinetics, tablet hardness, lubricant.

INTRODUCTION:

Oral drug delivery systems account for over 50% of the explosive growth in the pharmaceutical market in recent years¹. Although other routes of drug administration have recently been greatly improved, the oral route of drug delivery remains the preferred route due to its non-invasiveness, cost-effectiveness, and ease of administration².

Conventional oral drug delivery systems release all the drug immediately after administration, allowing rapid systemic absorption of the drug³. This results in a rapid increase in plasma drug concentration and may even reach toxic levels and then rapidly decline to sub-therapeutic levels, requiring frequent drug administration to maintain drug concentrations at therapeutic levels^4,5. To solve these problems, modified release systems, including sustained release systems, were developed⁶. The main goal of these systems is to reduce or eliminate the disadvantages of conventional dosage forms; improve patient compliance by reducing dosing frequency; or/and increase the effectiveness of the drug due to localization at the site of action⁷. Due to their controlled physical, chemical and mechanical properties, biodegradable polymers are widely used in producing controlled release systems, especially for oral administration. Polymeric controlled release systems can be divided, based on their mechanism, into the following six main categories:

1- diffusion systems: it is the most common mechanism for drug release from polymer systems, driven by a non-equilibrium concentration gradient⁸. Depending on the morphological structure, diffusion-based polymer systems are divided into:

a. Matrix-mediated release control: they are composed of various polymers and excipients, allowing prolonged and controlled release of the drug dissolved or dispersed therein⁹. In other words, the polymer is dispersed throughout the system and the drug is released as it passes through the matrix itself.

b. Membrane-mediated release control (reservoir): the release- controlling part is a water-insoluble polymer located on the surface of the system in the form of a membrane through which the aqueous medium flows (in) and the dissolved drug diffuses (out)¹⁰.

2- Dissolution systems: these can also be designed as matrix or reservoir systems and are prepared using slow-dissolving polymers, the dissolution rate of which determines the rate of drug release since the drug is released when the matrix or reservoir dissolves¹¹. Thus, one of the significant factors in selecting a suitable polymer for these systems is the solubility of the polymer.

It's worth saying that most of the above systems are a combination of dissolution and diffusion systems in which drugs are entrapped in polymeric matrices or membranes. However, one of these mechanisms sometimes dominates the other, resulting in dissolution- or diffusion-limited systems¹².

3- Stimulus-sensitive systems: some polymers can be activated to release the drug by different stimuli, including physical, chemical, electrical, magnetic, or mechanical stimuli, which create signals to activate polymers with specific properties¹³. Changes in pH, light irradiation, temperature, changes in redox potential, application of a magnetic field, and biological stimulation are widely used to induce drug release from these systems¹⁴.

4- Ion exchange systems: they typically consist of resins made from cross-linked polymers with many cationic and anionic functional groups. Body fluids can penetrate their structure thanks to a cross-linked polymer backbone with the replacement of mobile ions in ionic groups by other cations or anions. The rate of drug release can be controlled by the pH of the biological environment, the ionic strength, and the crosslink density of the resins¹⁵.

5- Solvent activated systems: based on their mechanism of action, they are divided into^16,17:

a. Osmotic-control systems: they are obtained by encapsulating an osmotically active drug or a combination of an osmotically inactive drug and an osmotically active substance within a semi-permeable polymer membrane with small holes in it, which serve as pathways for drug release. Through these holes, water penetrates the membrane and creates osmotic pressure, which is the driving force for drug release. Drug release can be controlled by various factors, including the permeability of the polymer membrane, the size of the holes, and the level of osmotic pressure.

b. Swelling-controlled systems: these contain polymers that can absorb significant amounts of water after immersion in an aqueous environment. The rate of drug release is controlled by the swelling of the polymer and the diffusion of the drug through the expanding polymer.

6- Chemically mediated systems: these are generally divided into two groups^15,18:

a. Erodible polymer systems: drugs are dispersed in the matrix and released because of its degradation and subsequent erosion. If the drug-loaded matrix is destroyed before drug diffusion occurs, then drug release is controlled by erosion, and in contrast, if the drug diffuses from the polymer with a much higher rate than the rate of the polymer matrix erosion, the release kinetics is controlled by diffusion.

b. Pendant chain polymer systems: the drug is covalently linked to the main polymer chain and the polymers are broken down by exposure to body fluids. These systems can be used mainly for targeted drug delivery, where the target has its own characteristics leading to enzymatic or hydrolytic degradation of drug-polymer bonds. The rate of hydrolysis and enzymatic degradation of drug-polymer conjugation determines the rate at which the drug is dissociated from the polymer backbone.

The use of polymers in pharmacy was initially limited to packaging rather than drug delivery, as they were used, for example, in the manufacture of polystyrene vials and rubber caps¹⁹. As for the modern use of polymers to control drug release, it dates to 1930s when shellac was used in aspirin tablets, but the technique of extending the release and the action of drugs using polymers has not reached the level it is at, except for the period between 1970 and 1990, when there was an increased need to reduce side effects and control plasma concentrations of drugs²⁰. The most used release-prolonging polymers include ethylcellulose (EC), Hydroxypropyl cellulose (HPC), Hydroxypropyl methylcellulose (HPMC), Hydroxypropyl methylcellulose phthalate (HPMCP), EUDRAGIT^®RL, EUDRAGIT^®RS, Kollidon^®SR. Among them, EC is widely used in the pharmaceutical technology in the preparation of oral and topical pharmaceutical dosage forms. It is an inert hydrophobic polymer with attractive characteristics such as biocompatibility, gastro-resistance, degradation to non-toxic and easily excreted products, good compressibility, and storage stability^21’22.

Domperidone, the synthetic benzimidazole compound, is a dopamine receptor antagonist used to treat vomiting, gastroesophageal reflux disorder, and peptic ulcers^23’24. In the literature, domperidone has been formulated in different sustained- release forms including: floating tablets by wet granulation using polymers such as HPMC K4M, carbopol 934P, and sodium alginate individually or in combination²⁵; matrix tablets by direct compression using different polymers including HPMC K100LV, HPC K100M and EC-22²⁶; matrix tablets by direct compression using polymers as polyox and HPMC²⁷; orodispersible tables by preparing extended-release microspheres and then tableting them with suitable excipients by direct compression²⁸; matrix tablets by direct compression using a mixture of Raphiaookeri gum and HPMC²⁹; matrix tablets by wet granulation using HPMC-5CPS or a combination of HPMC K100M and Acrypol 974p²⁴; and floating tablets by wet granulation using HPMC K4M, HPMC K15M, and HPMC K100M³⁰.

The aim of this work is to prepare sustained- release domperidone matrix tablets by wet granulation and using EC as matrix former; to investigate the kinetics and mechanism of drug release using various mathematical models; and to study the influence of different variables on the properties of the prepared tablets, in particular on dissolution.

MATERIAL AND METHODS:

Material:

EC, 100 cP (CAS 9004-57-3, Glentham Life Sciences, UK), domperidone (CAS 57808-66-9, Zhejiang Hangyu API Co., Ltd, China), lactose monohydrate (CAS 10039-26-6, DFE-Pharma, Germany ), starch (CAS 9005-25-8, Longchang chemical Co., Ltd., China), talc (CAS 14807-96-6, Zhejiang Haisen Pharmaceutical Co., Ltd., China), Mg stearate (CAS 557-04-0, FACI METALEST, Spain), PEG 6000 (CAS 25322-68-3, Servicebio, China). All other excipients and chemicals were of analytical grade.

Methods:

The methods used complied with the requirements of the State Pharmacopoeia of the Russian Federation, 15^th edition³¹.

Preparation of tablets:

The various formulations (table 1) were prepared by wet granulation method, in which domperidone, EC, lactose and starch were mixed until apparently homogeneous, and then isopropanol was added until a wet sticky mass was formed, which was then passed through a No. 10 mesh sieve and dried in a drying oven (LOIP LF-25/350-GS1/Russia) at a temperature of 45±3 ˚C. The dried granules were again passed through the same sieve, then subjected to quality control, after which they were lubricated and pressed using an 8 mm punch of a press machine (TDP 6s Desktop Tablet Press by LFA / Taiwan) to obtain matrix tablets.

Table 1: the composition of prepared formulations

Formulation	Ingredient (mg)							Tablet total weight (mg)
	drug	Matrix-former polymer	diluent	disintegrant	lubricant
	domperidone	EC	Lactose monohydrate	starch*	talc	Mg stearate	PEG 6000
T1	30	9	84.2	9	1.4	1.4	-	135
T2	30	18	75.2	9	1.4	1.4	-	135
T3	30	27	66.2	9	1.4	1.4	-	135
T4•	30	9	85.6	9	0.7	0.7		135
T5•	30	18	75.2	9	-	1.4	1.4	135
T6٭	30	9	84.2	9	1.4	1.4	-	135
T7٭٭	30	18	75.2	9	1.4	1.4	-	135

*The amount of starch was divided into two halves: one was added to the blend to be granulated, and the other with lubricants.

•T4 and T5 are different from T1 and T2 in the amount or the type of lubricant respectively, meaning that the granules used in the T1 and T4 tablets are the same, and T2 and T5 were also tableted from the same granules.

٭T6 is like T1, but it was prepared at a higher compressive strength.

٭٭T7 is like T2, but it was prepared at a lower compressive strength.

Evaluation of powder blends:

Flowability and compressibility:

a) Angle of repose: the powder flowed out of the funnel opening onto a flat horizontal surface, then the high and diameter of the resulting cone were measured to determine the tangent, and then the angle of repose.

b) Density Tests: they were performed as follows using a tap density tester (BHY-100A/ China):

Bulk density (D_B): an accurately weighted quantity (M) of the blend was placed in the cylinder of the density tester and its volume (V) was measured. Then the bulk density was calculated:

D_B =M/V

Tapped density (D_T): the previous blend in the density tester cylinder was subjected to 10, 500 and 1250 strokes and the corresponding volumes were determined, where V₁₂₅₀ represents tapped volume (V_T) if the difference between V₅₀₀ and V₁₂₅₀ is ≤ 2 ml, then tapped density was calculated:

D_T=M/V_T

Hausner ratio: calculated by the equation:

Hausner ratio = D_T/D_B

Carr index (Compressibility coefficient): calculated using the following equation:

Carr index = (D_T-D_B) *100/D_T

The tests of flowability and compressibility were repeated 3 times, and the results were assessed on the following scale:

Angle of repose, ˚	Hausner ratio	Carr index, %	Flowability/ Compressibility
25-30	1.00-1.11	1-10	Excellent
31-35	1.12-1.18	11-15	Good
36-40	1.19-1.25	16-20	Acceptable
41-45	1.26-1.34	21-25	Satisfactory
46-55	1.35-1.45	26-31	Poor
56-65	1.46-1.59	32-37	Bad
>66	>1.60	>38	Very bad

Uniformity of drug Content:

10 samples (each 0.1 g) were anonymously selected from each powder blend and individually dissolved in 50ml of HCl (0.1 N). The obtained solution was filtered then the absorbance of filtrate was measured by spectrophotometer (СФ-103 single-beam scanning spectrophotometer/Russia) at λ_max=287 nm after appropriate dilution, and concentration was calculated using pre-built calibration curve.

Evaluation of granules:

Flowability and compressibility:

These were evaluated in the same way as in powder blends, where the angle of repose, D_B and D_T were determined, and Hausner ratio and Carr index were calculated.

Uniformity of drug content:

The same procedure as for testing the content uniformity of the powder blends was carried out on 10 randomly selected samples from each formulation.

Weight loss on drying:

It was determined on 5 samples (1-2 g) of each formulation at a temperature of 105±2 ºC using an infrared moisture analyzer (FD-660 Kett/Japan).

Granule size Distribution:

30 g granules of each composition were vibrated for 5 minutes using a vibrating sieve (EVERSUN/China), and the percentage of granules on each sieve was calculated to construct a size distribution curve. The importance of this test is evident from the fact that the granules size influences the mechanical properties of resulting tablets and, correspondingly, can even affect drug release³².

Evaluation of tablets:

Description:

The tablets were characterized by noting their appearance and organoleptic properties.

Uniformity of weight:

It was carried out for each formulation by individually weighing 20 randomly selected tablets and calculating the average weight of the tablet and the deviation of the weight of each tablet from the average value.

Uniformity of drug content:

30 tablets from each formulation were randomly selected, of which 10 tablets were randomly selected for the content uniformity test (the remaining 20 tablets were retained for the second stage of testing if necessary). Each of the 10 selected tablets was crushed and dissolved in 100 ml of HCl 0.1 N. The solution was filtered, and the absorbance of filtrate was measured at λ_max =287 nm after appropriate dilution, and the drug content in the solution, and therefore in the tablet, was calculated using pre-developed calibration curve, then the mean value (X̄) of drug content, standard deviation (sd) and relative standard deviation (RSD) were calculated. According to the X̄ value, a standard value (M) is selected, and an acceptable value (AV) is calculated:

AV=|M- X̄|+k.sd; k: acceptability constant.

Mechanical properties:

Friability Test: since the weight of one tablet is less than 0.65 g, a number of tablets with a total weight of about 6.5 g were randomly selected, dedusted and weighed (W1), placed in a single-blade drum of friability tester (Erweka TAR II/Germany) and subjected to 100 cycles, after which the tablets were again dedusted and weighed (W2) and the friability (F) was calculated as follows:

F= [(W1-W2)/W1]*100%

Hardness test: it was carried out on 10 tablets, the hardness of each was measured (in Newton (N)) using a hardness tester (NANBEI; YD-1/China), then the mean value and sd were calculated.

Tablet disintegration:

6 tablets of each prepared formulation were placed in 900 ml of distilled water at a temperature of 37±0.5 °C in the basket of disintegration tester (Nanbei^®; BJ-Ⅱ/ China) and the time required for the complete disintegration of tablets was measured.

Dissolution test:

The test was conducted on 6 tablets of each formulation using dissolution tester (PTWS 120D/Germany); apparatus I (basket), 50 r/min, in 1000 ml of HCl 0.1 N for the first two hours, then in 1000 ml of phosphate buffer (pH = 6.8) for the remaining time (up to 24 h), and t=37±0.5 °C all over the time of the experiment. Samples of 5 ml were taken at certain intervals and replaced with 5 ml of pure medium (acid or buffer). The samples were filtered, and the absorbance of the filtrates was measured at λ_max= 287 nm to determine the amount of drug in the dissolution medium using pre-built calibration curve (in acidic medium or in phosphatic buffer).

Since the dissolution was studied in two media, a series of concentrations were prepared in each medium and a calibration curve was constructed for each by plotting the absorbance against concentration, and an equation in the form y=ax+b with a correlation coefficient (r²) was obtained. A linear calibration curve with r²>0.999 was obtained in each medium.

Mathematical modelling of drug release:

It was investigated using the following kinetic models (table 2), where the experimental data of drug release were fitted to each equation, and the correlation coefficient (r²) and rate constants (k) were calculated for each model^33,34,35. Drug release was described by the model with the best r² value.

Statistical analysis:

Student's t-test was performed and p-value was calculated, where the studied factor is statistically significant if p≤0.05.

Table 3: evaluation of powder blends and granules

Formulation		Angle of repose, º (mean±sd)	Bulk density, g/cm³ (mean±sd)	Tapped density, g/cm³ (mean±sd)	Hausner ratio (mean±sd)	Carr index, % (mean±sd)	Drug content, % (mean±sd)	Weight loss on drying,% (mean±sd)
T1	Powders	44.6±1.09	0.485±0.0011	0.653±0.0030	1.35±0.0017	25.73±0.011	100.18±0.97
	Granules	30.1±0.47	0.459±0.0008	0.526±0.0027	1.15±0.0020	12.74±0.012	99.01 ± 1.32
	Lubricated granules	26.4±0.39	0.436±0.0008	0.461±0.0008	1.06±0.0017	5.42±0.0015		2.13±0.39
T2	Powders	43.2±1.16	0.487±0.0007	0.654±0.0011	1.34±0.0039	25.54±0.0021	99.06±1.23
	Granules	30.9±0.81	0.457±0.0012	0.525±0.001	1.15±0.0027	12.95±0.0021	101.02±1.11
	Lubricated granules	26.6±0.58	0.437±0.0011	0.460±0.0011	1.05±0.0045	5.00±0.0041		2.07±0.51
T3	Powders	42.9±1.15	0.491±0.0008	0.652±0.0011	1.33±0.0042	24.69±0.0024	98.96±1.19
	Granules	30.1±0.69	0.458±0.0008	0.526±0.0008	1.15±0.0021	12.93±0.0016	100.23±1.12
	Lubricated granules	26.1±0.37	0.438±0.0005	0.460±0.0011	1.05±0.0038	4.78±0.0034		1.87±0.49
T4	Lubricated granules	28.7±0.48	0.427±0.0008	0.463±0.0011	1.08±0.0012	7.78±0.0011		2.16±0.26
T5	Lubricated granules	27.9±0.65	0.495±0.0008	0.540±0.0011	1.09±0.0038	8.33±0.0032		2.29±0.16

T4 differs from T1 in the amount of lubricant, and T5 differs from T2 in the type of lubricant, so only lubricated granules of T4 and T5 were tested.

Table 4: Evaluation of prepared matrix tablets

Formulation	Weight, mg	drug content, %		Friability, %	Hardness, N	Disintegration time, min
Formulation	(mean± sd)	(mean ±RSD)	sd	Friability, %	Hardness, N	Disintegration time, min
T1	136.0±1.25	100.15±1.278	1.28	0.22	62.76±0.46	47
T2	134.2±1.45	99.83±1.863	1.86	0.24	70.61±0.49	62
T3	136.8±1.05	101.11±1.315	1.33	0.22	77.47±0.40	79
T4	135.1±1.25	100.51±0.955	0.96	0.24	70.63±0.45	40
T5	136.1±1.09	101.05±1.108	1.12	0.25	82.57± 0.55	43
T6	134.6±1.32	100.57±0.855	0.86	0.19	79.43±0.49	60
T7	135.3±1.26	101.13±1.691	1.71	0.27	53.94±0.36	46

Mechanical properties:

All tablets showed suitable friability and hardness (table Ⅳ), as friability should be, according to used method, no more than 1% and hardness (for tablets with diameter 6-9 mm) no less than 30 N. However, hardness varied depending on various factors, including:

· The amount (percentage) of EC: it turned out that the higher the EC content, the higher (P<0.05) the hardness of the tablets (T1, T2, T3). This may be interpreted by stronger bonding forces between the particles of tablets, which in turn leads to a decrease in the porosity of the compressed tablets.

· Lubricants: halving the amount of Mg stearate and talc (T1, T4) or substitution of talc by PEG 6000 (T2, T5) increased (P<0.05) the hardness of tablets. This may be explained by the greater ability of Mg stearate and talc to coat particles than PEG 6000, which weakens their binding to each other.

· The compressive strength: hardness increased (P<0.05) with increasing applied compressive force (T1,T6) and vice versa (T2, T7). This may be related to the fact that increasing compressive strength increases the bonding area between particles and reduces matrix porosity.

Tablet disintegration:

The disintegration time increased due to an increase in the amount of EC in the matrix or the compressive strength, while a decrease in the amount of hydrophobic lubricant or the use of a hydrophilic one, or a decrease in the compressive force, led to a decrease in the disintegration time (table 4). This was accompanied by corresponding changes in the hardness of the tablets, except for T4 and T5 where halving the amount of hydrophobic lubricants/adding a hydrophilic lubricant increased the hydrophilicity of the matrix and reduced the resistance to penetration of the dissolution medium into the matrix.

Dissolution Study:

The dissolution study showed that the drug was released from prepared tablets at different rates depending on formulation and compression variables, including:

- The amount of EC: The drug was released from T1 at a higher (P<0.05) rate than from T2, which in turn showed a greater (P<0.05) release rate than T3 (fig. 2), which indicates that increasing the percentage of hydrophobic polymer EC leads to a decrease in dissolution rate. This may be interpreted by the decrease in the porosity of matrix and an increase in the tortuosity of the diffusion channels. Also, an increase in the amount of EC can lead to the encapsulation of drug molecules by the polymer and, as a result, to a slowdown in their release from the matrix.

Figure 2: the effect of hydrophobic polymer amount on drug release

The EC content in the tablet is 9 mg in T1, 18 mg in T2, and 27 mg in T3

- Lubricants: lubricants that are primarily hydrophobic in nature are known to increase disintegration time and reduce drug release from matrix tablets because they retard the wetting of the tablet particles by solvent media and repel water³⁷. It was the situation with T1 and T4, where the drug was released from T4, in which the content of hydrophobic lubricants (Mg stearate and talc) was halved, in a slightly greater rate than it from T1 (fig.3, a), but this difference wasn’t statistically significant (P>0.05). This may be explained by a balance between increased hydrophilicity and increased hardness of the matrix. On the other hand, comparison of T2 and T5 showed a higher (P< 0.05) drug release rate from T5 in which talc was replaced by PEG 6000, than from T2 (fig.3, b), which may be interpreted by the hydrophilic nature of PEG, its good solubilizing properties, and its tendency to form a film around the matrix particles, reducing the hydrophobicity of their surfaces³⁸.

Table 5: rate constants and correlation coefficients of studied kinetic models

Formulation	Zero order		First order		Model Higuchi		Model Hixson Crowell		Model Ritger-Peppas
Formulation	r²	K₀	r²	K₁	r²	K_H	r²	K_HC	r²	n	K_RP
T1	0.9013	6.522	0.9896	0.096	0.9925	25.045	0.9857	0.202	0.9911	0.42	30.70
T2	0.9088	4.410	0.9793	0.036	0.9943	18.534	0.9597	0.102	0.9970	0.41	23.78
T3	0.9125	3.554	0.9626	0.024	0.9952	14.915	0.9475	0.073	0.9978	0.41	18.99
T4	0.8949	7.281	0.9922	0.107	0.9916	26.571	0.9838	0.226	0.9903	0.41	32.70
T5	0.9120	4.972	0.9892	0.052	0.9950	20.864	0.9779	0.131	0.9971	0.41	26.42
T6	0.9131	5.113	0.9913	0.057	0.9949	21.430	0.9817	0.140	0.9949	0.42	26.36
T7	0.9211	5.052	0.9857	0.057	0.9968	21.116	0.9857	0.138	0.9974	0.43	25.31

CONCLUSION:

In the context of this study, matrix tablets of a poorly soluble drug were prepared by wet granulation using varying amounts of ethylcellulose as a release-prolonging polymer. The granules were evaluated and found to have suitable properties for compression into tablets. The obtained tablets met the requirements for uniformity of weight, uniformity of drug content and mechanical properties. According to dissolution test, some formulations successfully prolonged the drug release up to 18-24 hours, while other formulations failed to release all of the drug in 24 hours. The results of this study showed that increasing ethylcellulose content or compressive strength resulted in an increase in tablet hardness and disintegration time, as well as a decrease in dissolution rate. On the other hand, replacing talc with PEG 6000 resulted in an increase in tablet hardness and dissolution rate, as well as a decrease in disintegration time. Also, halving the amount of talc and Mg stearate resulted in an increase in tablet hardness and a decrease in disintegration time, but a statistically insignificant increase in dissolution rate. Mathematical modeling of drug release showed that the drug is released from the prepared formulations according to the Higuchi model and diffuses according to Fick's law.

CONFLICT OF INTEREST:

The authors have no conflicts of interest.

REFERENCES:

1. Kaur G, Arora M, Ravi Kumar MNV. Oral Drug Delivery Technologies-A Decade of Developments. J Pharmacol Exp Ther. 2019; 370(3): 529-543. doi: 10.1124/jpet.118.255828.

2. 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.

3. Vilas A, Siddheshwar SS. A Review on Floating Microsphere. Asian J. Pharm. Tech. 2024; 14(1): 31-35. doi: 10.52711/2231-5713.2024.00007.

4. Rahul Kh, Nilkanth B, Nilesh K. A Review on Applications of Hydroxy Propyl Methyl Cellulose and Natural polymers for the development of modified release drug delivery systems. Research J. Pharm. and Tech. 2021; 14(2): 1163-1170. doi: 10.5958/0974-360X.2021.00208.0.

5. Parikshit P. A Review on Nanoparticle-Loaded Hydrogels for Extended Drug Release. Asian J. Pharm. Tech. 2024; 14(1): 55-8. doi: 10.52711/2231-5713.2024.00011

6. Madat DV, Gohel MC, Ramkishan A. Development of Venlafaxine Hydrochloride Controlled Release Pellets Prepared Employing the Blend of Ethyl Cellulose and Polyethylene Oxide. Research J. Pharm. and Tech. 2012; 5(10): 1289-1292.

7. Deo Sh. Modified Release drug delivery systems. Concept Pharma. 2017; DOI:10.13140/RG.2.2.30034.15046

8. Murugesan S, Gowramma B, Lakshmanan K, et al. Oral modified drug release solid dosage form with special reference to design; An Overview. Current Drug Research Reviews, 2020, 12: 16-25.

9. Songire PR, Aher SS, Saudagar RB. Recent Research on Matrix Tablets for Controlled Release – A Review. Asian J. Pharm. Tech. 2015; 5( 4): 214-221. doi: 10.5958/2231-5713.2015.00031.8.

10. Koutsamanis I, Paudel A, Nickisch K, et al. Controlled‐Release from High‐Loaded Reservoir‐Type Systems—A Case Study of Ethylene‐Vinyl Acetate and Progesterone. Pharmaceutics 2020; 12, 103; doi:10.3390/pharmaceutics12020103.

11. Huynh CT, Lee,DS. Controlled Release. In: Kobayashi, S., Müllen, K. (eds) Encyclopedia of Polymeric Nanomaterials. Springer, Berlin, Heidelberg. 2015; 439–449. https://doi.org/10.1007/978-3-642-29648-2_314.

12. Siegel RA, Rathbone MJ. Overview of controlled release mechanisms. In: Siepmann J, Siegel RA, Rathbone MJ (eds) Fundamentals and applications of controlled release drug delivery. Advances in delivery science and technology. Springer, New York. 2012; 19–43. https://doi.org/10.1007/978-1-4614-0881-9_2.

13. Bruneau M, Bennici S, Brendle J, et al. Systems for stimuli-controlled release: Materials and applications. J Control Release. 2019; 294: 355-371. doi: 10.1016/j.jconrel.2018.12.038.

14. Marturano V, Cerruti P, Giamberini M, Tylkowski B, Ambrogi V. Light-Responsive Polymer Micro- and Nano-Capsules. Polymers (Basel). 2016; 9(1): 8. doi: 10.3390/polym9010008.

15. Geraili A, Xing M, Mequanin K. Design and fabrication of drug-delivery systems toward adjustable release profiles for personalized treatment. VIEW. 2021; 2: 20200126. https://doi.org/10.1002/VIW.20200126.

16. Son G-H, Lee B-J, Cho Ch-W. Mechanisms of drug release from advanced drug formulations such as polymeric-based drug-delivery systems and lipid nanoparticles. Journal of pharmaceutical investigation. 2017; 47(6): 287-296.

17. Luke E A. Naresh P. Modelling of Drug Release from a Polymer Matrix System. Nov Appro Drug Des Dev. 2017; 2(3): 555589. DOI: 10.19080/NAPDD.2017.02.555589.

18. Kherud R, Sarode S. Review on Control Drug Delivery System. International Journal of Science and Research (IJSR). 2022; 11(3): 349-355. DOI: 10.21275/MR22307132546.

19. Kamel S, Ali N, Jahangir K, et al. pharmaceutical significance of cellulose: a review. Express Polymer Letters. 2008; 2(11): 758–778.

20. Katdare A, Chaubal MV. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. Chapter 19: Polymeric Excipients for Controlled Release Applications. 2006, p.341.

21. Wasilewska K, Winnicka K. Ethylcellulose–a pharmaceutical excipient with multidirectional application in drug dosage forms development. Materials 2019; 12, 3386; doi:10.3390/ma12203386.

22. Trofimiuk M, Wasilewska K, Winnicka K. How to modify drug release in paediatric dosage forms? Novel technologies and modern approaches with regard to children’s population. Int. J. Mol. Sci. 2019, 20, 3200.

23. Avinash B, Suhas M K, Chirag VN, et al. Formulation and Evaluation of Mouth Dissolving Tablets of Domperidone. Research J. Pharm. and Tech. 2010; 3(3): 821-824.

24. Khan W, Siddique NF, Siddique J, et al. Formulation and Evaluation of Domperidone Sustained Release Tablet. Research J. Pharm. and Tech. 2018; 11(12): 5599-5610. doi: 10.5958/0974-360X.2018.01018.1.

25. Prajapati ST, Patel LD, Patel DM. Studies on Formulation and In Vitro Evaluation of Floating Matrix Tablets of Domperidone. Indian Journal of Pharmaceutical Sciences. 2009; 71(1): 19-23. DOI: 10.4103/0250-474X.51944.

26. Asif Khan M, Saeed M, Badshah A, et al. Design, formulation, optimization and evaluation of sustained release tablets of domperidone. African Journal of Pharmacy and Pharmacology. 2011; 5(16): 1882-1887,

27. Mor J, Kumar N. Formulation and evaluation of extended release tablets of domperidone. Pharma Research. 2013; 10(1): 75-83.

28. Patil HG, Tiwari RV, Repka MA, et al. Formulation and development of orodispersible sustained release tablet of domperidone. Drug Development and Industrial Pharmacy. 2015; 42(6): 906–915. https://doi.org/10.3109/03639045.2015.1088864.

29. Olorunsola EO, Majekodunmi SO. Development of extended-release formulation of domperidone using a blend of Raphia hookeri gum and hydroxypropyl methylcellulose as tablet matrix. Tropical Journal of Pharmaceutical Research. 2017; 16 (10): 2341-2347.

30. Kumar R, Tripathi A. Formulation, Development and Optimization of Floating Sustain Release Tablets of Domperidone for the Effective Treatment of Antiemetic During Chemotherapy. IJIRT. 2021; 8(7): 451-456.

31. State Pharmacopoeia of the Russian Federation. XV ed. (2023). Moscow. URL: https://pharmacopoeia.regmed.ru/pharmacopoeia/izdanie-15/. (accessed 10.07.2024). (In Russ.)

32. Tousey M. D. Pharmaceutical technology tableting and granulation; The Granulation Process 101- Basic Technologies For Tablet Making. 2002; 8-13.

33. Patel AJ, Singh RP, Patel V. Goswami Sh. 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.

34. Alrouhayya R, Sheshko TF, Markova EB, et al. 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.

35. Salome Ch ,Godswill O, Ikechukwu O. Kinetics and Mechanisms of Drug Release from Swellable and Non Swellable Matrices: A Review. Research Journal of Pharmaceutical Biological and Chemical Sciences. 2013; 4(2): 97-103.

36. The International pharmacopeia, 11th edition, 2022

37. Mishra A, Yadav SK. Development of sustained release metoprolol succinate matrix tablets using kappa carrageenan as monolithic polymer. Research J. Pharm. and Tech. 2016; 9(9):1311-1316. doi: DOI: 10.5958/0974-360X.2016.00249.3.

38. Alrouhayyah R, Sheshko TF, Suslina SN. Improving the Dissolution rate of Mefenamic acid by preparing Solid Dispersions with Polyethylene glycol 4000. Research J. Pharm. and Tech. 2023; 16(7): 3115-9. doi: 10.52711/0974-360X.2023.00512.

Received on 11.05.2024 Revised on 08.07.2024

Accepted on 18.08.2024 Published on 20.01.2025

Available online from January 27, 2025

Research J. Pharmacy and Technology. 2025;18(1):345-354.

DOI: 10.52711/0974-360X.2025.00054

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Kinetic model	Equation	Symbol interpretation
Zero order	M_t= K_o t	M_t- the amount of drug released over time t, M₀- the initial amount of the drug in the dosage form (at the moment 0), M- the amount of drug remaining at time t, M_∞- the amount of drug released at infinite time, K₀, K₁, K_H, K_HC, K_RP: rate constants for zero order, first order, model Higuchi, model Hixson-Crowell, model Ritger –Peppas, respectively. n: the degree of release, associated with the release mechanism, where: n≤0.45: diffusion according to Fick's law; 0.45<n<0.89: anomalous diffusion, i.e. drug release is controlled by diffusion and erosion; n>0.89: case II transport, i.e. transport of the drug molecules within the polymer is a result of degradation of the polymer matrix.
First order	M₀ log ------- = K₁ t/2.303 M
Model Higuchi	M_t= K_Ht^1/2
Model Hixon-Crowell	M₀^1/3– M^1/3 = K_HCt
Model Ritger -Peppas	M_t /M_∞ = K_RP tⁿ