INTRODUCTION:

Risperidone is a commonly prescribed atypical antipsychotic drug approved for the treatment of neuropsychiatric disorders in children and adolescents, including autism and schizophrenia. It has low solubility and exhibits high lipophilicity, which has significant influence on its pharmacokinetic properties. Because the ethnic variation of glucuronidation is large, inappropriate dosing can lead to severe adverse effects.

Although the adult dosage is suitable for children older than 12 years old, the children under 12 years tend to be more sensitive to the drug than that older considering the onset and disappearance of effect. In addition, the conventional oral tablet has been carried out with major side effects including abnormal body weight gain, sexual dysfunction, altered glucose metabolism, dyslipidemia, and more¹. Because of the limited authorization of pediatric use, improper dosing may occur in recent years. Therefore, the development of proper pharmaceutical formulation for children is much more important as medication errors involving inaccurate dosing occurs frequently. Furthermore, young population prefers a formulation with a pleasant taste, easy swallowing, and shorter treatment duration. However, it is difficult to use the typical dosage forms such as tablet and capsule since they have a bitter or unpleasant flavor and are not easy to swallow. Thus, the ideal formulation that are suitable for pediatric patients are those that with the desirable characteristics including rapid and consistent dissolution, formulation stability, good palatability, and easy administration². according to bio pharmaceutical classification system RIS is belong to class II this mean that RIS have a properties of low aqua solubility and high permability and therefore we need to prepare a proper dosage form with the greater solubility or to improve the solubility of RIS. there where several researchers has been conducted to improve their solubility in water with proper dosage forms, but however the optimum dosage forum till now was not being conducted^4-7. Continuous research has been directed towards alternate innovative drug delivery systems which can assuage the problems related to non-compliance and improve therapeutic efficacy. Jellies are one such dosage form which can, to a certain extent, address the problem of non-compliance. Pediatric jellies marked by the advantage of development and use of non-toxic, safe, orally disintegrable and sparkling products with pleasing texture and flavors have gained tremendous popularity in the formulation of various therapeutic agents. Such dosage forms are known to be assimilated more effectively in comparison to syrup, solution and suspension due to the exposure of the huge absorptive area of the oral cavity to the medicament. The solid dispersion technology is one of the revolutionary innovations in formulation which has been utilized extensively to enhance solubility of poorly water soluble drugs. In this venture, the objective of the present study is to develop and evaluate the pediatric jelly formulation of risperidone utilizing solid dispersion technology, considering optimal gel and taste masking ^8-10.

Solid Dispersion Techniques:

Solid dispersion technique is one of the most effective ways to enhance the solubility and bioavailability of highly lipophilic drugs. Hot-melt and solvent methods are the common methods to prepare solid dispersion for poorly soluble drugs. The method and selection of carrier play an important role to the successful preparation of solid dispersion. However, hot melt method can only use thermal stable carrier, otherwise it will cause the formation of unknown compounds throughout the whole process ^11-15.

Selection of Excipients:

As we know, there are a number of factors that needs to be considered for selection of excipients for formulation. Safety is one of the most important concerns while formulating pediatric jellies. From a Pharmacological standpoint, Excipients should be bioinert and non-immunogenic. The payment of excipients should be kept at a minimum. Apart from the toxicity considerations, palatability, aesthetic appearance, physical properties of the jellies, stability as well as bioavailability considerations are of primary importance. Further, all pharmaceutical excipients must meet the specifications of the Pharmacopeia, which ensure material quality and consistency. Explanation of the above factors warrants an interesting excursion into the characteristics of typical excipients that have the potential to be commercialized as jellies. Initially, different types of excipients were screened for the selection of excipient for formulation of jellies. Once generally recognized as safe excipients were selected, individual excipient-specific studies were carried out. Gelling agents combination selected for the formulation consisted of carbomers, free from preservatives, and low molecular weight gelling agents such as gelatin, designed to melt and deliver medication to the wounded or irritated tissue. gelling agents produced gelatinous or liquid composition within the optimum pH range on contact with aqueous and was well tolerated. They are also non-toxic and economical. Jellies thus produced with active agent concentrations between 2% and 13% w/v produced soft and easy-to-spread jellies due to a balance between low molecular weight gelling agent and the high molecular weight polymer. Jellies produced were also physically stable and required no refrigeration due to the absence of a suitable aqueous environment for microorganism growth. Also, controlled release of the active agent would be expected ^16-20.

MATERIALS AND METHODS:

Materials:

Risperidone was obtained as a gift sample. D-mannitol, citric acid monohydrate, pectin from citrus, and potato starch were purchased. Propylene glycol, glycerin, ethanol, and sodium saccharin were purchased. Distilled water was prepared in the laboratory. Other chemicals and solvents used were of analytical grade. HPLC-grade water was prepared using distilled water. Ethanol and a few of the chemicals used in the preparation of solid dispersions and other formulations were purchased.

Preparation of risperidone solid dispersion

Solid dispersions of risperidone were prepared by a solvent evaporation method using pectin. First, pectin was properly dissolved using a magnetic stirrer in a suitable amount of the specified solvent, and then required drug was mixed in the above solution with stirring. The organic solvent was then evaporated using a rotary evaporator until a dry solid was obtained. Dried solid of solid dispersion was powdered, passed through sieve # 60, and stored in a pre-weighed desiccator until further use^21-25. Different solid dispersion formulations of risperidone were prepared in a similar way but by varying the ratio of drug and pectin. The compositions of various solid dispersion formulations are shown in table .

Table 1: Composition of risperidone solid dispersion formulas

Formula code	Carrier	Drug: Carrier ratio (W: W)
SD1	PVP K30.0	One to one
SD2	PVP K30.0	One to two
SD3	PVP K30.0	One to three
SD4	PVP K30.0	One to five

Characterization of prepared risperidone solid dispersion formulas:

Evaluation of the percentage yield (%PY) of the formulated risperidone solid dispersions:

The created RIS-solid dispersion's percent yield (PY%) has been determined to assess the effectiveness of each SD preparation technique for every formula. The actual weight of the solid dispersion that resulted was divided by the theoretical mass of the medication and carrier to determine the PY%²².

Actual weight of solid dispersion

PY% = ------------------------------------------------- X 100

Theoretical weight of solid despersion

Determination of risperidone content in prepared solid dispersion

The RIS solid dispersion, equivalent to 10mg of RIS, was dissolved in 100mL of 0.1N HCl and combined with a vortex mixer. The solution was serially diluted before being filtered via Whatman filter paper. The RIS content at 277nm was determined by spectrophotometric techniques. This formula is crucial for figuring out how much medication is in the solid dispersion that is created ²³.

Actual weight of RIS

Drug content (%) --------------------------------- X 100

Theoretical weight of RIS

Determination of the saturated solubility of risperidone solid -dispersion:

The resulting solubility in aqueous solutions was assessed. In order to do the solubility investigation, extra RIS solid dispersion was added to the vials containing ten milliliters of water. For 48 hours, the firmly sealed vials are maintained at 25±0.5°C in a water bath shaker. After centrifugation and subsequent filtration, the supernatant solutions were filtered through a 0.45μm membrane. The concentration of dissolved risperidone was then determined using UV spectrophotometric analysis^24-25.

In-vitro evaluation of dissolution behavior for risperidone solid dispersions and the unprocessed drug

The prepared solid dispersion formulations and pure RIS were both put through a dissolving test. The test was conducted using a USP standard dissolving apparatus II with paddle in 900ml of pH 6.8 phosphate buffer, at a rotational speed of 50rpm, and at a media temperature of 37 0.5°C. The percentage of drug released is then calculated using spectrophotometric measurements after filtering the samples²⁶.

Evaluations of the optimum formula:

FTIR analysis technique:

To look for any potential intermolecular interactions between the drug and polymers, FTIR studies of RIS, and the ideal formula (SD4) were carried out. The materials were placed on a disk of potassium bromide (KBr) and then read using an FTIR machine (Shimadzu 8000, Japan). The 4000-400cm^-1 scanning range was used²⁷.

Differential scanning calorimeter (DSC):

An automated thermal analyzer (Shimadzu, DSC-60, Japan) was used to investigate the thermal properties of pure RIS, PVP K30 polymer, and the optimal formula (SD4)²⁸.

Powder X-ray diffraction (PXRD):

Powder X-ray diffraction analysis was performed to evaluate the crystalline nature of pure risperidone and to characterize the selected formulation SD4. The measurements were carried out using a Cu target with Kα radiation, operated at 45kV and 30mA under standard conditions.

Preparation of risperidone solid dispersion as oral jellies:

By heating and congealing of gelatine, jellies laden with RIS solid dispersion were created. As shown in Table (2) gelatine was tuned at a concentration that produced jellies with different consistency. A modified version of the Sarojini et al. technique was used to create the jellies ⁽²⁰⁾. In a beaker, 85g of sucrose were liquified in 100mL of water, and the mixture was heated to 80C while being constantly stirred. Then, ten mL of warm water with steady mixing was added to the gelatine gelling agent which was then combined with the sucrose solution. RIS solid dispersion (SD4) equivalent to 3mg of RIS was dissolved in 1ml of distilled water and was added to a gelling agent-sucrose solution with continuous stirring. Glycerine, sodium benzoate, and citric acid, flavouring and colouring agent were dissolved in warm water separately and added to the mixture while being continuously stirred. Then the result solution were placed in container, allowed to settle for two hours, and then refrigerated²⁹.

Table (2): Composition of formula of RIS-solid dispersion oral jellies (5g)

Content	F1	F2	F3	F4	F5
Gelatine	4	6	8	10	12
Glycerine	2	2	2	2	2
Citric acid	1	1	1	1	1
Sugar syrup	70.0	70.0	70.0	70.0	70.0
Sodium benzoate	0.01	0.01	0.01	0.01	0.01
Flavouring agent	0.2	0.2	0.2	0.2	0.2
Colouring agent	0.01	0.01	0.01	0.01	0.01
SD 4	0.36	0.36	0.36	0.36	0.36
Water	22.42	20.42	18.42	16.42	14.42

Estimation of the prepared risperidone oral jellies formulations:

Stickiness and grittiness:

The jellies' stickiness and grittiness could be manually determined with ease, and any sensation of such unfavourable qualities was noted by rubbing medicated jellies between two fingers.

pH value:

The pH was measured in triplicate for 1% aqueous solution of the prepared oral jelly under a constant temperature³⁰.

Content uniformity:

To perform the analysis, a single medicated jelly was dissolved in phosphate buffer (pH 6.8) to achieve a theoretical concentration of 0.1mg/mL. The resulting solution was then appropriately diluted, and the absorbance was measured at 277nm using a UV-Visible spectrophotometer³¹.

Test for Syneresis and Texture profile analysis (TPA) first Syneresis:

happens when the jelly contracts after being stored and the water separates from the jelly. All the jellies were examined for indications of syneresis at ambient temperature (25°C±0.5°C) and ( 0°C-8°C)^25,26. Texture profile analysis(TPA): was done by using Copley texture analyzer. The shape of the probe used to compress the jellies was square with a diameter of 5 cm. RIS jellies were compressed twice to their original height. The compression rate was 5.0mm per second with a 5-second delay.

Fourier-transform infrared spectral analysis:

The FTIR spectrophotometer (Shimadzu 8300, Japan) was utilized to assess the compatibility between the gelling agent and RIS solid dispersion in the creation of the optimal oral jelly formula. The KBr disc method was employed to measure the range of 4000–400 cm^-1. The absorption maxima in the spectra were monitored and compared to check for any shifting or the emergence of additional peaks that matched the functional groups³².

Evaluation of the taste masking effect:

With the aim of evaluating the effectiveness of the taste masking, the prepared RIS oral jellies were placed in (50 ml) beaker, followed by the addition of (5ml) of (pH 6.8 buffer) (to simulate the salivary volume and pH) at 37± 0.5ºC, and left for (120 sec). The solution was then filtered and analysed by UV-visible spectrophotometer at 277 nm for RIS content. The analysis was done in triplicate, and the results were expressed in mean value±SD ³³.

In-vitro dissolution study:

The Percent of drug released in 30 min (% D30min) was determined in three repetitions and expressed as an average value ± SD^34-35.

Statistical analysis:

Our result was analysed by using IBM SPSS V 26 for calculation of the Variance (ANOVA) and P value when p<0.05 this mean statistically significant and not significant if P>0.05 ³⁶.

RESULTS AND DISCUSSION:

The saturation solubility of pure risperidone was assessed by performing solubility studies over a 48-hour period at a controlled temperature of 25°C. The experiments were carried out in three different media: distilled water, 0.1N hydrochloric acid, and phosphate buffer with a pH of 6.8 with a pKa of 8.76, risperidone is a weak basic that demonstrates a greater solubility up to approximately 10.5mg/ml in an acidic media, as anticipated. Risperidone, on the other hand, has a poor solubility value of 1.52mg/ml in phosphate buffer. However, as noted in the literature, risperidone's solubility in water was the lowest at around 0.063 mg/ml, making it nearly insoluble^37-40.

Characterization of risperidone solid dispersion:

Various risperidone solid dispersion formulations were developed according to the procedure outlined in the materials and methods section. The characterization outcomes are detailed in the following sections. All prepared systems demonstrated drug content within the range of 91% to 102% (w/w), indicating acceptable incorporation efficiency of RIS across the formulations⁴¹.

Figure 1: The percentage of risperidone released from solid dispersions—formulated via solvent evaporation and tested in phosphate buffer (pH 6.8) at 37°C—was influenced by the proportion of drug to PVP K30 in the formulation.

Evaluation of risperidone release profile from solid dispersion systems under in-vitro conditions:

Effect of RIS:Carrier ratio:

Figure (1) presents the dissolution profiles of risperidone from various solid dispersion formulations containing different drug-to-carrier ratios. The formulations were prepared using the solvent evaporation method with PVP K30 serving as the polymeric carrier. For comparison, the dissolution behavior of pure (unformulated) risperidone was also included. The data revealed a statistically significant enhancement (P<0.05) in drug release from the solid dispersion systems compared to the unprocessed drug, with higher release efficiency observed as the polymer content increased. when the amount of PVP K30 was increased in formulations (SD4>SD3>SD2>SD1). When RIS was released after five minutes, the formula SD4 showed the greatest percentage (100%) compared to SD3(87%), SD2(72%), SD1(71%), and pure RIS (7%). Because of the enhanced drug wettability and conversion to amorphous forms, RIS solid dispersions made with larger percentages of water-soluble carriers dissolve more readily in vitro.

Evaluation of optimum formula:

The pure RIS's FTIR spectrum (Figure 2-A) revealed distinctive peaks at 3064 cm^-1 from the aromatic ring's stretching vibration and peaks at 2941 and 2758 cm^-1 from the asymmetric and symmetric (C-H) alkane's stretching vibration. The carbonyl group's (C=O) stretching vibration is also responsible for the peak at 1644 cm^-1. Peak at 1531 cm^-1 is caused by the vibration of (C=N) stretching⁴²

Figure 2: FTIR spectra of (A) pure risperidone, (B) optimized solid dispersion formula (SD4), and (C) physical mixture of RIS with PVP K30.

The FTIR profile of the SD4 formulation retained all the characteristic absorption bands of risperidone, suggesting the absence of any significant chemical interaction between the drug and the PVP K30 polymer. Notably, the observed reduction in peak intensity in spectrum B, compared to that of pure RIS in spectrum A, is likely attributed to the polymer's dilution effect within the formulation.

DSC-Based Thermal Characterization:

Figure 3 illustrates the differential scanning calorimetry (DSC) profiles for pure risperidone, PVP K30, and the optimized solid dispersion (SD4). In the case of unprocessed risperidone, a distinct thermal event was recorded at approximately 172.39°C, consistent with its known crystalline melting behavior, as supported by previous studies (4,5). For PVP K30, a broad thermal signal was observed at 88.13 °C, likely linked to retained moisture, while a glass transition was noted around 160 °C. In the thermogram of the SD4 system, a single thermal event appeared near 156.37 °C, which aligns closely with the glass transition region of the polymer, suggesting molecular dispersion of the drug within the carrier. Although a subtle thermal response was seen near 172.39 °C, it was not as prominent, implying that risperidone had largely transitioned from its crystalline state to a more disordered or amorphous form in the dispersion⁴³.

Figure 3: DSC thermograms of (A) risperidone, (B) PVP K30,and (C) SD4 formula.

Powder X-Ray Diffraction (PXRD):

To evaluate the crystalline structure of pure RIS, its physical mixture with PVP K30, and the optimized solid dispersion formula (SD4), powder X-ray diffraction (XRD) analysis was conducted. The aim of this analysis was to investigate the physical state of RIS within the solid dispersion matrix. Figure 4 illustrates the diffractograms of both pure RIS and the SD4 formulation. The XRD profile of pure RIS exhibited a distinct sharp diffraction peak at 2θ = 20.9872, confirming its crystalline nature, alongside several additional peaks at 2θ values of 14.0024, 18.6207, 19.4645, 22.8554, and 28.6129, with corresponding intensities of 3518, 853, 1654, 851, 1035, and 1100. In contrast, the SD4 sample showed significant reduction or complete disappearance of these characteristic peaks, suggesting a transformation of RIS from a crystalline to an amorphous or less ordered state within the formulation⁴⁴.

Figure 4: Powder XRD of (A) pure risperidone (B) the optimum (SD4) formula

Formulation of risperidone solid dispersion as a chewable jellies dosage form.

During experimental work, about 11 formulas of RIS jellies were prepared. Only five formulations were embraced. The main components of all formulations were fixed except the concentration of gelatin jellifying agent. The jellifying agent, which has used was gelatin. The formulation F1-F5 had a good general appearance that made it a good candidate for release study after which the decision of keeping or excluding them from further investigations was related to the in vitro release results. F1(4% gelatin), F2(6% gelatin), F3(8% gelatin), F4(10% gelatin) and F5(12% gelatin).

Evaluation parameters of the prepared risperidone oral jellies:

Physical appearance:

By visual inspection, the appearance of all formulations from F1-F5 was characterized. The taste and flavor of jelly was tested by preparing formulations containing all ingredients except RIS solid dispersion. Volunteers tested these formulations and according to volunteers records all of the formulations had an acceptable tastes and flavors. All formulas were transparent, smooth and had light pink color

Stickiness and grittiness:

By crushing of formulations among two fingers, the grittiness and stickiness properties were determined. The grade of grittiness and evaluated by comparing formulas of F1 and F2 were slight sticky and non-gritty while F3, F4 and F5 were non sticky and non-gritty.

pH value of formulas:

The pH investigation in all formulas was within an acceptable range for use in oral cavity which is neutral or around neutral, since highly acidic or highly alkaline pH may irritate oral mucosa⁴⁰. Here was no significant change in the pH was observed upon increasing the gelatin concentration from 4-12% in F1 and F5 which can be explained by the fact that gelatin has amphoteric polypeptide nature which contains both positive and negative charges^44-46.

Content uniformity:

The drug content of medicated jelly evaluated by UV-Spectrophotometer. All formulations showed a uniform distribution of drug ranging from 96.41% to 99.83% . These results were within acceptable range according to USP which stated that drug content is accepted if it was (90%-105%) of total drug dose³⁶.

Syneresis:

Syneresis is the term that describes water oozing out of jellies. Type and concentration of jellifying agent show a golden role in determining the occurrence and degree of syneresis. The most popular cause of syneresis is the using of the jellifying agent in low concentration and this will affect the consistency and efficacy²⁵.

Texture analysis:

Table 3: Hardness, adhesiveness and cohesiveness of risperidone oral jellies

Formula code	Hardness	Adhesiveness	Cohesiveness
F1	1.67± 0.131	0.0135 ± 0.0007	0.732 ± 0.05
F2	2. 936 ± 0.184	0.0043± 0.0006	0.87 ± 0.03
F3	2.237 ± 0.00	0.012 ± 0.0000	0.793 ± 0.00
F4	3.287± 0.189	0.0127 ± 0.0011	0.891 ± 0.08
F5	3.719 ± 0.202	0.0445 ± 0.0163	0.917 ± 0.03

Mean±SD, n=3

Texture Profile Analysis (TPA) is a standardized method used to evaluate textural characteristics using a texture analyzer and specific probe. The test simulates two chewing bites through double compression, generating a force-time curve. Key parameters such as hardness, adhesiveness, and cohesiveness are calculated from this curve. Table 3 presents these values for RIS jellies⁴⁷.

Solid dispersion-jellifying agent polymer compatibility study by FTIR:

The FTIR spectrum of gelatin (Figure 9) revealed characteristic absorption bands associated with its functional groups. A broad band observed around 3264 cm⁻¹ corresponds to overlapping N–H stretching vibrations and O–H stretching from alcohol groups. The signal at 3079 cm⁻¹ is attributed to C–H stretching within aromatic structures. Bands near 2935 and 2850 cm⁻¹ are due to asymmetric and symmetric C–H stretching vibrations typical of aliphatic chains. A strong absorption at 1631 cm⁻¹ represents C=O stretching, indicating the presence of carbonyl groups. Peaks at 1527 and 1500 cm⁻¹ are related to C=C stretching within aromatic rings. Additional peaks at 1443 and 1329 cm⁻¹ suggest C–H bending in alkane chains. A noticeable band at 1234 cm⁻¹ corresponds to C–N stretching, while the peak at 1073 cm⁻¹ is associated with C–O stretching in secondary alcohols. Lastly, the peak at 877 cm⁻¹ indicates out-of-plane bending of aromatic ring components, consistent with previous literature findings ⁴⁸.

Figure 9: FTIR of (A) pure gelatin (B)gelatin and physical mixture of risperidone and PVP K30 (1:5) (C) gelatin and SD4 formula

In-vitro dissolution study:

The dissolution study results are shown in figure (10). In this study phosphate puffer pH 6.8 is used to show the release profile of medicated jelly of RIS solid dispersion in pH value simulates oral cavity media. The volume of dissolution media was 900 ml.

Table 4: Results of risperidone oral jelly release after 30 minutes in phosphate buffer pH 6.8

Formulation code	% of release after 30 min± SD n=3
F1	65.33 ± 0.57
F2	76.66 ± 0.57
F3	90.5 ± 0.86
F4	93.16 ± 0.76
F5	99.66 ± 0.57

Figure 10: percent of risperidone release from (4%, 6%, 8%, 10%and 12%) gelatin oral jellies in phosphate buffer pH 6.8

The jelly formulations F1-F5, which contain gelatin polymer, showed fast release due to rapid melting of gelatin at 37 °C⁴⁹. The higher percentage of drug release after 30 minute (% D30) min. upon using gelatin to formulate the oral jellies resulted from the unique characteristic of the gelatin being highly soluble in hot water in addition to the low melting temperature of this polymer providing faster drug release^{49,50 ,}as shown in table (4) . F5 risperidone oral jelly holding 12% gelatin is selected as the optimum formula giving better taste masking property than other formulas, with a good physical and release and accepted pH value.

10. Physical Stability study:

Throughout the storage period, which was about three months for formulations, the clarity, odor, general appearance, pH and drug content were observed monthly. Some formulations was stored in 25 °C and some stored at ( 0-8)°C^50-52. The results of the physical properties and pH evaluation of the selected RIS oral jelly (F5) showed no significant difference(p>0.05) upon storage for one and three months at 0ºC and 25ºC. Furthermore, no syneresis was observed after storing in the same conditions. Moreover, no significant alteration in the content uniformity data of the selected formula (F5) was observed. These data together indicating the suitable formulation of the selected oral jelly formula which retained its properties after storing at refrigerator and room temperature.

Figure 11: An image showing the appearance of F5 formula

CONCLUSION:

Depending on the gained results of this research, one can achieve that risperidone was successfully ready as solid dispersion with enhanced solubility by solvent evaporation method using PVP K30 polymer. The formula (SD4) with RIS: PVP K 30(1:5) ratio considered to be the best formula as it formed highest solubility and dissolution rate. Gelatin was able to produce risperidone chewable jelly from SD4 in different ratios 4% gelatin (F1), 6% gelatin (F2), 8% gelatin (F3), 10% gelatin (F4) and 12% gelatin (F5). Risperidone oral jelly (F5) containing 12% gelatin was selected as the optimum formula This study was successful to formulate a risperidone oral jelly that can be used as a new easily swallowed dosage form for the pediatric population with improved bioavailability.

CONFLICTS OF INTEREST:

None.

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Received on 16.09.2022 Revised on 08.07.2024

Accepted on 17.05.2025 Published on 02.08.2025

Available online from August 08, 2025

Research J. Pharmacy and Technology. 2025;18(8):3492-3500.

DOI: 10.52711/0974-360X.2025.00503

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