Formulation Development and Evaluation of Flunarizine HCl Tablet by using Tablet in Tablet Technique

Akshay H. Aher, Rajendra K. Surawase

Department of Pharmaceutics, Loknete Dr. J. D. Pawar College of Pharmacy,

Manur (Kalwan) 423501, Maharashtra, India.

*Corresponding Author E-mail: akshayaher045@gmail.com

ABSTRACT:

The present research focuses on developing a tablet-in-tablet dosage form containing Flunarizine HCl to provide both immediate and sustained drug release in a single unit. Flunarizine HCl is a poorly water-soluble drug primarily used for migraine treatment. In this study, the inner core tablet was designed for sustained release using HPMC K4M and Eudragit RS 100, while the outer shell was designed for immediate release using Crospovidone and MCC. The effects of important excipients on drug release and assay were investigated in order to optimize the formulation using a 2² factorial approach. Pre- and post-compression properties such as strength, thickness, flexibility, moisture level, FTIR compatibility, DSC thermograms, and the formulations' in vitro drug release were evaluated. batch that was optimized had favourable physical characteristics, consistent drug content, and appropriate release profiles. According to the study's findings, the tablet-in-tablet method shows promise in producing modulated release and enhancing patient adherence for long-term illnesses like migraines.

KEYWORDS: Modified Drug delivery system, Solventless coating, Tablet-in-tablet technique, Flunarizine HCl, 2² factorial design.

INTRODUCTION:

Tablets are the most commonly favored form of medication due to their ease of use for patients, economical to manufacture, and visually appealing¹. Around 75% of all medications are administered as tablets. Most pharmaceutical tablets have an outer coating, which can serve different purposes — from modifying or controlling the drug release to simply masking the unpleasant taste of the active pharmaceutical ingredient (API). coating methods enhance visual attributes like texture, colour, and taste, and the ability to mask flavours².

The coating acts as a protective layer, safeguarding the drug both physically and chemically. In the 19th century, sugar coating was introduced to hide the bitter taste of certain medicines. However, this method had notable disadvantages: it took 6–7 days to complete, involved several complex steps (sealing, sub-coating, smoothing, coloring, polishing, etc.), and required highly skilled operators. Additionally, it was difficult to automate, resulted in significant tablet weight gain, and the sugar solution posed a risk of bacterial contamination³. Film coating later emerged, utilizing either aqueous or organic polymer solutions. Nevertheless, both methods have their own limitations. Organic solvent-based coatings can be flammable, toxic, and leave residual solvents in the finished film, increasing both health risks and production costs. In contrast, aqueous film coating demands higher drying temperatures and longer processing times, leading to greater manufacturing expenses⁴. Despite these advances, traditional coating techniques still face several challenges that need to be overcome. Among alternative approaches, the tablet-in-tablet (compression-coated) system stands out as one of the most effective options to address these issues⁵. Tablet-in-tablet (TiT), Press coating, sometimes known as dry coating, is one of the earliest solvent-free coating methods created^6,7. it improves patient compliance by enabling the combination of multiple drugs into one tablet⁸.

MATERIAL:

The experimental work was carried out using Flunarizine HCl as the active pharmaceutical ingredient (API), obtained from Balaji Drugs, commonly used in the treatment of migraine by relaxing blood vessels. Excipients used were of LR grade and sourced from Fine Chem Industries, Mumbai. These included HPMC K4M as a binder and matrix former, Eudragit RS 100 as a release modifier, Magnesium Stearate as a lubricant, Crospovidone is a super disintegrant, lactose and MCC are diluents, and colloidal silicon dioxide is a glidant.

METHODS:

1) Spectrometric and Compatibility Studies

a) UV spectroscopy was used to determine λmax and prepare the calibration curve.⁹

b) FTIR analysis was performed to check drug-excipient compatibility.¹⁰

c) DSC analysis was carried out to assess thermal behaviour and interactions.^11,12

2) Moisture Content Determination:

Moisture content of the API and each excipient was determined using a moisture balance. This was done to ensure stability and avoid potential processing issues.¹³

3) Evaluation of inner Core tablet and outer layer tablet

In order to evaluate flow characteristics and powder flowability, the powder blends were tested for pre-compression parameters such as bulk density, tapped density, Carr's index, Hausner's ratio, and angle of repose. To guarantee consistency and quality, the tablets were assessed for weight fluctuation, hardness, thickness, friability, and drug content (assay) after compression.^14,15.

4) In Vitro Dissolution Study:

Dissolution studies were conducted on the core tablets for up to 10hours to assess sustained release, while the outer layer tablets were evaluated for immediate release over 30 minutes, with both studies using 0.1 N HCl as the dissolution medium.^16,17.

5) Analysis of data:

Models of factorial design the impact of independent factors (e.g., HPMC K 100M, Eudragit RS 100, MCC) on dependent responses (%CDR, friability) was investigated using a 2³ factorial design. To visually assess the impact of factors on drug release and tablet qualities, 3D response surface plots and contour plots were created.

Formulation and Development of Flunarizine HCL Tablet in Tablet:

Flunarizine HCL tablet formulation and development were done using a 2³factorial design. by considering 2 factors and 3 levels (high, low) HPMC K4M, eudragit RS 100, MCC, starch and Crospovidone considered as independent factors and Drug Release and % assay was dependent variables. Because to found best optimization batch in research.¹⁸

Preparation Method and Evaluation of SR core tablet:

Table 1: Independent factors and levels for 2³ factorial designs

Sr. No.	Independent Factor	Unit	Low (-1)	High (+1)
1.	HPMC K100 M	mg	15	35
2.	Eudragit RS 100	mg	5	15
3	MCC	mg	20	40

Table 2: Formulation table for Inner Core Tablet

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8
Flunarizine HCL	5	5	5	5	5	5	5	5
HPMC K100 M	15	15	35	35	15	35	15	35
Eudragit RS 100	5	5	15	15	15	5	15	5
MCC	20	40	40	20	20	40	40	20
Mg. Stearate	2	2	2	2	2	2	2	2
Lactose	53	33	3	23	43	13	23	33
Water	qs	qs	qs	qs	qs	qs	qs	qs
Total Weight (Mg)	100	100	100	100	100	100	100	100

Note: The above ingredients are all in mg.

Tablet-in-Tablet Manufacturing Process:

All of the materials were precisely weighed before being uniformly sieved through a #60 mesh screen to create the core tablet. Using a mortar and pestle, the powders were combined with lactose for ten minutes. The process of granulation involved gradually adding water to make a moist substance, which was subsequently sieved through a #18 mesh screen to yield granules. To achieve the proper moisture content, these granules were lubricated with magnesium stearate, sieved through a #12 mesh screen, and then dried at 60°C. A rotating tablet press fitted with concave punches that were 6 mm round was then used to crush the granules into core tablets.^19,20.

Preparation Method and Evaluation of Tablet-in-Tablet:

Table 3: Independent factors and levels for 2³ factorial designs.

Sr. No.	Independent Factor	Unit	Low (-1)	High (+1)
1.	MCC	mg	15	45
2.	Crospovidone	mg	3	9
3.	Starch	mg	5	15

Table 4: Formulation table for outer layer Tablet

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8
Core Tablet	100	100	100	100	100	100	100	100
FlunarizineHCL	5	5	5	5	5	5	5	5
Crospovidone	3	9	3	9	3	3	9	9
MCC	15	15	15	45	45	45	15	45
Starch	15	15	5	5	5	15	5	15
Mg. Stearate	5	5	5	5	5	5	5	5
Collidal Silicon Dioxide	1	1	1	1	1	1	1	1
Lactose	156	150	166	130	136	126	160	120
Total Weight (Mg)	300	300	300	300	300	300	300	300

Note: The above ingredients are all in mg.

Preparation of Outer Tablet Shell:

All ingredient (Table 4) was carefully weight and uniformly sieved through #60 screen. powders were mixed thoroughly on butter paper for 30 minutes. The API was then added and blended geometrically using a mortar and pestle for 10 minutes to ensure even distribution²¹.

Compression of Outer Tablet Shell:

Half of the blended powder was placed into an 8 mm round concave punch die as the lower layer. The 100 mg optimized core tablet was carefully positioned at the centre. The remaining half of the powder was added on top, and the final compression was carried out to form the complete tablet.^22,23

RESULT AND DISCUSSION:

Spectrometric Analysis:

The UV range of 200–400nm was used to test flunarizine HCL (10mg/ml). The maximum absorption wavelength of flunarizine HCl in 0.1 N HCl was 265 nm

Table 5: Concentration and absorbance in 0.1 N HCl

Sr. No.	Concentration (µg/ml)	Absorbance (265nm)
1	5	0.093
2	10	0.193
3	15	0.306
4	20	0.398
5	25	0.504

Fig.1: UV Spectrum of flunarizine HCL in a 0.1 N HCl

Fig. 2: Calibration curve of Flunarizine 0.1N HCl

Fourier Transform Infrared Spectroscopy (FTIR):

A combination with a 1:1 ratio was made. The same method was followed for other drug-excipient mixtures. These mixtures were then tested using an FTIR spectrophotometer, which recorded their IR spectra in the range of 4000 to 400 cm⁻¹.

Fig. 3: Pure drug Flunarizine HCl

Fig. 5: Flunarizine HCl+ Crospovidone

Fig. 4: Flunarizine HCl+ Eudragit S100

Fig. 6: Flunarizine HCl + MCC

Fig. 7: Flunarizine HCL + Magnesium stearate

FTIR Analysis and Discussion:

The characteristic peaks of pure Flunarizine HCl were clearly observed at specific wavenumbers corresponding to its functional groups. among these were a prominent peak at about 3061 cm⁻¹, which was ascribed to aromatic C–H stretching vibrations; a peak for aliphatic C–H stretching at around 2953 cm⁻¹; and peaks at approximately 1697 cm⁻¹ and 1612 cm⁻¹, which corresponded to C=O and C=C stretching vibrations, respectively. When comparing the spectra of the drug with its physical mixtures, all major characteristic peaks of Flunarizine HCl were retained without significant shifting or disappearance. This shows that the medicine and excipients do not have any significant chemical interactions or incompatibilities. no new peaks were observed in the spectra of the mixtures, confirming that no new chemical bonds were formed during the mixing and formulation processes. This stability is crucial for ensuring that the drug maintains its therapeutic efficacy throughout the manufacturing and storage period.

Differential scanning colorimetry (DSC):

Fig. 8: Pure drug Flunarizine HCL

Fig. 9: Flunarizine API+ Excipient

DSC Analysis and Discussion:

Differential Scanning Calorimetry (DSC) was conducted to assess the thermal behavior and possible interactions between Flunarizine HCl and the excipients used in the tablet-in-tablet formulation. At about 240°C, which is also its melting point, the pure drug's DSC thermogram showed a clear, abrupt endothermic peak that attests to the crystalline nature and great purity of flunarizine HCl. The DSC curve of Flunarizine HCL shows sharp exothermic peak at 194.50C at 15.86min. and sharp endothermic peak at 156.97 C at 12.11min.

Importantly, no new peaks appeared and the original endothermic peak of Flunarizine HCl did not disappear in any of the mixture thermograms. This confirms that there was no evidence of strong chemical interaction, incompatibility, or solid-state change that occurs during the formulation process among the medicine and additives. These data points demonstrate that Flunarizine HCl remains thermally stable and chemically compatible with all chosen excipients. The crystalline nature of the drug is maintained, ensuring its integrity and performance in the final dosage form.

Moisture Content Determination: Excipients and Drug were as follows:

Flunarizine HCl had a moisture content of 1.2%, HPMC K100M had 4.5%, Eudragit RS 100 had 1.5%, MCC had 4.2%, starch had 9%, crospovidone had 3.7%, magnesium stearate had 0.9%, and colloidal silicon dioxide had 2.5%.

Evaluation of inner core Tablet:

Table 6: Precompression evaluation of inner core Tablet

Formulation	Bulk density (g/ml)	Tapped density(g/ml)	Carr’s index (%)	Hausner’s ratio	Angle of repose(θ)
F1	0.170±0.05	0.198±0.05	14.14±0.05	1.16±0.05	41.44±0.05
F2	0.175±0.05	0.199±0.05	12.06±0.02	1.13±0.05	36.31±0.05
F3	0.191±0.05	0.208±0.05	8.17±0.05	1.08±0.05	29.89±0.05
F4	0.170±0.05	0.180±0.05	5.55±0.12	1.05±0.05	27.78±0.05
F5	0.168±0.02	0.177±0.6	5.08±0.04	1.05±0.08	30.24±0.02
F6	0.176±0.11	0.189±0.08	6.87±0.07	1.07±0.18	32.40±0.06
F7	0.183±0.06	0.195±0.15	6.15±0.05	1.06±0.21	29.22±0.10
F8	0.169±0.04	0.180±0.06	6.11±0.08	1.05±0.10	26.73±0.08

All formulations had tapping densities ranging from 0.177 to 0.208g/ml and bulk densities between 0.168 and 0.191g/ml. Compressibility was measured using Carr's index, which was highest in F1(14.14%) and lowest in F5(5.08%). In general, excellent to good flow qualities are indicated by a Carr's index below 15%. Hausner's ratio, another measure of flowability, varied between 1.05 and 1.16 among formulations, with the majority of formulations showing values below 10%. F8 had the lowest angle of repose (26.73°), while F1 had the highest (41.44°). Overall, these results suggest that most of the prepared core tablet formulations exhibited satisfactory to excellent flow and compressibility characteristics, suitable for consistent tablet production. Among them, formulations F3 to F8 showed superior flow behavior.

Table 7: Post compression evaluation of inner core tablet

For-mulation	Weight variation	Hardness (kg/cm2)	Thickness (mm)	Friability (%)	% Assay
F1	98.20	4.4±0.05	3.4±0.02	0.35±0.04	91.23
F2	102.12	4.4±0.05	3.4±0.02	0.30±0.02	94.88
F3	101.25	4.4±0.05	3.4±0.02	0.28±0.10	98.34
F4	97.58	4.5±0.05	3.5±0.02	0.32±0.06	93.21
F5	104.02	4.2±0.02	3.5±0.04	0.29±0.02	95.79
F6	98.87	4.6±0.04	3.3±0.01	0.36±0.08	91.93
F7	103.11	3.9±0.02	3.4±0.08	0.27±0.04	96.23
F8	101.34	4.2±0.06	3.6±0.02	0.38±0.06	92.78

Weight variation for all formulations ranged from 97.58 to 104.02mg, falling within the acceptable limits specified by pharmacopeial standards (±7.5% for tablets under 130mg). Hardness values ranged from 3.9 to 4.6 kg/cm². Thickness was consistent across all batches, varying from 3.3 to 3.6mm, Friability values for all formulations were below 1% (ranging from 0.27% to 0.38%), indicating excellent mechanical resistance and minimal weight loss during handling. Notably, F3 (0.28%), F5(0.29%), and F7(0.27%) showed particularly low friability, reflecting good robustness.

Fig. 10: % Assay of Flunarizine HCl Core Tablet

Assay (% drug content) values ranged from 91.23% to 98.34%. Formulation F3 demonstrated the highest assay (98.34%), indicating excellent medication contents uniformity.

In vitro Dissolution Study

Table 8: In vitro Dissolution study of inner core tablet

Drug Release (Hrs)	F1	F2	F3	F4	F5	F6	F7	F8
0	0	0	0	0	0	0	0	0
2	48.95±0.05	60.09±0.05	61.43±0.05	58.07±0.05	48.76±0.05	39.88±0.05	44.78±0.05	40.78±0.05
4	64.19±0.05	70.92±0.05	77.01±0.05	74.09±0.05	52.94±0.05	46.89±0.05	51.33±0.05	47.28±0.05
6	77.28±0.05	83.51±0.05	88.02±0.05	84.89±0.05	64.25±0.05	57.48±0.05	69.55±0.05	56.45±0.05
8	83.27±0.05	88.59±0.05	92.69±0.05	91.19±0.05	78.56±0.05	69.88±0.05	74.12±0.05	68.93±0.05
10	87.29±0.05	92.33±0.05	96.43±0.05	94.87±0.05	83±0.05	79.6±0.05	81.21±0.05	76.4±0.05

Fig. 11: In vitro Drug Release

Formulation F3 showed the highest overall drug release (96.43% at 10 hours), which suggests an optimal balance between HPMC K100M and Eudragit RS 100 concentrations, Formulation F6 demonstrated the lowest drug release (79.6% at 10 hours), indicating a more retarded release, likely due to a higher concentration of matrix-forming polymer or less effective channel formation. formulation F3 was found to be the most promising, offering high cumulative release, appropriate mechanical properties, and excellent drug content uniformity. This formulation was therefore selected for further development and use in the final tablet-in-tablet system.

Analysis of Data:

To evaluate the effects of three different ingredients on drug release and friability, a polynomial equation was applied within a full factorial design framework. This regression model provides insight into the results by analyzing both the size and sign of each coefficient. Whereas a negative sign suggests that the response falls as the value of the related variable rises, a positive sign shows that raising the variable causes the response to rise.

Fig 12: % CDR

Fig 13: Friability

3D Response Surface Plot % CDR and Friability:

An investigation on the effects of HPMC K100M was conducted using a three-dimensional response surface plot, Eudragit RS 100, and MCC on the drug release profile of Flunarizine HCL. The surface plot for Y1 (drug release) exhibited a positive trend, indicating a notable enhancement in drug release. This increase was particularly evident as the concentration of MCC increased from 20mg to 40mg, HPMC K100M from 15 mg to 35mg, and Eudragit RS100 from 5mg to 15mg. On the other hand, the response plot for Y2 (%friability) showed a decreasing pattern, reflecting an improvement in the mechanical strength of the tablets. Statistical evaluation identified the eighth formulation run as optimal, achieving a drug release of 96.43% and a friability value of 0.28%.

Evaluation of outer layer Tablet

Table 9: Precompression evaluation of outer layer Tablet

Formulation	Bulk density (g/ml)	Tapped density(g/ml)	Carr’s index (%)	Hausner’s ratio	Angle of repose(θ)
F1	0.411±0.05	0.485±0.10	15.26	1.18	32.99±0.05
F2	0.384±0.05	0.437±0.10	12.13	1.14	30.21±0.05
F3	0.324±0.05	0.413±0.10	21.55	1.27	27.24±0.05
F4	0.338±0.05	0.501±0.10	32.53	1.48	30.56±0.05
F5	0.402±0.02	0.511±0.10	21.33	1.27	35.68±0.05
F6	0.380±0.04	0.466±0.10	18.45	1.23	32.55±0.05
F7	0.405±0.05	0.523±0.10	22.56	1.29	28.98±0.05
F8	0.491±0.02	0.582±0.10	15.63	1.19	26.28±0.05

Bulk density values ranged from 0.324 to 0.491g/ml. F8 showed the highest bulk density (0.491g/ml), suggesting better packing ability, while F3 had the lowest (0.324 g/ml). Tapped density values ranged from 0.413 to 0.582 g/ml, Carr’s index %, an indicator of compressibility and flowability, varied between 12.13% (F2) and 32.53% (F4). A Carr’s index below 15% generally indicates good flow, Hausner’s ratio, another measure of flowability, varied between F2(1.14) and F4(1.48). The range of angle of repose values was 26.28° (F8) to 35.68° (F5). The findings indicate that formulations F2, F3, F7, and F8 had superior flow characteristics overall.

Table 10: Post compression evaluation of outer layer tablet

Formulation	Weight variation	Hardness (kg/cm2)	Thickness (mm)	Friability (%)	% Assay
F1	298.45	5.4±0.05	5.10±0.02	0.34±0.05	95.45
F2	297.64	5.4±0.05	5.13±0.02	0.3±0.05	91.74
F3	312.10	5.2±0.05	5.15±0.02	0.28±0.05	90.43
F4	305.15	5.5±0.05	5.05±0.02	0.31±0.05	94.56
F5	295.85	5.3±0.05	5.15±0.02	0.26±0.05	96.58
F6	297.41	5.4±0.05	5.15±0.02	0.33±0.05	95.84
F7	290.75	5.3±0.05	5.15±0.02	0.25±0.05	97.27
F8	305.05	5.5±0.05	5.15±0.02	0.27±0.05	98.23

Weight variation ranged from 290.75mg (F7) to 312.10 mg (F3), all within pharmacopeial limits (±5% for tablets above 250mg). Hardness values ranged from 5.2 to 5.5kg/cm², suggesting good mechanical strength suitable for handling, transport, and storage without risk of breakage. Thickness was consistent among all batches, ranging from 5.05 to 5.15mm. Friability values were all below 1% (ranging from 0.25% to 0.34%), confirming excellent tablet integrity.

Assay (% drug content) values ranged from 91.43% (F3) to 98.23% (F8), demonstrating acceptable drug content uniformity across all formulations. The highest assay values were observed in F8 (98.23%) and F7 (97.21%), suggesting excellent drug distribution and minimal loss during processing.

Fig.14: % Assay of Flunarizine HCL outer Tablets

In vitro Dissolution Study:

Table 11: In vitro Dissolution Study of outer Layer Tablet:

Drug Release (Min)	F1	F2	F3	F4	F5	F6	F7	F8
0	0	0	0	0	0	0	0	0
5	29.12±0.05	32.54±0.05	36.48±0.05	39.87±0.05	39.87±0.05	39.87±0.05	39.87±0.05	39.87±0.05
10	46.75±0.05	52.34±0.05	58.45±0.05	54.78±0.05	56.46±0.05	48.84±0.05	51.58±0.05	52.24±0.05
15	58.13±0.05	67.89±0.05	68.45±0.05	65.34±0.05	69.77±0.05	59.41±0.05	68.12±0.05	68.98±0.05
20	64.65±0.05	74.76±0.05	76.34±0.05	75.45±0.05	80.12±0.05	67.33±0.05	72.58±0.05	74.68±0.05
25	79.45±0.05	87.12±0.05	88.85±0.05	87.89±0.05	89.65±0.05	79.88±0.05	84.25±0.05	86.10±0.05
30	87.50±0.05	91.2±0.05	93.5±0.05	92.0±0.05	95.6±0.05	90.4±0.05	96.2±0.05	97.5±0.05

Fig. 15: Time vs % Drug release

All formulations showed a rapid increase in drug release within the first 10–15 minutes, indicating effective dissolution properties. Among all batches, F8 exhibited the highest cumulative drug release (97.50% at 30 minutes), confirming excellent immediate release characteristics. Based on these findings, formulation F8 was identified as the most promising outer layer formulation due to its highest cumulative drug release.

Analysis of Data:

Using a full factorial design, a polynomial equation was utilized to examine the effects of three different ingredients on drug release and friability.  By analyzing the size and direction (sign) of each coefficient, this regression model aids in the interpretation of the results.  While a negative coefficient implies that the reaction would drop as the associated variable grows, a positive coefficient shows that the response will increase as the related variable increases.

Fig 15: % CDR

Fig 16: Friability

3D Response Surface Plot % CDR and Friability:

The impact of MCC was assessed using a 3D response surface plot, Crospovidone, and Starch on the drug release time of Flunarizine HCL. The response surface for Y1 (drug release) demonstrated a rising trend, indicating enhanced drug release. Specifically, drug release increased significantly when MCC was raised from 15mg to 45mg, Starch from 5mg to 15mg, and Crospovidone from 3mg to 9mg. Conversely, the response surface for Y2 (%friability) revealed a noticeable decline, suggesting improved tablet strength. According to the statistical model, the optimal formulation was found in the eighth experimental run, which achieved a drug release of 97.5% and a friability value of 0.27%.

CONCLUSION:

A tablet-in-tablet system of Flunarizine HCl was successfully designed to offer both immediate and sustained release in one formulation. The optimized core tablet (F3) showed controlled, prolonged drug release over 10 hours, while the outer layer tablet (F8) provided quick release within 30 minutes. Excellent medication content, homogeneity, and outstanding mechanical strength were all validated by the evaluation results.  FTIR and DSC compatibility tests revealed no interactions between the medication and excipients.  This method, which combines quick onset and sustained action in a single tablet, can increase patient compliance and guarantee successful migraine therapy.

CONFLICT OF INTEREST:

Regarding this study, the authors report that they have no conflicts of interest.

ACKNOWLEDGMENTS:

The author is grateful to the Institute of Pharmaceutics at Loknete Dr. J. D. Pawar College of Pharmacy, Manur (Kalwan), for providing the resources and assistance required to complete this study.  Our particular thanks go out to Dr. Rajendra K. Surawase, our research guide, for his invaluable advice, unwavering support, and perceptive recommendations during the project.

We also extend our appreciation to the laboratory staff and all colleagues who contributed their time and expertise. Finally, we acknowledge the support and motivation from our families and friends, which greatly helped us complete this work successfully.

REFERENCES:

1. Aher Akshay H, Rajendra K. Surawase, Wagh Rakesh M, Khairnar Darshan B, Gangurde Lalit H, Review on Tablet in Tablet Techniques. 2025; 7(20: 13.

2. Gaikwad and Kshirsagar Beni. Review on Tablet in Tablet techniques. Suef University Journal of Basic and Applied Sciences.  2020; 9: 1 https://doi.org/10.1186/s43088-019-0027-7

3. Mehta Bansari, Jigar Vyas and Umesh Upadhyay. A concise review on tablet in tablet. National Journal of Pharmaceutical Sciences. 2022; 2(2): 43-53

4. Shabana Naz Shah, Huma Ali, Riffat Yasmin, Shaheen Perveen, Farya Zafar, Fozia Israr, Nousheen Aslam. Design and optimization studies of tablet in tablet formulation of Diclofenac and misoprostol. https://doi.org/10.1101/2022.11.04.515246

5. Tejaswi Santosh Ubhe, Preeti Gedam. A Brief Overview on Tablet and It’s Types. Journal of Advancement in Pharmacology. 2020; 1(1): 21–31.

6. Nilottama S. Gundgal. A review: novel solventless coating techniques for tablet dosage form. 2013; 1(4): 60-66

7. Nadim Khan, Shubhangi Zende, Nishant Vairage, Saurabh Waghe, Satyam Ukarinde, Shubham Waghmare. Compression coating technique: A Review. International Journal of Humanities Social Science and Management (IJHSSM). 2023; 3(2): 596-601.

8. Rohit Pawar. Compression coated tablets as drug delivery system (tablet in tablet): A review. 2014; 6(1): 21 - 33.

9. Jyoti Mittha, Bhavana Habib. UV Spectrophotometric Method Development and Validation of Dasatinib in Bulk and Formulation. Asian Journal of Pharmaceutical Analysis. 2021; 11(3): 203-6.

10. Duggi Adilakshmi, Abdul Saleem Mohammad, Nuha Rasheed, Kathula Umadevi, Chandana Pasupuleti. Simultaneous Formulation, Estimation and Evaluation of Allopurinol Sustained Release Tablets using various suitable Excipients. Asian J. Pharm. Ana. 2016; 6(3): 155-166.

11. Noorussaba, Afaq Ahmad. Synthesis, Infrared spectroscopic and Thermal studies of [0.7(Cu2CdI4):0.3(AgIx: CuI(1-x))] of fast-ion conductor (x = 0.2, 0.4, 0.6 and 0.8 mol. wt. %). Asian J. Research Chem. 2015; 8(2): 131-140.

12. Monica RP Rao, Devidas G Bachhav, Ramdas B Rode, Komal R Nikam, Namrata D Pathade. Compatibility Study of Aceclofenac and Tablet Disintegrants by Thermal and Nonthermal Methods. Research J. Pharm. and Tech. 2011; 4(3): 423-427.

13. N. Sravanthi, K. Alekhya, S. Punitha. Formulation and Process Scale up of Misoprostol Tablets. Research J. Pharm. and Tech. 2011; 4(11): 1673-1675.

14. Vinay R. Kothawade, Yashpal M. More, Pallavi P. Ahire. Development and Evaluation of Bilayer Tablets of Bimodal release of Bisoprolol Fumarate. Research Journal of Pharmaceutical Dosage Forms and Technology. 2024; 16(4): 309-6.

15. Vishal Kumar, Attish Bhardwaj, Navdeep Singh1, Kamya Goyal, Shammy Jindal. A Review on Tablet Dosage Form: Recent Advancements with Special Emphasis on Rapid Disintegrating Tablet. Asian Journal of Research in Pharmaceutical Sciences. 2021; 11(3): 237-246.

16. Nishanth I., Elango K., Deattu N., Stephen P. Formulation Development and Evaluation of Bilayer Tablets of Telmisartan for Immediate Release and Metformin Hydrochloride for Sustained Release. Research J. Pharma. Dosage Forms and Tech. 2013; 5(3): 139-144.

17. Shyamaladevi D., S. Suresh Kumar. Formulation and Evaluation of Bilayer Tablets of Montelukast Sodium Immediate Release and Doxofylline Sustained Release. Research J. Pharm. and Tech. 2013; 6(12): 1370-1374.

18. Bipin Gandhi, Ajay Bhagwat, Swarup Matkar, Anant Kuchik, Tejal Wale, Onkar Kokane, Nitin Rode. Formulation and Evaluation of Bilayer Tablets of Atenolol and Amlodipine for the Treatment of Hypertension. Research Journal of Pharmacy and Technology. 2025; 18(5): 2037-2.

19. Shital Dhuppe, S.S. Mitkare, D.M. Sakarkar. Recent techniques of pharmaceutical solventless coating: A review. 2012; 3(7).

20. Ms. Nandini D. Banerjee, Mrs. Sushma R. Singh. Formulation And Evaluation of Compression Coated Tablets of Cefpodoxime Proxetil. International Journal of Pharma Sciences and Research (IJPSR). 2013; 4(7).  

21. Sunirmal Bhattacharjee, Beduin Mahanti, Kaustav Dasgupta. Solventless coating for tablet: A technical review. www.wjpps.com. 2016; 5(8): 485-500. 10.20959/wjpps20168-7385.

22. Pallavi. K, B. Gayathri, K. Chandralekha, K. Tejaswi. Solventless Coating - A Pliable Technique for future Coating Prospects. Pharma Times. 2015; 47(12). https://www.researchgate.net/publication/284726017.

23. Herbert A. Lieberman, Leon Lachman, Joseph B. Schwartz. Pharmaceutical Dosage Forms: Tablets, Second Edition, revised and expanded. Marcel Dekker, INC.

Received on 16.07.2025      Revised on 25.08.2025

Accepted on 23.09.2025 Published on 18.10.2025

Available online from November 03, 2025

Res.  J. Pharma. Dosage Forms and Tech.2025; 17(4):247-256.

DOI: 10.52711/0975-4377.2025.00034

©AandV Publications All Right Reserved

This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License. Creative Commons License.