Formulation and Evaluation of Methyl Phenidate Sustained Release Tablets

Debjit Bhowmik¹*, Amrendra Singh² , Praveen Khirwadkar², Nishi Shukla³, Vikas Kumar Chaudhari⁴

¹Himachal Institute of Pharmaceutical Education & Research (HIPER), Nadaun H.P.

²Institute of Pharmacy, Vikarm University, Ujjain, Madhya Pradesh

³Advance Institute of Biotech and Paramedical Sciences, Kanpur

⁴KHBS College of Pharmacy, Jaunpur Uttar Pradesh

*Corresponding Author E-mail: kishor.desale9@gmail.com

ABSTRACT:

Methyl phenidate is a medication that belongs to the drug class called central nervous system stimulants. Methylphenidate is prescribed for treating narcolepsy (uncontrollable sleepiness), and attention-deficit hyperactivity disorder (ADHD). The aim of the current investigation is to design oral twice a daily sustained release matrix tablets of methylphenidate 20mg, used for the treatment of narcolepsy and ADHD which can release the drug for 10 to 12 hours. The matrix tablets were prepared by the wet granulation method using varying concentrations of sustained release polymers HPMC, Eudragit and Ethyl cellulose. The compatibility of the drug with polymers and other excipients was ruled out by FT-IR studies and found to be compatible. The Methyl phenidate powder and the powder-blends of tablets were evaluated for their physical properties like angle of repose, bulk density and compressibility index and found to be good and satisfactory. The manufactured tablets were evaluated for in process and finished product quality control tests including appearance, dimensions, weight variation, hardness, friability, drug content uniformity, and in vitro drug release. The results of dissolution studies indicated all formulations released up to 12 hours and formulation containing ethyl cellulose (5%) i.e. F7 was the most successful formulation with 96.72% drug release at the end of 12 hours. Based on mathematical models the formulation F7 fitted into zero order and Korsmeyer- Peppas plot with 0.942 and 0.999 regression values respectively and show Fickian diffusion mechanism release.

KEYWORDS: Methyl phenidate, Sustain release tablets, In-vitro dissolution study.

INTRODUCTION:

Oral drug delivery system is the most popular route, which is due to the ease of administration and to the fact that gastrointestinal physiology offers more flexibility in dosage form design than most other routes. An ideal drug delivery system (DDS) should be able to deliver an adequate amount of drug, preferably for an extended period of time for its optimum therapeutic activity. Most of the drugs are inherently not long lasting in the body and require multiple daily dosing to achieve the desired blood concentration to produce therapeutic activity. To overcome such a problem, controlled release (CR) and sustained release (SR) delivery systems are receiving considerable attention from the pharma industry world-wide. A CR-DDS not only prolongs the duration of action, but also results in predictable and reproducible drug-release kinetics. One important advantage of CR dosage forms is enhanced patient compliance. The aim of research work was to formulate and evaluate the sustained release matrix tablets of a psycho stimulant drug by wet granulation technique, using sustained release polymers like hydrophilic and hydrophobic to retard the release of drug. The drug taken for the present study is among the atypical anti-psychotic group, with the strength of 20mg for therapeutic response against treatment of attention-deficit hyperactivity disorder (ADHD), postural orthostatic tachycardia syndrome and narcolepsy.

MATERIALS AND METHODS:

Methyl phenidate procured from Aurobindo Pharmaceuticals, Hyderabad, Ethyl Cellulose N-20, Eudragit S-100, HPMCK4M, Starch, Di-calcium Phosphate procured from Drug India Pvt. Ltd.

FORMULATION DEVELOPMENT

Sustained release tablets containing 4 mg of model drug were prepared with a total tablet weight of 200mg. Considering the preformulation studies and the literature survey conducted the excipients were selected and an attempt to produce Sustained release tablets with basic tablet properties was made.

FORMULATION OF DIFFERENT BATCHES

The main aim of the present study was to formulate different batches using three various sustained release agents in varying concentrations .So different batches of formulations was planned accordingly. According to that F1, F2, and F3 (with HPMC 5%, 10%, 15%), F4, F5, and F6 (with Eudragit 5%, 10%, 15%) F7, F8, and F9 (with Ethyl cellulose 5%, 10%, 15%) was formulated. The model drug was among the Atypical Anti psychotic group.

Table.1Formulations of different batches (All ingredients taken in mg quantity)

Ingredients	Formulation Codes
Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
Methylphenidate	20	20	20	20	20	20	20	20	20
Starch	113.5	106	98.5	113.5	106	98.5	113.5	106	98.5
Ethyl Cellulose N-20							7.5	15	22.5
Eudragit S-100	-	-	-	7.5	15	22.5	-	-	-
HPMC K4M	7.5	15	22.5	-	-	-	-	-	-
Dicalcium Phosphate	50	50	50	50	50	50	50	50	50
Magnesium Stearate	6	6	6	6	6	6	6	6	6
Talc	3	3	3	3	3	3	3	3	3
Total	200	200	200	200	200	200	200	200	200

RESULTS AND DISCUSSION:

Preformulation Studies

The following preformulation studies were performed

API evaluation

a) Organoleptic evaluation

Organoleptic properties such as description, taste, color, and odor were evaluated.

b) Solubility

The drug Methylphenidate was found to be soluble in methanol and insoluble in water.

c) Melting Point

The melting point of the drug is measured by open capillary method. The melting point of the drug Methylphenidate was found to be 170^oc which is similar to the standards.

Analytical method and identification

UV Absorption Maxima (λ_max) of drug sample

UV scanning of the model drug sample was carried out using Shimadzu UV spectrophotometer and the λ_max was found to be at 280 nm.

Development of calibration curve

The scanning of drug solution in UV range showed maximum absorbance at 280 nm and hence, the calibration curve was developed at this wave length. The calibration curve was linear between 1-5μg/ml concentration ranges.

Drug excipients interaction studies

FT-IR Studies

The Compatibility studies were performed using FT-IR spectrophotometer. The FT-IR spectrum of pure drug and physical mixture of drug and different polymers were studied. Drug- excipient interactions play a vital role with respect to release of drug from the formulation amongst others. FT-IR techniques have been used here to study the physical and chemical interaction between drug and excipients used. In the present study, it has been observed that there is no chemical interaction between drug and the polymers used. It was observed that there were no changes in these main peaks in FT-IR spectra of mixture of drug and polymers, which show there were no physical interactions because of some bond formation between drug and polymers. The peaks obtained in the spectra's of each polymer correlates with the peaks of drug spectrum. This indicates that the drug was compatible with the formulation components.

Evaluation of tablet blend (Pre-compression parameters)

Bulk density and tapped density

The bulk density of the tablet blend was measured by Bulk Density apparatus. The bulk density and tapped bulk density for all formulations were found in the range of 0.39- 0.45 gm/cm³ and 0.46- 0.52 gm/cm³respectively. The results are shown in Table 10.

Carr’s index and Hausners Ratio

The results of Carr’s consolidation index or (%) compressibility index for the entire formulation blend ranged from 13 to 17 shows excellent compressibility index result in good to excellent flow properties. Hausner’s ratio was found in the range of 1.15 to 1.19 shows good flow and compressibility property. The results are shown in Table 10.

Angle of repose

It is determined by Fixed Funnel Method and is the measure of the flow ability of powder/granules. All the formulations prepared by wet granulation method showed the angle of repose was in the range of 22-25, which reveals the powder blend has excellent flow property. It is shown in Table 10.

Evaluation of tablets (Post compression parameters)

Hardness test

The tablet hardness values ranged from 5.7 to 5.9 kg/cm² for all formulations and were almost same. The results are shown in Table 11 and in figure no.13.

Weight variation test

The entire tablet passes weight variation test as the average % weight variation was within the pharmacopoeial limit of 7.5%. It was found to be 198±1.3 mg to 203.5±1.72 mg. The results are shown in Table 11 and figure no.14.

Thickness

In all formulations, tablet thickness was within mean ±5%. The thickness of all the tablets ranges between 3.8±0.02 mm to 3.9±0.04 mm. The results are shown in Table 11 and in figure no.15.

Friability test

The friability values were found to be within the limit (0.1 – 0.2%). The above evaluation parameter shows no significant difference between F1, F2, F3, F4, F6, F7, F8, F9 formulations. The results are shown in Table 11 and in figure no.16.

Drug content uniformity

The maximum drug content among all the formulations was found to be 101.48±0.5 and minimum % drug content from the all formulation was found to be 96.23±1.22. The results of drug content of all batches are shown in Table 11 and in figure no.17.

In-vitro Dissolution studies

All the 9 formulations of Methylphenidate sustained release tablets are subjected to dissolution studies. Dissolution is carried out in USP 2 type apparatus at 50rpm in the volume of 900ml dissolution media (phosphate buffer pH 6.8) for 12hours. Formulations F1, F2, and F3 which contained HPMC showed percentage drug release of 93.71%, 87.69%, and 82.11% Formulations F4, F5, and F6 which contained Eudragit shows percentage drug release of 94.57%, 88.98%, and 83.83% respectively. Formulations F7, F8, and F9 which contained ethyl cellulose shows percentage drug release of 96.72%, 90.27%, and 82.54% respectively. The percentage drug release of all the formulations are shown in table 12 (F1-F3), table 13 (F4-F5) and table 14 (F7-F9) and the comparative release profile are shown in figures 20 to figure 23. It has been observed that the dissolution rate was found to decrease linearly with increasing concentration of Sustained release agent.

Release kinetics

The dosage forms most commonly release the drug either in the zero order or in the first order pattern. Sustained release dosage form of Methylphenidate was prepared and studied for their dissolution behavior. In vitro release data of time points between 2 to 12 hours were considered and are shown in Table-12-14. The release profiles of Methylphenidate from the tablets of the formulations (F1- F9) were processed into graph (Figure.21). From release profiles of all formulations, F-7 being the higher release of drug upto 96.72±0.16 at the end of 12 hours is selected and release kinetics are carried out for F-7 formulation. For comparison of different orders of drug release and to understand the linear relationship, i.e., kinetic principles, the data were processed for regression analysis using MS-Excel statistical functions.

Different models like zero order, first order, Higuchi's, and Peppas plots were drawn for formulation f-7. The regression coefficient (r²) value for zero order, first order, Higuchi's, and Peppas plots (figures 23-26 and table 15) for formulation f-7 was found to be 0.942, 0.933, 0.966, and 0.999 respectively. The formulation f-7 follows zero order release and Peppas plot. Since the regression coefficient of Peppas was 0.999 and slope ‘n’ value is less than 0.5 which confirms that the drug release through the matrix was Fickian diffusion.

Drug –polymer compatibility studies by FTIR

Figure.1.FT-IR spectra of Methylphenidate

Figure.2.FT-IR spectra of Methylphenidate+ Di-calcium phosphate

Figure.3.FT-IR spectra of Methylphenidate+ Starch

Figure.4.FT-IR Spectra of Methylphenidate+ HPMC

Figure.5.FT-IR spectra of Methylphenidate+ Eudragit

Figure.6.FT-IR spectra of Methylphenidate + Ethyl cellulose

Figure.7.FT-IR spectra of Methylphenidate+ Talc

Evaluation of tablet blend (Pre-compression parameters)

Table.2.Evaluation of tablet blend (F1-F9)

Formulations	Bulk density (gm/cm³)	Tapped density (gm/cm³)	% Compressibility	Hausner ratio	Angle of repose (θ)
F1	0.405	0.47	13.82	1.16	24.15
F2	0.43	0.511	15.85	1.18	24.2
F3	0.41	0.496	17.33	1.20	24.61
F4	0.39	0.462	15.58	1.18	24.23
F5	0.43	0.515	16.50	1.19	24
F6	0.41	0.48	14.58	1.17	23.6
F7	0.42	0.496	15.32	1.18	22.61
F8	0.45	0.52	13.46	1.15	22.9
F9	0.41	0.478	14.22	1.16	23.42

Evaluation of tablets (Post compression parameters)

Table.3.Evaluation of Methylphenidate sustained release tablets

Formulation	Hardness (kg/cm²)	Friability (%)	Weight Variation (mg)	Thickness (mm)	Drug content Uniformity (%)
F1	5.8±0.37	0.13	203.5±1.7	3.85±0.02	98.18±0.86
F2	5.8±0.45	0.14	200.5±1.8	3.86±0.04	96.23±1.22
F3	5.8±0.52	0.17	202±1.54	3.86±0.019	98.05±1.58
F4	5.9±0.52	0.27	204.3±1.3	3.54±0.04	98.62±1.51
F5	5.8±0.49	0.13	201.6±1.9	3.85±0.03	97.59±0.52
F6	5.9±0.61	0.13	199.4±1.42	3.86±0.03	100.11±1.78
F7	5.8±0.32	0.29	199.5±1.8	3.85±0.03	99.5±0.52
F8	5.9±0.68	0.17	198.2±1.3	3.86±0.02	98.83±1.04
F9	5.8±0.44	0.15	202.9±1.6	3.85±0.02	101.48±0.5
Ritalin-SR (marketed product)	5.8±0.25	0.29	201.5±1.6	4.12±0.36	99.56±0.67

Figure.9.Hardness of Methylphenidate SR formulations

Figure.10.Weight Variation of Methylphenidate SR formulation

Figure.11.Thickness of Methylphenidate SR formulation

Figure.12.Friability of Methylphenidate SR formulations

Figure.13.Content uniformity of Methylphenidate SR tablets

Figure.14.Drug release of Methylphenidate SR formulation containing varying concentrations of HMPC

Figure.15.Drug release of Methylphenidate SR formulation containing varying concentrations of Eudragit

Figure.16.Drug release of Methylphenidate SR formulation containing varying concentrations of Ethyl cellulose

Figure.17.Drug Release of All Methylphenidate SR Formulations

Figure.18.comparison of Marketed product with best formulation F-7

Table.4.Kinetic Model Fitting for Formulation F7

Time in min	SQRT of time	Log time	%CDR	Log %CDR	Cu % Drug remain	Log Cu % Drug remain
0	0	0	0	0	100	2
120	11	1.04	28.4	1.45	71.6	1.85
240	15.5	1.19	44.1	1.64	55.9	1.74
360	19	1.27	62.6	1.79	37.4	1.57
480	21.9	1.34	79	1.89	21	1.32
600	24.5	1.38	89.7	1.95	10.3	1.01
720	26.8	1.42	96.7	1.98	3.3	0.51

Figure.19. In vitro release profile of Methylphenidate from tablets of F7 fitted in zero order release

Figure.20.In vitro release profile of Methylphenidate from tablets of F7 fitted in first order release

Figure.21.In vitro release profile of Methylphenidate from tablets of F7 fitted in Higuchi plot

Figure.22. In vitro release profile of Methylphenidate from tablets of F7 fitted in Korsmeyer-Peppas plot

CONCLUSION:

The incorporation of drugs into polymer matrices is considered a valid tool in order to optimize insufficient features of the drug molecule, like solubility, stability or toxic effects. In the present work, the incorporation of Methyl phenidate was performed in inert HPMC, eudragit and ethyl cellulose to retard the release of drug as sustained release polymers. All polymers are used in different concentrations to achieve sustained release of the drug. The Methyl phenidate powder and the powder-blends of tablets were evaluated for their physical properties like angle of repose, bulk density and compressibility index and found to be good and satisfactory. The manufactured tablets were evaluated for in process and finished product quality control tests including appearance, dimensions, weight variation, hardness, friability, drug content uniformity and concluded to be within limits. Hardness values ranged from 5.8 to 5.9 kg/cm² , weight variation ranged from 198±1.3 mg to 203.5±1.72 mg, thickness of all the tablets ranges between 3.5±0.04 mm to 3.86±0.03 mm and friability values were in range of 0.1 – 0.29%. The maximum drug content among all the formulations was 101.48±0.5 and minimum % drug content from the all formulation was 96.23±1.22. From the dissolution studies, it was observed that all batches gave the release by diffusion-dissolution controlled mechanism. The dispersion of the drug in the polymer network altered its dissolution profile at ph 6.8, thus making it possible to obtain a gradual and prolonged release. The dissolution profile data shows that F7 (ethyl cellulose 5%) has more prominent linear release compared to other formulations and marketed product. Based on mathematical models, it was concluded that F7 fitted into zero order and Korsmeyer- Peppas plot with Fickian diffusion mechanism release.

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Received on 05.06.2016 Modified on 16.06.2016

Res. J. Pharm. Dosage Form. & Tech. 2016; 8(3): 199-206.

DOI: 10.5958/0975-4377.2016.00027.6