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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2022 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access  Full Text Article                                                                                                                                                                            Research Article 

Formulation and Evaluation of Orodispersible Tablets Containing Co-Crystals of Modafinil

Rajeev Kumar*, M.A. Sheela, Monika Sachdeva

Raj Kumar Goel Institute of Technology, Ghaziabad, U.P., India

 

 

1. INTRODUCTION

To define the effectiveness of a drug, solubility, and percentage of drug release are the important aspects that play a crucial role in the development and preparation of effective drugs in the pharmaceutical industry.¹ Nevertheless, about sixty percent of medicines are synthesized and the remaining forty percent of drugs possess solubility challenges that trigger bioavailability disputes and compatibility issues. Various strategies were proposed to boost the solubility and % of drug release of sparingly soluble drugs. The addition of cyclodextrins, solid dispersion, salt formation, micro emulsification, and the inclusion of complex formations contribute to the improvement of solubility profile of the drugs. ^1 2

Co-crystallization is one of the promising techniques used in the pharmacy sector that can be effective in life cycle management due to its potential benefits of improved solubility, dissolution, bioavailability, permeability, and stabilisation of unstable compounds through intermolecular interactions.³ The Biopharmaceutical Classification System divides poorly soluble medications into classes BCS II & IV. ⁴ Since pharmaceutical crystallization is also applicable to non-ionisable APIs, this adds an additional advantage in the era of salt formation technique.² Physically, solid form of drug can be obtained from active pharmaceutical ingredient prepared by co-crystals  that helps in achieving an elevated dissolution amount in contrast to amorphous form crystals.⁵ Pharmaceutical co-crystals contain a couple of molecules or supplementary molecules which are vowed by H-bonding and stoichiometric ratio. Pharmaceutical co-crystals unite pharmaceutically satisfactory conformational isomer and the drug into the similar crystal network which led to the origination of new composition of the API /APIs. In addition to this, it was identified that co-crystals are scrutinized as drug discrete instead a new APIs bearing a momentous impact on the drug.^6 7 The present study was focused to improve the solubility as well as bioavailability of Modafinil which is a CNS stimulant used in the treatment of day time sleepiness, in Narcolepsy and other sleep related disorders. ^8 9

2. MATERIALS AND METHOD:

2.1 Drug & excipients:

Modafinil was gift sample from the Sidmak Lab Pvt. Ltd (India). All other chemicals including Sodium acetate, Urea, Nicotinamide, Benzoic acid, Succinic acid, Sodium starch glycolate, Crospovidone, Croscarmellose sodium, Microcrystalline cellulose, Mannitol, Aspartame, Magnesium stearate, Talc were taken from the college drug store.

2.2 Instruments: Digital balance, PH meter, UV spectrophotometry, Melting point apparatus, Hardness tester, Thickness tester, Disintegration apparatus, Probe sonicator, Fourier Transform Infrared Spectrophotometer, Friability test apparatus, Differential scanning calorimeter.

2.3 Pre-formulation studies: Determination of λ_max, Calibration curve, Solubility of pure drug, FT-IR study.

2.4 Formulation of Co-crystals ¹⁰

The method used to prepare Modafinil co-crystals was dry grinding. To create co-crystals, drug and coformer were combined in a mortar and pestle for 45 minutes at varied molar ratios (1:1 and 1:2). This was dried at room temperature for an entire night before being sealed in containers. The following 10 coformers were screened: Benzoic acid, citric acid, urea, nicotine, succinic acid, glutaric acid, cinnamic acid, adipic acid, sodium acetate, and saccharine sodium.

2.5 Formulation of Orodispersible tablet ^11 12

All additional excipients and a precisely weighed quantity of Modafinil co-crystal equal to 100 mg of Modafinil were filtered through a 60-mesh sieve before being combined in a mortar and pestle for 30 minutes. A single punch tablet machine was used to immediately compress the mixture into tablets. With the exception of the super disintegrant and the binder, all excipient quantities remained constant as given in table 1.

 

 

 

Table 1: Composition of different batches of tablets

S.No.	Ingredients	F1 (mg)	F2 (mg)	F3 (mg)	F4 (mg)	F5 (mg)	F6 (mg)
1.	Co-crystals	147	147	147	147	147	147
2.	SSG	9	15	-	-	-	-
3.	CP	-	-	9	15	-	-
4.	CCS	-	-	-	-	9	15
5.	MCC	118	112	118	112	118	112
6.	Mannitol	54	54	54	54	54	54
7.	Aspartame	2	2	2	2	2	2
8.	Magnesium Stearate	2	2	2	2	2	2
9.	Talc	2	2	2	2	2	2

 

 

 

2.6 Evaluation of Co-crystals

2.6.1 Determination of Melting Point

Automated melting point apparatus was used to measure the melting point of manufactured co-crystals.

2.6.2 Saturation Solubility ¹³

By dissolving extra co-crystals in water-filled 10 ml vials, the solubility was ascertained. The vials were shaken on a rotary shaker and left for 24 hours to allow for equilibrations. After 24 hours, the co-crystals were filtered, diluted with water, and subjected to 222 nm UV Spectrophotometer analysis.

2.6.3 Drug content of the prepared Co-crystals ¹⁴

Drug content was calculated by adding 25 mg of co-crystals in 50 ml of ethanol. The solution was kept for 24 hr then, filtered and diluted with ethanol to make a concentration 10µg/ml. This was analyzed by using UV Visible spectroscopy. Drug percentage was calculated by the formula given below:

% Drug content = Obtained Conc. / Theoretical Conc. * 100

2.6.4 IR Spectroscopy ¹⁵

FTIR was used to assess whether the medication and co-former had any interactions. Separately placed on an IR plate, pure drug and mixture of drug and manufactured co-crystals produced spectra between 4000 and 400 cm-1.

 

2.7 Evaluation of Post Compression Parameter

2.7.1 Weight variation ¹⁶

A random sample of 20 tablets from a batch was weighed separately, and the average weight was calculated using an electronic balance (Shimadzu).To determine the % average weight formula used as: 

% weight variation = weight of individual tablet – Average weight of tablets/ Average weights of tablets x100

2.7.2 Thickness ¹⁶

Vernier caliper was used to determine the tablets' thickness. From each batch, ten tablets were chosen at random, and the thickness was measured. The results are shown as the mean standard deviation (SD).

2.7.3 Hardness ¹⁷

The crushing load, also referred to as hardness, is the amount of force required to crack a tablet in a radial direction. Ten tablets were randomly selected from each batch and tested for hardness using Monsanto's hardness tester. Each batch's mean values and standard deviation were computed.

2.7.4 Friability ¹⁸

Using a Roche friabilator of the USP type, the friability of tablets was tested. Tablets equivalent to 6.5gm were weighed and putted into a friabilator chambered that was connected to a motor and rotated at 25 rpm for 4 minutes. The tablets were then cleaned, weighed again, and the formula was used to determine the % weight reduction:

% Friability = {(Initial weight – Final weight) / Initial weight)} × 100

2.7.5 Wetting Time ¹⁹

Six round tissue papers with a 10 cm diameter were placed in a petri dish, and 10 ml of water dyed with amaranth was added to it to test whether the tablet surface had been completely moistened. In a Petri dish with tissue paper on top, a tablet was carefully positioned at room temperature. Wetting time is the duration that it takes for water to thoroughly moistening the tablet's top surface. The research was carried out in duplicate, and stopwatches were used to record the time.

2.7.6 Drug Content ²⁰

The weight and powder of twenty tablets were done. Weighed amount was dissolved in some amount of ethanol, and diluted with 0.1N HCl a single dose of modafinil powder was analyzed for drug concentration at 222 nm using a UV-Visible spectrophotometer (Shimadzu).

2.7.7 In Vitro Disintegration Time ²¹

Using distilled water at 37°±2⁰C and the digital tablet disintegration test device, the in vitro disintegration time (DT) was calculated. The mean SD value was calculated as the number of seconds required for the pill to completely dissolve with no residue remaining in the apparatus.

2.7.8 In Vitro Drug Release Study ²²

Utilizing the USP dissolving test apparatus (Lab India) and the paddle method, drug release investigations were carried out. 900 ml of 0.1N hydrochloric acid was used as dissolution media, and test was performed at 37±0.5°C and 50 rpm with the paddle. At predefined intervals (5 min), samples (5 ml) were taken and replaced with an equivalent volume of new medium. The samples were filtrated through a 0.45-m membrane filter and then examined at 222 nm using a UV spectrophotometer after the study had been running for 45 minutes (Shimadzu).

Dissolution Apparatus	USP type II (Paddle)
Media volume	900ml
Temperature	37+ 0.5
RPM	50 RPM
Volume withdrawn	5ml
Media used	0.1 N Hcl
Stirrer	Paddle Type

 

3. RESULT AND DISCUSSION

3.1 Pre-Formulation studies:

3.1.1 Determination of λ_max of Modafinil

The λ_max was found to be 222 nm in ethanol.

3.1.2 Calibration curve of Modafinil in Ethanol, Methanol, 0.1 N HCl and water

 

 

Table 2: Absorbance in different solvent

S.No.	Concentration (μg/ml)	Absorbance at 222 nm
		Ethanol	Methanol	0.1 N HCl	Water
1.	0	0	0	0	0
2.	2	0.215	0.185	0.138	0.118
3.	4	0.329	0.309	0.241	0.181
4.	6	0.495	0.428	0.339	0.265
5.	8	0.700	0.618	0.459	0.345
6.	10	0.820	0.755	0.597	0.428

 

 

Figure 1: Calibration curve in ethanol

 

Figure 2: Calibration curve in methanol

 

Figure 3: Calibration curve in 0.1N HCl

 

Figure 4: Calibration curve in water

 

 

 

 

 

 

3.1.3 Solubility study of pure drug

Solubility of pure drug was found to be 0.487 mg/ml.

3.1.4 FT-IR study for drug and carrier compatibility

FT-IR study was done for drug, co-former separately and then for the prepared co-crystals. The resulted spectrum revealed that there is no interaction between drug and co-former. The result showed that no functional group interfered that means drug and co-former are chemically compatible and also there is no change in drug’s major peak as mention in table 3.

 

 

 

Table 3: Interpretation of IR-spectrum

Ingredients	C-H stretching	-NH- stretching	C-O stretching	C=C stretching	C=O stretching
Modafinil	3033	3336	1400	-	-
Sodium Acetate	-	-	-	1408	1736
Modafinil + Sodium acetate	3005	3338	1409	-	-

 

 

Figure 5: FT-IR spectrum of pure Modafinil

 

Figure 6: FT-IR spectrum of Sodium acetate

 

Figure 7: FT-IR spectrum of Modafinil and Sodium acetate

 

 

3.2 Evaluation of Co-crystals

Using a dry grinding process, a total of five coformers were evaluated for the possibility of co-crystal formation with Modafinil. Modafinil only successfully reacted with sodium acetate to produce a new co-crystal form. Modafinil co-crystal that was obtained underwent physicochemical analysis and orodispersible tablet formulation.

3.2.1 Melting point and saturation solubility

As a first step in the screening process for probable co-crystals, these two characteristics were estimated. Table 4 lists the determined melting points of pure drug, coformers, and co-crystals. Solubility was also determined and noted in a table 4. Co-crystal melting values were lower than those of Modafinil. Melting point depression revealed multi-component systems and indicated co-crystal formation. The interaction between Modafinil and coformers, a variation in the crystallinity of the molecules, or a new packing arrangement could all be responsible for the changing melting points of co-crystals. This contact causes a modification in the molecular arrangement, resulting in a new crystal structure with altered solubility and/or melting point. With each co-former, co-crystal solubility increased, but sodium acetate significantly (2.5 folds) improved it. This shows that Modafinil and coformers were able to interact effectively and produce co-crystals. Based on the findings, the co-crystal of modafinil sodium acetate, referred to as modafinil co-crystal in the parts that follow, was further studied and used in the creation of orodispersible tablets.

 

 

 

Table 4: Melting point and solubility of co-crystals

Drug/Coformer	Melting point (co-former)	Crystal Melting Point (1:1)	Solubility (mg/ml) (1:1)	Crystal Melting Point (1:2)	Solubility (mg/ml) (1:2)
Modafinil	164-166 0C		0.487
Modafinil-Sodium acetate	324 0C	148 - 150 0C	1.22	153 – 155 0C	0.990
Modafinil-Urea	133-135 0C	137 – 140 0C	0.781	130 – 132 0C	0.891
Modafinil-Nicotinamide	125-130 0C	135 – 137 0C	0.914	140 – 142 0C	1.101
Modafinil-Benzoic acid	120 – 122 0C	147 – 149 0C	0.902	148 – 149 0C	0.962
Modafinil-Succinic acid	184 – 186 0C	142 – 144 0C	0.973	138- 140 0C	0.720

 

 

3.2.2 Drug Content

Formulation of co-crystal with sodium acetate in 1:1 ratio showed highest drug content (97.97 %), while Benzoic acid in ratio 1:2 showed least drug content (56.48%). Data obtained showed that drug content was decreased on increasing co-former amount, as seen in 1:2 ratios of drug and co-former.

 

 

Table 5: Drug content of prepared co-crystals

Co-crystals with coformers	% Drug Content (1:1)	% Drug Content (1:2)
Sodium acetate	97.97	84
Nicotinic acid	91	78.6
Succinic acid	70.08	63.84
Urea	64.32	59.64
Benzoic acid	60	56.48

 

3.3 Pre-Compression parameters

Table 6: Pre-compression parameters result

Parameter	F1	F2	F3	F4	F5	F6
Bulk density (gm/cm3)	0.349	0.346	0.331	0.344	0.397	0.369
Tapped density (gm/cm3)	0.399	0.422	0.390	0.420	0.472	0.425
Hausner’s ratio	1.14	1.22	1.12	1.22	1.19	1.15
Compressibility index (%)	12.31	18.00	10.79	18.01	15.89	13.18
Angle of repose	29.74	27.14	29.05	30.47	30.47	31.22

 

 

3.4 Post-Compression Parameters:

The resulted data of post compression parameters revealed that all the prepared tablets had uniform weight. Weight variation and thickness were found to be in acceptable range. Tablet hardness was retained in range of 3.18-3.25 kg/cm² for all the tablets. Friability was also in acceptable range between 0.74 to 85%. The hardness and friability data indicated that the tablets had good mechanical resistance. Formulation F1 was promising as it exhibited least disintegration time (34 ± 3.71 sec), and wetting time (24 ± 0.45 sec).

 

 

Table 7: Post compression parameters result

S.No.	Weight Variation (mg) ± SD	Hardness (Kg/cm2)	Thickness (mm)	Disintegration time (Sec)	Friability (%)	Wetting Time
F1	398.55 ± 5.80	3.21 ± 0.28	6.27 ± 0.41	34 ± 3.71	0.74	24 ± 0.45
F2	396.05 ± 7.11	3.25 ± 0.26	6.28 ± 0.32	35 ± 5.49	0.81	26 ± 0.68
F3	397.65 ± 7.13	3.18 ± 0.30	6.18 ± 0.23	35 ± 6.09	0.84	26 ± 0.34
F4	400.45 ± 5.63	3.24 ± 0.26	6.13 ± 0.21	36 ± 3.22	0.78	28 ± 0.59
F5	400.1 ± 4.86	3.23 ± 0.30	6.15 ± 0.29	41 ± 2.16	0.80	30 ± 0.25
F6	401 ± 4.94	3.15 ± 0.25	6.1 ± 0.23	42 ± 3.14	0.85	33 ± 0.86

 

 

3.4.1 In-vitro drug release:

In-vitro studies showed that formulation with SSG, obtained higher drug release. Formulation F2 showed highest drug release (96%) while formulation F3 had lowest drug release (83%). The results obtained are given below in Table 8.

 

 

Table 8: % drug release of prepared batches

% Drug Release
Time (min)	F1	F2	F3	F4	F5	F6
0	0	0	0	0	0	0
5	32	39	24	28	31	32
10	49	53	46	42	46	49
15	58	61	52	63	53	52
20	68	70	69	71	69	70
30	81	88	78	79	81	86
45	86	96	83	89	85	89

Figure 9: Comparative drug release profile of prepared batches

 

 

4. CONCLUSION: 

The current study was conducted to formulate and evaluate orodispersible tablets containing co-crystals of poorly soluble Modafinil, to improve its dissolution rate, solubility and hence bioavailability. All the prepared batches of tablet were found to have physicochemical parameters in acceptable limit. Among all the formulated batches, F2 showed highest drug release containing SSG as super disintegrant that makes it a promising approach for increasing solubility of poorly water soluble drugs. Orodispersible tablets of Modafinil could be considered convenient oral delivery systems to enhance the drug bioavailability.

5. Conflict of interest: 

There is no conflict of interest.

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