INTRODUCTION:

The oral route is the most preferred route of administration of dosage forms, due to its potential advantages like ease of administration, convenient dosing, self-medication, no pain and patient compliance. Hence tablets and capsules are the most popular dosage forms¹, but the important drawback of these dosage forms is dysplasia² which can be solved by developing a novel drug delivery system (NDDS), fast dissolving sublingual tablet (SLT).

The sublingual route usually produces a faster onset of action than orally ingested tablets and the portion absorbed through the sublingual blood vessels bypasses the hepatic first‐ pass metabolic processes. A fast dissolving tablet system can be defined as a dosage form for oral administration, which, when placed in the mouth, rapidly dispersed or dissolved and can be swallowed in the form of liquid. For these formulations, the small volume of saliva is usually enough to result in disintegration in the oral cavity. The drug can then be absorbed partially or entirely into the systemic circulation from blood vessels in the sublingual mucosa, or it can be swallowed as a solution to be absorbed from the gastrointestinal tract^3‐5. Nifedipine (NFD) is used for treating high blood pressure, certain types of angina, and coronary heart failure. It is a dihydro pyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the trans‐ membrane influx of calcium ions into vascular smooth muscle and cardiac muscle⁶. It is a crystalline powder with a molecular weight of 567.1 g/Mol. It is slightly soluble in water. Its absolute bioavailability has been estimated to be between 64% and 80% only, due to its extensive hepatic metabolism, when taken as a conventional tablet, hence it is a suitable candidate for to formulate as SLTs. The purpose of this investigation was to formulate NFD SLTs by direct compression technique. The present study was aimed to study the effect of co-processed superdisintegrants prepared by solvent evaporation technique on enhancing the dissolution of NFD from its SLTs.

MATERIALS AND METHODS:

Materials:

Nifedipine was obtained from Hetero Drugs Pvt. Ltd., Hyderabad, India as a gift sample, powder vanilla flavor was a gift sample from Firmenich, Chennai, sodium starch glycolate (Primogel®), croscarmellose sodium (Ac-Di-Sol®), Crospovidone (Crospovidone M®), microcrystalline cellulose (Avicel PH102), mannitol (Pearlitol® 200 SD), aspartame and sodium stearyl fumarate. All the excipients used in the study were of pharmaceutical grade.

Methods:

The Standard calibration curve of NFD in pH 6.8 phosphate buffer solution (PBS):

Preparation of pH 6.8 PBS:

Place 50 mL of 0.2M potassium hydrogen phosphate in a 200 mL volumetric flask, add the 22.4 mL of 0.2 M sodium hydroxide and the add water to the volume.

Preparation of stock solution-I (1000 μg /mL):

Was prepared by dissolving 50 mg of NFD in 10 mL of methanol in a 50 mL volumetric flask and the volume was made up to mark with pH 6.8 PBS.

Preparation of working dilutions:

Aliquots of (0.25, 0.5, 0.75, 1.0, 1.25 and 1.5 mL) of Stock-I was transferred into a series of 10 mL volumetric flasks and the volume was made up to mark with pH 6.8 PBS to obtain concentrations of (25, 50, 75, 100, 125 and 150 μg/mL respectively). The obtained dilutions were analyzed at the λ_max235 nm using a UV-Visible spectrophotometer (UV-1700, Shimadzu, Mumbai, India) and their absorbance were noted. The Standard calibration curve was plotted by taking the concentration of drug solution (μg/mL) on X-axis and absorbance on Y-axis⁷.

Drug-excipient compatibility (FT-IR) studies:

Were performed on NFD and (1:1 ratio) physical mixtures of NFD with normal and co-processed superdisintegrants by an IR spectrophotometer (Shimadzu, FTIR 8700), in the region between 400 and 4000 cm^-1 by the direct sampling method⁸.

Preparation of NFD SLT:

All the formulations were prepared by direct compression method, by keeping the amount of NFD constant at 10 mg. The composition of other excipients is varied as mentioned in formulation table (Table 1). In these formulations CPV, CCS and SSG are used as superdisintegrants, mannitol as a directly compressible diluent, aspartame is an artificial sweetener, powder vanilla flavor as a flavoring agent, sodium stearyl fumarate as a water soluble lubricant. NFD and all the other excipients excluding sodium stearyl fumarate were co-sifted through Sieve No. # 40 (ASTM), blended uniformly in a poly bag for 10 min and lubricated with Sieve No. # 60 (ASTM) passed sodium stearyl fumarate by mixing in a same poly bag for an additional 2-3 min. Tablets were compressed on a tablet compression machine (10 station, Yogesh Pharma Machinery Pvt. Ltd., India) fitted with 8mm standard round punches with an Avg. wt. of 150 mg and 3-4 kg/cm²ofhardness⁸.

Table 1. Formulation table of NFD SLTs

Ingredient(s)	Qty/ tablet (mg)
	F1	F2	F3	F4	F5	F6
	CCS	SSG	CPV	CCS: SSG	CCS: CPV	SSG: CPV
Nifedipine	10	10	10	10	10	10
Croscarmellose sodium	15	-	-	7.5	7.5	-
Sodium starch glycolate	-	15	-	7.5	-	7.5
Cross povidone	-	-	15	-	7.5	7.5
Aspartame	3	3	3	3	3	3
Powder vanilla flavor	1.5	1.5	1.5	1.5	1.5	1.5
Mannitol	72	72	72	72	72	72
Micro crystalline cellulose	47	47	47	47	47	47
Sodium stearyl fumarate	1.5	1.5	1.5	1.5	1.5	1.5
Total	150 mg	150 mg	150 mg	150 mg	150 mg	150 mg

Pre-compression studies:

The directly compressible NFD SLT blends were evaluated for their flow and compression properties⁹.

Angle of Repose (θ):

Was determined by funneling method, the blend was poured through the walls of a funnel, which was fixed at a position such that its lower tip was at a height of exactly 2 cm above hard surface. The blend was poured till the time when the upper tip of the pile surface touched the lower tip of the funnel. The θ is calculated by the equation.

θ = tan ^–1 h/ r Eq. No. (1)

Where,

θ = angle of repose,

h = height of the heap and

r = radius of base of heap circle.

Bulk density (BD): A quantity of 2 gm of SLT blend from each formulation, previously lightly shaken to break any agglomerates formed, was introduced into a 10 mL measuring cylinder and the volume is noted as bulk volume. The BD was calculated by the equation.

BD = wt. of blend/ Bulk volume. Eq.No. (2)

Tapped density (TD): After the determination of BD, the measuring cylinder was fitted to a tapped density apparatus. The tapped volume was measured by tapping the powder for 500 times. Later the tapping was done for another 750 times and the tapped volume was noted (the difference between these two volumes should be less than 2%). If it is more than 2%, tapping is continued for another 1250 times and the constant tapped volume was noted. The TD was calculated by the equation.

TD = Wt. of blend / Tapped volume Eq. No. (3)

Carr’s Index (CI): The percentage of CI is calculated by the equation.

CI = (TD-BD) ×100/TD. Eq. No. (4)

Hausner’s Ratio (HR):

Is a number that correlates to the flow ability of a powder. It is calculated by the equation.

HR =TD/BD. Eq. No. (5)

Post compression studies⁹:

Avg. wt. of tablets:

An electronic balance (Mettler Toledo, 3- MS-S / MS-L, Japan) was used to accurately weigh the individual wt. of twenty tablets (n=20) which were randomly selected from each formulation and checked for the acceptability of wt. variation.

Friability test:

The friability of the 20 tablets from each batch (n=1) was tested by a friabilator (SINGLA, TAR 120, Germany) at a speed of 25rpm for 4min. The tablets were then dedusted, reweighed, and percentage weight loss was calculated by the equation,

(Initial Wt.- Wt. after friability)

% Friability = --------------------------------------× 100 /

Initial Wt. Eq. No (6)

Hardness test:

To evaluate the diametrical crushing strength, 3 tablets from each formulation were tested using a hardness tester (Monsanto type hardness tester, MHT-20, Campbell Electronics, India).

Thickness:

Thickness of 3 tablets from each formulation was determined using a Vernier caliper (Mitutoyo Corporation, Japan).

In vitro disintegration time & fineness of dispersion:

It is specified in the European Pharmacopeia (EP 6.0), the disintegration time determination procedure for fast disintegrating tablets is same as that of conventional uncoated tablets and the tablets should be dispersed within less than 3 min. The obtained tablet’s dispersion was passed through a sieve screen with a nominal mesh aperture of 710 mm to confirm the fineness of dispersion¹⁰.

Wetting time and Swelling Index:

A piece of tissue paper folded twice was placed in petri dish having an internal diameter of 5.5 cm, containing 6 mL of water. A tablet was placed on the paper and the time required for complete wetting was measured as wetting time (WT), using a stopwatch. The wetted tablet was then reweighed and swelling index (SI) was determined using the following equation¹¹.

SI = [(W_a – W_b) / W_b] × 100 . Eq. No (7)

Where,

W_b and W_a were the weights of the tablet before and after swelling.

Assay:

To evaluate the drug assay, 3 tablets (n=3) from each formulation were powdered in mortar and pestle. Blend equivalent to 1 mg of NFD was accurately weighed and transferred into a 100 mL volumetric flask containing 10 mL of methanol, and the volume was made up to 100 mL with pH 6.8 phosphate buffer and ultra-sonicated for 2 min to extract the NFD from the tablet blend and filtered through 0.45 µm poly tetra flour ethylene (PTFE) filter disc. The filtrate was suitably diluted if necessary and its absorbance was measured by UV- Visible spectrophotometer at 235 nm⁸.

In vitro dissolution studies:

Were performed on 10 mg of pure drug (NFD) and 6 tablets from each batch (n=6) using the dissolution apparatus (Lab India Disso2000, Lab India Analytical Instruments Pvt. Ltd., India) with USP-II / Paddle. Each dissolution flask contains 900 mL of pH 6.8 Phosphate buffer; the speed of the paddle was maintained at 50 rpm; the temperature was kept stable at37 ⁰C± 0.5 ⁰C. At required time intervals, 5 mL of dissolution media was withdrawn with a pipette containing 0.45 µ (PTFE) filter disc, suitably diluted if necessary and its absorbance was measured by UV-Visible spectrophotometer at 235 nm. Furthermore, 5 mL of fresh pH 6.8 phosphate buffer was replaced to the dissolution flask to keep the volume of dissolution medium constant⁸.

In vitro dissolution kinetics:

The in vitro drug release data was fitted into zero-order plots/ dissolution profiles (%CDDVs time) and first order plots (Log % CDUDVs time) as per the following equations¹¹.

Zero order equation: Q_t = Q₀+ K₀t Eq. No. (8)

First order equation: Log Q_t = Log Q₀– K₁t/2.303.

Eq. No. (9)

Where Qt is the amount of the drug dissolved in time t, Q₀is the initial amount of drug in the solution; K₀& K₁refers to the rate constants of zero & first order respectively.

Dissolution Efficiency at 30 min (DE₃₀) by Trapezoid Rule¹²; and time for 50 % drug release (t₅₀) were calculated from dissolution profiles.

Equations for calculating DE₃₀:

[AUC]= Ʃ[(c₁+c₂) (t₂-t₁)]. Eq. No (10)

DE_{30 =}Eq. No. (11)

Where,

[] = Area under curve between time points t₁to t₂

Total area under 30 min = 30 x 100 = 3000 cm²

Accelerated stability studies of the optimized NFD SLTs (F6): Were carried according to an international conference on harmonization (ICH) guidelines. 20 tablets were packed in each 10 CC HDPE bottle and sealed thermally and were placed in a humidity chamber (NSW-175, Narang Scientific work, India) maintained at 45 °C ± 2 °C and 75 % ± 5 % RH. Up to 3 months, at the end of every month the respective samples were withdrawn and evaluated for post compression studies¹³.

RESULTS AND DISCUSSION:

The standard calibration curve of NFD in pH 6.8 phosphate buffer:

Based on the measurement of absorbance at ʎ _max of 235 nm in pH 6.8 phosphate buffer in the conc. range of 0-150 µg/mL, a straight line with an equation, y = 0.003 x - 0.004 and a regression coefficient (r²) of 0.999 was obtained, which indicates it follows the Beers-Lambert law in the mentioned concentration range.

Drug-excipient compatibility (FT-IR) studies:

The FT-IR spectrum of NFD is characterized by sharp characteristic peaks at 3300.20 cm^–1: (N-H) free, trans-isomer, 3158.50 cm^–1: Ar-H/ -CH band, 1651.08 cm^–1: C=O stretching vibration, and 1616.08 cm^–1: Ring vibration. All the above characteristic peaks appear in the (1:1 ratio) physical mixtures of NFD with superdisintegrants at same wave numbers indicating no modification or interaction in the drug with the combination of superdisintegrants used in the study¹⁴ (Fig .1).

Fig.1. FTIR Spectra of A. NFD, B. CCS+CPV+NFD, C. CPV+SSG+NFD & D. SSG+CCS+NFD

Pre-compression studies: The directly compressible blends of NFD SLTs, reveals that the AR was found between 22˚.51’ ± 2.01 to 26˚.28’± 0.73, HR between 1.30 to 1.40 and CI between 21.82 to 28.92 %. The micromertic studies indicate good flow and compression characteristics of all the blends. In these formulations sugar based excipient, directly compressible mannitol is used as diluent, which imparts good flow and compressibility to the blends. It also exhibits good aqueous solubility along with sweetness and negative heat of solution. Hence, it imparts a pleasant mouth feel¹⁵. Pre-compression studies of all the formulations carried out in triplicate (n=3); the consolidated results (mean ± SD) were tabulated in (Table 2).

Table 2. Results of pre-compression studies on NFD SLTs

F. Code	Angle of repose (°)	BD (gm/cm³)	TD (gm/cm³)	CI* (%)	HR* ( )
F1	26.27±0.62	0.32±0.02	0.46±0.05	27.92	1.38
F2	23.64±2.15	0.46±0.01	0.62±0.02	22.81	1.32
F3	25.19±2.27	0.44±0.01	0.58±0.09	23.80	1.40
F4	26.37±2.31	0.40±0.01	0.54±0.02	26.41	1.36
F5	26.28±0.73	0.33±0.04	0.47±0.06	28.92	1.39
F6	22.51±2.01	0.45±0.02	0.53±0.03	21.82	1.30

*All the tests expect for CI & HR were performed in triplicate (n=3) and the values are expressed as (mean ± SD). CI & HR were calculated from the mean values of BD & TD.

Post-compression studies:

Of all the NFD SLT, reveals that the Avg. wt. of tablets of was found to be 296±1.10 to 301±0.98 mg. The Avg. thickness of tablets was found to be 5.3±0.02 to 5.7±0.03 mm. The Avg. hardness of the tablets ranges between 3.5±1.22 to 4.2±1.70 Kg/cm², indicating satisfactory mechanical strength. The % wt. loss in the friability test ranges from 0.06 to 0.12 %, which was NMT 1 % w/w as per pharmacopeia limits indicating a good mechanical resistance of tablets. Assay of all the prepared batches is within 97.6±0.85 to 99.6±0.86% of the labeled content, indicating the content uniformity of all the formulations. The DT of F6 (10% w/w SSG: CPV; 1:1) achieved the fastest (52.12±1.11sec) of all, as it produces the highest tablet breaking force at a given compression force. The wetting time of all the formulations was obtained in the range of 22.21 ±1.11 to 78.21±1.06 sec. Wetting is related to the inner structure of the tablets, hydrophilicity of the components and swelling mechanism of superdisintegrant. The swelling index is also related to the hydrophilicity of the matrix. The SLTs with CPV were fully hydrated and soft throughout because CPV quickly wicks water into the tablet by imparting porosity¹⁶. Water wicking is the ability to draw water into the tablet matrix. Both the extent and the rate of water uptake are critically important. Exposure to water can cause ingredients to swell and exert pressure against surrounding tablet ingredients, causing existing bonds between particles to break¹⁷. Water wicking and swelling are the two most important mechanisms of disintegrant action for CCS¹⁸. SSG is a commonly used super disintegrant employed to promote rapid disintegration by swelling mechanism¹⁹. The water insoluble superdisintegrants show better disintegration property than the slightly water-soluble ones, since they do not tend to swell. Superdisintegrants that tend to swell show slight retardation of the disintegration property due to formation of viscous barrier²⁰. Hence, among the used superdisintegrants CPV is superior²¹.The order of normal and co-processed superdisintegrants efficiency was observed as SSG: CPV>CCS: CPV> CCS: SSG>CPV > SSG > CCS, indicates co-processed superdisintegrants are superior to normal ones²². The formulation F6 (10% w/w of SSG: CPV; 1:1) which shows min wetting time of 22.21 ±1.11 sec and disintegration time of 52.12±1.11 sec and highest SI of 262±1.52 %. Post compression studies of all the formulations, except for Avg. wt. (n=20) and friability test (n=1); carried out in triplicate (n=3); the consolidated results as, (mean ± SD) were tabulated in (Table 3). Pictures while measuring the DT of optimized NFD SLT F6 was shown in (Fig.2).

Fig.2. Pictures while measuring the DT of optimized NFD SLT; F6 A) Initial stage, B) at 20 sec and C) at 52.12 sec

In vitro dissolution studies:

The order of normal and co-processed superdisintegrants in enhancing the dissolution rate of NFD from its SLTs is SSG: CPV>CCS: CPV>CCS: SSG>CPV > SSG > CCS. The dissolution profiles were represented graphically in (Fig.3).

Fig. 3. In vitro dissolution profiles of NFD SLTs

In vitro dissolution kinetics: Reveals formulation F6 (10% w/w of SSG: CPV; 1:1) had the highest DE₃₀ (24.33 %); K₁ (0.018min^-1) with r² (0.959) and lowest t₃₀ (15 min). Hence, it is considered as an optimized NFD SLT. First order dissolution rate constant (K₁) and regression coefficient (r²) of first order profiles were calculated from first order plots. The consolidated in vitro dissolution kinetic parameters of NFD SLT were tabulated in (Table 4).

Table 4. Results of in vitro dissolution kinetic studies on NFD SLTs

F. Code	Dissolution plots		First order plots
F. Code	t₃₀(min)	DE₃₀ (%)	K₁(min^-1)	r²
NFD	ˉˉ	0.49	ˉˉ	ˉˉ
F1	60	5.19	0.005	0.956
F2	60	9.13	0.005	0.996
F3	45	13.07	0.007	0.982
F4	45	18.70	0.012	0.974
F5	30	21.51	0.014	0.967
F6	15	24.33	0.018	0.959

Accelerated stability studies of the optimized NFD SLTs (F6):

There were no significant differences in post compression studies of initial and accelerated stability samples of optimized NFD SLTs; F6 (10% w/w of SSG:CPV; 1:1) up to 3 months in a 20 cc HDPE pack, hence it passes the test for stability as per ICH guidelines. The consolidated results of post compression studies on accelerated stability samples of optimized NFD SLT F6; except Avg. wt. (n=20) and friability test (n=1), the other was carried out in triplicate (n = 3) and the results as (mean ± SD) were tabulated in (Table 5). In vitro dissolution profiles of initial and accelerated stability samples of optimized NFD SLTs (F6) were represented graphically in (Fig.4). Comparative FTIR spectra of NFD, optimized NFD SLT F6-Initial sample and 45°C/ 75% RH-3M sample is shown in (Fig. 5).

Fig.4. In vitro dissolution profiles of accelerated stability samples of optimized NFD SLTs (F6)

Fig.5. Comparative FTIR spectra of A. NFD, B. Optimized NFD SLT F6-Initial sample & D. Optimized NFD SLT F6-45°C/ 75% RH-3M sample

CONCLUSION:

In the view of the above findings, there is drug-excipient compatibility between NFD, normal and co-processed super-disintegrants used in the study. All the formulations passed the pre- & post- compression evaluation parameters as per USP. The order of normal and co-processed superdisintegrants efficiency was observed as SSG: CPV>CCS: CPV> CCS: SSG >CPV > SSG >CCS. The combination of superdisintegrants SSG and CPV is superior among others. The optimized NFD SLTs; F6 (10% w/w of SSG: CPV; 1:1) passes the test for stability as per ICH guidelines. Hence co-processed super-disintegrants are more beneficial in the dissolution rate enhancement of poorly soluble drugs like NFD, than conventional ones.

ACKNOWLEDGEMENTS:

The authors are thankful to Padmasree Dr. M. Mohan Babu, Chairman, Sree Vidyanikethan Educational Institutions, Tirupati; A.P.; INDIA for providing us the required facilities and being a constant support to carry out this academic research.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 21.08.2019 Accepted on 18.09.2019

Asian J. Pharm. Res. 2019; 9(4):253-259.

DOI: 10.5958/2231-5691.2019.00041.8

F. Code	Avg Wt.* (mg)	Hardness (Kg/cm²)	Thickness (mm)	*Friability (%)**	SI (%)	WT (Sec)	DT (Sec)	Assay (%)
F1	296±1.10	4.2±1.70	5.3±0.02	0.06	65±1.12	78.21±1.06	99.12±2.13	98.8±0.92
F2	297±0.92	3.5±1.22	5.4±0.03	0.07	92±1.25	72.15±1.21	93.52±2.31	99.6±0.86
F3	298±1.11	4.2±1.71	5.6±0.03	0.12	103±0.99	65.22±0.66	85.11±2.12	97.6±0.85
F4	301±0.98	4.1±1.22	5.5±0.04	0.08	163±1.48	58.12±1.52	71.22±5.12	97.9±0.88
F5	299±1.26	3.5±1.21	5.7±0.03	0.06	231±1.21	55.21±1.22	64.24±2.14	98.6±0.95
F6	299±1.11	4.1±1.74	5.6±0.02	0.07	262±1.52	22.21 ±1.11	52.12±1.11	98.9 ±0.95

Parameter	Initial	45°C / 75% 4RH
Parameter	Initial	1M	2M	3M
Avg. wt. (mg)	299±1.11	298±1.12	298±1.09	297±1.10
Hardness (kg/cm²)	6.5±1.74	6.5±1.5	6.5±1.44	6.4±1.74
Thickness (mm)	5.6±0.02	5.5±0.09	5.5±0.04	5.4±0.02
*Friability (%)	0.070	0.068	0.064	0.060
Assay (%)	98.9 ±0.95	98.6 ±0.92	97.7 ±0.95	96.9 ±0.91
DT (Sec)	105.12±1.11	105.11±1.12	105.08±1.03	104.07±1.04
WT (Sec)	22.21 ±1.11	22.19 ±1.10	22.12 ±1.01	21.09±1.05
SI (%)	53±1.52	52.8±1.98	52.5±1.09	52±1.10

MATERIALS AND METHODS:

BD = wt. of blend/ Bulk volume. Eq.No. (2)

TD = Wt. of blend / Tapped volume Eq. No. (3)

Post compression studies9:

RESULTS AND DISCUSSION:

Post compression studies⁹: