Formulation and Evaluation of Stable Montelukast Sodium Sublingual Tablet by using Lyophilization Technique

 

Dipti G. Phadtare¹*, Amol R. Pawar²*, Dr. R.B. Saudagar¹, Govind K.Patil³

¹Department of Pharmaceutical Chemistry, R. G. Sapkal College of Pharmacy, Anjaneri, Nashik

²Department Quality Assurance Techniques, R. G. Sapkal College of Pharmacy, Anjaneri, Nashik

³University Institute of Chemical Technology, NMU, Jalgoan.

 

 

ABSTRACT:

The aim of present work research work was formulation and evaluation of stable montelukast sodium sublingual tablet. Since The thermal stress testing study of Monte in solutions at 65°C showed that it is highly stable in NaOH solution, while it degrades rapidly in both acidic and H₂O₂ solutions. Hence lyophilization technology was adopted to increase the stability of montelukast sodium. Before lyophilization three trials were carried out to optimize the process parameters in which Trial 2 was considered as optimized process. The Lyophilization was carried out in nine different batches by varying the total cycle time, freezing and holding time, primary drying and secondary drying time by maintaining the quantities of all the active pharmaceutical ingredients constant and selection of cryoprotectant ratio. An optimized lyophilization cycle of 56 hours has been achieved. The optimized lyophilized product was subjected to Tablet compression.   In this process the batch-9 formulation was considered as an optimized Formulation for compression with the process. All the in-vitro evaluation parameters complies the limits as per the specification. Stability studies were conducted and from the result it was concluded that the optimized formulation was found to be stable. Finally, it is concluded that the lyophilization is a suitable technique to increase the stability and bioavailability of Montelukast sodium.

 

 

 

INTRODUCTION:

The present research work was to formulate a sublingual tablet of montelukast sodium which is anti asthmatic agent. lyophilization technology was adopted to increase the stability and bioavailability of the formulation. Lyophilization also known as freeze drying is widely used for pharmaceuticals to improve the stability and long term storage of labile drugs.

 

Sublingual tablet manufactured using freeze drying have been the most successful commercially. Tablets manufactured using this technology, generally exhibit rapid disintegration and dissolution due to their highly porous nature, which allows penetration of saliva into the matrix of the tablets, resulting in disintegration. The freeze-drying process involves the transition of water from liquid to solid during freezing, and then solid to vapor during sublimation. A particular advantage of freeze-drying is that the solution is frozen such that the final dry product is a network of solid occupying the same volume as the original solution, resulting in a light and porous product which is readily soluble. Mannitol which is used as a cryoprotectant in the formulation of freeze-dried sublingual tablet. These materials are responsible for forming the highly porous matrix structure of the dosage form. mannitol (a sugar alcohol) provides crystallinity, hardness and elegance. Water is used as a manufacturing process media, which induces the porous structure upon sublimation during the freeze drying stage. Before lyophilization three trials were carried out to optimize the compounding process. It was carried out in three different trials varying the processing parameters keeping the quantities of the entire active pharmaceutical ingredient constant. The trials are subjected to in vitro parameters like Loss on drying, product collapse, and physical characteristics. The lyophilization was carried out in different batches by varying the total cycle time, freezing and holding time, primary drying and secondary drying time by keeping the quantities of all the active pharmaceutical ingredients constant.

 

The fundamental process steps of lyophilization are:

1.      Freezing:

The product is frozen. This provides a necessary condition for low temperature drying.

 

2.      Vacuum:

After freezing, the product is placed under vacuum. This enables the frozen solvent in the product to vaporize without passing through the liquid phase, a process known as sublimation.

 

3.      Heat:

Heat is applied to frozen product to accelerate sublimation.

 

4.      Condensation:

Low temperature condenser plates remove the vaporized solvent from the vacuum chamber by converting it back to a solid. This completes the separation process. In pharmaceutical industry “technology transfer” refers to the processes that are needed for Successful progress drug discovery to product development to full scale commercialization.

 

MATERIALS:

Montelukast sodium from Glenmark pharmaceutical Ltd Mumbai, L-Arginine from modern science Ltd. Nasik. other excpients from Research-LAB-Fine Chemical Industries, Mumbai. 20ml flint type I glass vials, siliconised chlorobutyl-isoprene 20mm rubber stoppers for lyophilization and flip of seals 20mm (polypropylene/ aluminum) were used as packing material.

 

METHODS:

Preformulation of drug:

The main purpose of preformulation study is to ascertain that the drug substance complies with the standards. The preformulation studies of the drug Montelukast sodium carried were: Description, Solubility, Loss on drying, Identification by IR, Melting point, pH study. Solubility study with different solublizer.

 

Compatibility studies with excipients:

Conducting an excipients compatibility screen at the early preformulation stage of the development gives valuable information about potential incompatibilities between drug and excipients. Compatibility between drug and excipients can be affected by many factors, such as moisture content, physical form, particle size, surface area, and morphology and trace impurities of either component. The stressed storage conditions used to accelerate reactions between drug and excipients, so that measurable changes occur in short time frame. Compatibility studies with Montelukast sodium and selected excipients were studied for duration of one month.

 

DSC of Montelukast sodium:

It has been reported that DSC is a very useful tool in the investigation of thermal properties of CD complexes and can provide both qualitative and quantitative information about the physicochemical state of the drug inside the CD complexes. In general, complexation results in the absence of endothermic peak or shifting to different temperature, indicating a change in the crystal lattice, melting, boiling, or sublimation points. The DSC thermogram of Montelukast exhibited an endothermic peak at 69.810C corresponding to its melting point. The physical state of Montelukast sodium in the inclusion complex was investigated since it would have an important influence on the in-vitro release characteristics. DSC curve of pure MTLK-Na shown in figure.

 

DSC of Montelukast Sodium with excpients Complex:

It has been reported that DSC is a very useful tool in the investigation of thermal properties of CD complexes and can provide both qualitative and quantitative information about the physicochemical state of the drug inside the CD complexes. In general, complexation results in the absence of endothermic peak or shifting to different temperature, indicating a change in the crystal lattice, melting, boiling, or sublimation points. The physical state of Montelukast sodium in the inclusion complex was investigated since it would have an important influence on the in-vitro release characteristics. DSC curve of Drug-excpients complex MTLK-Na show

 

DISCUSSION:

The DSC thermogram of Montelukast exhibited an endothermic peak at 69.810C corresponding to its melting point. The DSC thermograms of Montelukast and excpients showed slight shift in peaks which indicates interaction between Montelukast and excpients.

 

Fig A.Thermogram of Montelukast Sodium 

 

Fig B. DSC of Montelukast Sodium with Excipients

Figure No. 1: Fig A.Thermogram of Montelukast Sodium, FigB DSC of Montelukast Sodium with Excipients

 

Formulation Development:

First we studied the solubility of montelukast sodium in water. It is found that the drug is not soluble in water. So, we need a solvent to dissolve montelukast sodium in water.

 

Table No.1: solubility studies using different solublizer

Sr. no.	Solvents	Solubility  [mg/ml]
1	Water	0.15
2	Phosphate buffer 6.8	0.25
3	Phosphate buffer 7.4	0.47
4	pH 4.5 Acetic acid buffer	0.47
5	pH 1.2 HCL	0.50
6	pH 9.2 alkaline borate buffer	0.54
7	0.5% SLS solution	0.96
9	Sodium hydroxide	1.11
10	Hydroxypropyl Beta Cyclodextrin	1.36
11	L-Arginine	2.54
12	Ethanol	3.01
14	Methanol	4.01

 

Screening of components by studies with different Marketed formulation:

Table No.2: Screening of components by studies with different Marketed formulation

Sr. no.	Formulation	Appearance	pH
1	Suspension	Turbid	5.92
5	Syrup	Clear	8.35

 

The pH studies of marketed syrup and suspension will carry out and its shows the increasing pH will be increase the solubility of drug .Hence the selection of alkaline pH was done for further study.

 

Determination of concentration of solublizer and stabilizer on molar ratio

Table No.3: Determination of concentration of solublizer and stabilizer on molar ratio

Ratio	Hydroxypropyl Beta Cyclodextrin			Sodium hydroxide			L-Arginine
Ingredients	1:1	1:2	1:5	1:1	1:2	1:3	1:1	1:3	1:5	1:10	1:15
Montelukast Sodium	10	10	10	10	10	10	10	10	10	10	10
Solubilizer and stabilizer	22.73	67.84	113.07	0.65	1.97	3.98	3.45	10.36	17.26	34.33	51.59
Solubility (mg/ml)	1.18	1.36	2.21	0.61	0.98	1.11	1.40	1.68.	2.19	2.54	3.02

 

The solubility study with different solubility in different molar ratio was done with Sodium hydroxide, L-Arginine and Hydroxypropyl Beta Cyclodextrin. The solubility was found increase in the increasing molar ratio of different solublizer. Hence this different ratio selected for further Lyophilization study.

 

Determination of the concentration of cryoprotectant and water phase for formulation of Lyophilization cycle Determination of solvent and cryoprotectant ratio:

Depending upon higher and lower solubility of drug solvent and cryoprotectant in the following ratio of drug: cryoprotectant: water was study as below table.

 

 

Table No.4:. Determination of solvent and cryoprotectant ratio

Ratios	Mannitol	Stabilizer Solublizer	Drug	Distilled Water	Observation
1:1	10mg	34.33mg	10mg	4ml	Clear
1:2	20mg	34.33mg	10mg	4ml	Clear
1:3	30mg	34.33mg	10mg	4ml	Clear
1:4	40mg	34.33mg	10mg	4ml	Turbid

 

The selection of cryoprotectant depending upon higher solubility in minimum of water. Hear the ratio 1:4 shows the turbidity and ratios 1:1, 1:2 and 1:3 shows solution clear solution. Hence the increasing the ratio of drug and cryoprotectant leads no insolubility of cryoprotectant in the ratio of 1:1, 1:2, 1:3.

 

Determination of Lyophilization cycle:⁴

L-argininre, Hydroxypropyl Beta Cyclodextrin, Sodium hydroxide and Montelukast sodium was dissolved in different vials with distilled water at about 40°C. Followed by the addition of mannitol in different ratio to from a solution. The solution was frozen at -70˚c for freeze dried (VIRTIS BENCHTOP-K) according to following regimens primary drying for thirty hours at self temperature -40˚c.Secondary drying for fifteen hours at self temperature of 20°C and vacuum pressure of 50m Torr. A minimum of ten tablets prepare in batch.   

 

Table no.5: Lyophilization cycle

 

 

 

 

Table no.6: Trial batches of montelukast sodium for Lyophilization.

Ratio	Hydroxypropyl Beta yclodextrin			Sodium hydroxide			L-Arginine
Ingredients	1:1	1:2	1:5	1:1	1:2	1:3	1:1	1:3	1:5	1:10	1:15
Montelukast Sodium	10	10	10	10	10	10	10	10	10	10	10
Solubilizer and stabilizer	22.73	67.84	113.07	0.65	1.97	3.98	3.45	10.36	17.26	34.33	51.59
Mannitol	20	20	20	20	20	20	20	20	20	20	20
Water	4	4	4	4	4	4	4	4	4	4	4

 

Trial batches of montelukast sodium for Lyophilization:

The trial batches taken for the the selection of the stabilizer. The selection based on the various evaluation parameters.

 

Evaluation of Lyophilization trial batches montelukast sodium:

The trial batches taken with the selection of the stabilizer. The selection based on the various evaluation parameters like

 

A)    Collapsed product:

The Lyophilization cycle was carried out. There will be change in the batch the Product collapse happen and Hydroxypropyl Beta Cyclodextrin, L- Arginine give the amorphous powder drug.

B)     Physical Characteristics:

The physical characteristics was carried out their will be give amorphous powder drug determine in both batch. It cannot found the degradation. Hence the Hydroxypropyl Beta Cyclodextrin and L-arginine select for further study.

 

C)    Loss on drying:

The loss on drying was determined using hot air oven. And there will be change of weight will happen into Hydroxypropyl Beta Cyclodextrin was maximum and slight change in weight will happen into L-arginine. it shows the L- arginine have minimum loss on dying was observe . Hence the L-arginine batch selection for further study of Lyophilization.

 

 

Table No.7: Evaluation of Lyophilization of different ratio

Ingredients	Hydroxypropyl Beta Cyclodextrin			Sodium hydroxide	L-Arginine
Ratio	1:1	1:2	1:5		1:3	1:5	1:10	1:15
Collapsed Product	No	No	No	Yes	No	No	No	No
Initial weight	52.73	97.84	143.07	-	40.36	47.26	64.33	81.95
Weight after drying	51.01	95.80	140	-	39.84	46.88	63.91	81.30
LOD	1.72	2.4	3.07	-	0.52	0.38	0.42	0.65

The L-Arginine ratio was selected from above evaluation for further study of Lyophilization.

 

 

Design Formula for Lyophilization of montelukast sodium different batches:

Table no.8: Formula for Lyophilization batch:

 

 

 

 

Table No.9: Evaluation of Lyophilization of different ratio

Ingredients	L-Arginine Different Ratio
Ratio	M1	M2	M3	M4	M5	M6	M7	M8	M9
Collapsed Product	Yes	No	No	Yes	No	No	Yes	No	No
Initial weight	-	47.26	57.26	-	64.53	74.53	-	81.16	91.16
Weight after drying	-	46.84	56.75	-	64.0	73.91	-	80.95	90.54
LOD	-	0.42	0.51	-	0.53	0.62	-	0.21	0.62

 

Table No.10: In Vitro Dissolution of lyophilized montelukast sodium of different batches

 

Evaluation parameters of Lyophilization different ratio:

The evaluation parameter was carried out on (M1toM9) batches. The (M1, M4, M7) batch showing the result of collapse product the damp mass found in this batches. Hence these batches are rejected. And remaining batch continues for further dissolution study.

 

In Vitro Dissolution of lyophilized montelukast sodium of different batches:

In vitro dissolution study was carried out on remaining evaluated batches it shows the results above table no. the M2and M3 have minimum %CDR Compared  to M8 and M9 but M8  and M9 maximum weight as compared to M5and M6 as per molar ratio. Hence they increase the Wight of tablet. The %CDR of M5 and M6 having minute changes but loss on drying of M6 is more as compared to M5. Hence M5 batch selected for further study of tablet compression

Optimization of batch of Lyophilization:

The selection of the optimize lyophilized formula on the basis of different properties of powder % CDR and loss on drying. In this the M5 batch of L-arginine will give good result in that the crystalline montelukast sodium converts into amorphous form. And also give good solubility and %CDR. Hence the M5 batch of lyophilized montelukast sodium selected for further tablet compression study

 

Table No.11 Optimize batch of lyophilized montelukast sodium for compression

 

 

Formulation and Development of tablet containing lyophilized Montelukast sodium using different superdisintegrant.

Table No.12: Formulation of tablet containing lyophilized Montelukast sodium using different superdisintegrant

 

Manufacturing process lyophilized Montelukast Sodium sublingual tablet:

·        Step1:

Microcrystalline cellulose, Aerosil, Talc, Sodium starch Glycolate passed through 40# mesh.

 

·        Step2:

Lyophilized montelukast sodium, croscarmellose sodium, crosprovidone, mannitol passed through 40# mesh.

·        Step3:

Mix in the mixture well and then add Magnesium state and mix for 5-6 min.

·        Step 4:

Then mix well all ingredients and passed through 40# mesh.

 

·        Step 5:

Mix the mixtures of step 1, step 2 and step 3.

The accurately weighed powder were then subjected to direct compression to form a  Lyophilized montelukast sodium sublingual tablet by using 6 mm on Rotary tablet minipress-I (Rimek, Karnavati Engineering Ltd., Mehsana, Gujarat).

 

EVALUATION OF GRANULE BLEND:

Precompression parameters^5:

Prior to compression into tablets, the blend was evaluated for properties such as;

 

A. Angle of repose:

 Angle of repose was determined by using funnel method. Powder was poured from a funnel that can be raised vertically until a maximum cone height, h, was obtained. Diameter of heap, D, was measured. The angle of repose, was calculated by formula

tan Ө = h / r

Ө = tan-1 (h / r)

 

Where, Ө is the angle of repose, h is the height in cm and r is the radius.

 

B. Bulk Density:

Apparent bulk density was determined by pouring presieved drug excipient blend into a graduated cylinder and measuring the volume and weight “as it is”. It is expressed in g/ml and is given by

Db = M / V0

Where, M is the mass of powder and V0 is the Bulk volume of the powder.

 

C. Tapped density:

It was determined by placing a graduated cylinder, containing a known mass of drug- excipient blend, on mechanical tapping apparatus. The tapped volume was measured by tapping the powder to constant volume. It is expressed in g/ml and is given by

Dt = M / Vt

Where, M is the mass of powder and Vt is the tapped volume of the powder.

 

D. Powder flow properties:

The flow properties were determined by

i) Carr’s Index (I)

It is expressed in percentage and is expressed by

I = Dt - Db / Dt

Where, Dt is the tapped density of the powder and Db is

the bulk density of the powder.

 

ii) Hausner ratio

It is expressed in percentage and is expressed by

H= Dt / Db

 

Evaluation of tablet:^{6- 9}

All the tablets were evaluated for following different parameters which includes;

 

1. General appearance:^{14, 15}

Five tablets from different batches were randomly selected and organoleptic properties such as color, odor, taste, shape, were evaluated.

 

2. Thickness and diameter:¹⁶

Thickness and diameter of tablets were determined using Vernier caliper. Five tablets from each batch were used, and an average value was calculated.

 

3. Hardness:^{17, 18}

For each formulation, the hardness of five tablets was determined using the Monsanto hardness tester (Cadmach).

 

4. Friability:

The friability of a sample of 10 tablets was measured using a Friability tester (Electro Lab). Ten tablets were weighed, rotated at 25 rpm for 4 minutes. Tablets were reweighed after removal of fines (de dusted) and the percentage of weight loss was calculated.

 

5. Uniformity of weight:

Twenty tablets were randomly selected from each batch individually weighed, the average weight and standard deviation of 20 tablets was calculated.

 

6. In vitro Disintegration test:

The disintegration time was measured using disintegration test apparatus. One tablet was placed in each tube of the basket. The basket with the bottom surface made of a stainless-steel screen (mesh no. 10) was immersed in water bath at 37 ± 20C. The time required for complete disintegration of the tablet in each tube was determined using a stop watch. To be complied with the pharmacopoeial standards, dispersible tablets must disintegrate within 3 min when examined by the Disintegration test for tablets.

 

8. Drug content:

Twenty tablets were taken randomly and individual tablet were crushed, an amount of the powder equivalent to 10 mg of montelukast sodium was dissolved in the 50 ml methanolic water. Shaken for 30 min and added sufficient methanolic water to produce 100 ml and filtered, diluted suitably and analyzed for drug content at 283 nm using UV-Visible spectrophotometer.

 

 

 

 

Evaluation of Bulk Powder:

Table No.13: Evaluation of Bulk Powder

Formulation code	Angle of repose(θ°) Mean± S.D	Bulk density (gm/cm3) Mean± S.D	Tapped density (gm/cm3) Mean± S.D	Compressibility index (%)Mean± S.D	Hausner’s ratio Mean± S.D
M1	27.83±0.01	0.348±0.03	0.40±0.04	14.15±0.01	1.16±0.02
M2	29.62±0.02	0.333±0.02	0.40±0.03	18.01±0.01	1.21±0.01
M3	29.96±0.04	0.333±0.02	0.37±0.04	10.61±0.11	1.11±0.01
M4	32.21±0.08	0.340±0.03	0.38±0.03	10.43±0.04	1.11±0.02
M5	30.75±0.01	0.348±0.06	0.40±0.01	14.77±0.07	1.17±0.02
M6	31.22±0.07	0.337±0.01	0.38±0.02	13.34±0.04	1.13±0.01
M7	30.49±0.01	0.335±0.04	0.40±0.06	12.84±0.05	1.19±0.02
M8	31.96±0.04	0.343±0.05	0.39±0.01	12.57±0.03	1.10±0.01
M9	30.24±0.01	0.340±0.03	0.40±0.04	16.39±0.03	1.19±0.08

 

Evaluation of Lyophilized Montelukast sodium tablet

Table No.14: Evaluation of Lyophilized Montelukast sodium tablet

 

 

Table No.14: Countineu

 

 

Table No.15: Dissolution study of Montelukast Sodium: L-Arginine

Montelukast Sodium : L-Arginine
Time  (Min)	% Drug release
	M1	M2	M3	M4	M5	M6	M7	M8	M9	Marketed
1	81.45	83.63	86.31	84.06	81.9	85.43	83.49	83.64	85.23	20.91
3	85.22	86.01	88.25	86.6	84.36	87.81	88.25	88.72	88.68	23.58
5	87.52	89.13	91.17	88.58	86.5	89.63	90.39	90.21	90.21	28.49
7	91.5	94.55	95.81	93.59	90.36	93.33	94.13	93.99	93.18	30.60

 

 

 

In Vitro Dissolution:

In vitro dissolution studies were performed for the tablets  using USP dissolution apparatus II (paddle type), at 50 rpm, thermostatically maintained at temperature 37 ± 0.5 C, with dissolution medium of 900 ml having 0.5 % of sodium lauryl sulphate in it. Dissolution study was carried out for duration of 2min with sampling interval of 1 minutes, 3 minutes, 5 minutes, and 7 minutes. The absorbance of both test solution and standard solution at 283 nm taking 0.5 % Sodium Lauryl Sulphate as blank.

 

The selection of the optimize batch based on the various evaluation parameters of tablet are mention above. The F3 batch was optimize batch selected from above evaluation parameters. The selection of the M3 batch based on the various evaluation parameters of tablet is mention above. The disintegration time of M3 batch is below 1 minute and % CDR is 86.31 in 1 minute also maximum as compared to other batches. Hence the M3 batch selected for further stability study.

 

Stability study:

Formulation M3 was kept for stability study. These formulations were evaluated for following parameters after stability study.

 

Appearance:

Tablets kept for stability studies were examined. The color of all the formulations, i.e. M3 was stability studies.

 

Fig.2: In- vitro dissolution study of (F1-F9) tablet Formulation and marketed formulation.

 

Drug content: ^{11, 14}

Drug content was determined after every specified interval of time. At the end of 30 days the drug content of M3 was 99.79 ± 0.04 which was within acceptable limits of I. P. This indicates that Montelukast sodium is stable in presence of the excipients used at high temperature and in presence of high humidity.

 

Physical and chemical parameter of montelukast sodium tablet (M3) at 40±2 ⁰c/ 75±5% RH

Table no.16:  Stability study.

Parameters	Time in Days
	0 (initial)	30 Days
Hardness (Kg/cm2)	3.14±0.14	3.14±0.02
Thickness(mm)	2.975±0.025	2.975±0.01
Drug Contents (%)	99.79±0.04	99.60±0.3
Colour and Appearance	No Change	No Change

 

Dissolution profile montelukast sodium tablet (M3) At 40±2 ⁰c/ 75±5% RH

Table No.17:  Dissolution profile.

Figure No.3: In-vitro dissolution stability study of Formulation.

 

CONCLUSION:

The study performed on “Formulation and evaluation stable Montelukast sodium sublingual tablet by using Lyophilization technique” reveals following conclusion: The main advantage of this drug delivery system is that it contains a lower drug dose, sufficient for therapeutic effect for immediate release time as it bypass first pass metabolism The study show that process parameters such as pH adjustment can have a significant influence on the dissolution time.

·        The sublingual tablets of Montelukast sodium could be prepared using Lyophilization technique. First drug will be lyophilized in alkaline atmosphere and prepared tablet formulations were found to be good without capping and chipping.

·        Lyophilization technique using vacuum oven would be an effective alternative approach to use of more expensive adjuvant and sophisticated instruments in the formulation of sublingual  tablets

·        The prepared sublingual tablet tablets subjected to DSC study suggested that there was no drug-polymer and polymer-polymer interaction.

·        All the prepared tablets were in acceptable range of weight variation, hardness, thickness, friability and drug content.

·        As the amount of lyophilized drug in the tablets increases, the drug release rate and stability of drug

·        The in-vitro release of Montelukast sodium sublingual tablet 86.31 % at the 1 min and disintegrate within 40sec.

·        The prepared sublingual tablets of Montelukast sodium were stable. Hence, the sublingual tablets of Montelukast sodium can be prepared and enhanced bioavailability and prolonged therapeutic effect for the better management with the help of freeze drying technique. The study conducted so far reveals a promising result suggesting scope for pharmacodynamic and pharmacokinetic evaluation.

·        Overall it was concluded that the lyophilization of crystalline montelukast sodium convert into amorphous form in presence of alkaline atmosphere increase stability as well as bioavailability

 

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Received on 21.08.2016       Modified on 13.09.2016

Accepted on 05.12.2016     ©A&V Publications All right reserved