Rapimelts of Venlafaxine Hydrochloride- An Approach to Formulation and In-vitro Evaluation

INTRODUCTION

On an average, 50-60% of drugs are administered by oral routes. Tablets are popular because of ease of administration, accurate dosage, self-medication, pain avoidance, and most importantly the patient compliance.¹ One of the most common demerits of conventional tablets is difficult to swallow.² For these reasons, tablets that can quickly break down or disintegrate in the oral cavity have pulled a lot of attention. Rapimelts are not just shown for individuals who have gulping challenges yet additionally are perfect for dynamic individuals.³ Rapimelts are also called fast-dissolving tablets, melt-in-mouth tablets, orodispersible tablets, quick dissolving tablets, porous tablets, etc. Rapimeltsare those when put on tongue break down promptly and release the medication which disintegrates in the saliva.⁴

The quicker the medication into solution form, the quicker the absorption and onset of clinical effect. Some drugs are absorbed from the mouth, pharynx, and oesophagus as the saliva passes down into the stomach.⁵ In such cases, bioavailability of the drug is significantly greater than those observed from conventional tablets dosage form. The benefit of rapimelts are progressively being perceived in both, industry and academics.⁶

Rapimelts are entrenched dosage forms which captured accessibility in the pharmaceutical market. Because of the various points of interest that they offer to the patients as far as consistence in their stability, drug release, advantages as such manufacturers grab this opportunity in order to rise their revenue by extending line of products and they understood the return on investment on new drug delivery system.⁷Colossal work has been done in this field, wherein a portion of the researchers have built up their very own techniques for formulation and evaluation methods.⁷

Ideal properties of rapimelts⁸

Patients don’t expect water to swallow this type formulations, therefore they should break down in the mouth in matter of seconds probably within 30 sec. They should have acceptable taste, if the taste of the drug is bitter, then bitter taste should be masked by suitable methods.They should be convenient without delicacy concern. They must have a wonderful mouth feel. They should leave least residue or no residue after oral intake in oral cavity. They should show low touchy to ecological condition, for example, temperature and mugginess. They should permit the manufacturer for the ease of processing during manufacture in simplest way and ease of packaging and transport.

In the ongoing past, a few new trend setting innovations have been presented for the detailing of rapimelts with extremely interesting highlights, as incredibly less disintegrating time, uncommon taste veiling capacity and sugar free tablets for diabetic patients. These procedures of manufacture depend on the standards of expanding porosity as well as expansion of superdisintegrants and water solvent excipients in the tablets.⁹

In the present investigation, an antidepressant drug, venlafaxine HCl, was chosen since the drug has low dose of 25mg and oral bioavailability of 45%.⁷ Rapimelts of Venlafaxine HCl were prepared using different superdisintegrants by the direct compression method.

MATERIALS AND METHODS

Materials

Venlafaxine HCl was obtained as free sample from the LupinPharmaceuticals, Goa. Sodium StarchGlycolate (Primojel), Croscarmellose Sodium (AC-Di-Sol), Crosspovidone (Polyplasdone XL10), Aspartame, vanilla flavour, pineapple flavour, magnesium stearate, microcrystalline cellulose (Avicel-PH 112) and Aerosil were used of analytical grade.

Methods

Formulation of venlafaxine HClrapimelts includes micro crystal line cellulose as diluent, aspartame as sweetener, vanilla as flavouring agent, magnesium stearate as lubricant, and talc as a glidant, Crosspovidone (CP), Sodium Starch Glycolate (SSG) andCroscarmellose Sodium (CCS) were used as super disintegrants. The best super disintegrant was determined by subjecting all the three superdisintegrants in the formulations in the concentration range of 2-5%w/w.

Venlafaxine hydrochloride tablets were manufactured for the nine batches R-I to R-IX using the ingredients mentioned in Table 1, keeping the total weight of the tablet constant (150 mg) in all the formulations. The direct compaction method was used to manufacture the tablets. The active pharmaceutical ingredient (Venlafaxine Hydrochloride) and additives were passed through #60-sieve. Polybag was used for proper mixing via geometric dilution method where drug and other diluents were mixed except magnesium stearate for 20 min manually, further lubrication was enhanced by adding magnesium stearate. The total mixture was allowed for removal of moisture content by drying the mixture in dryer at 45±1 o C, the mixture was compressed on Minipress-I Tableting machine 10 station “B” Tooling having flat-faced punches of 8 mm diameter.

Pre-compression study

FT-IR: In the preparation of tabletformulation, drug and excipients may interact as they are in close contact with each other, which could lead to the instability of the formulation. The drug-excipients interactions are therefore very critical. FT-IR spectroscopy was employed to ascertain the compatibility between venlafaxine hydrochloride and the excipients. Potassium bromide, Venlafaxine HCl, and the excipients (SSG, CP, CSS, and MCC) were heated to 105 o C for one hour to remove the moisture content if present in a hot air oven. Then in presence of IR lamp, potassium bromide was mixed with drug and drug-excipients in 9:1 ratio and the spectra were taken in FT-IR spectrophotometer (4100, Jasco Corporation, Tokyo, Japan). FTIR spectrum of venlafaxine hydrochloride was compared with FT-IR spectra of venlafaxine hydrochloride with excipients. FT-IR spectra of venalafaxine hydrochloride and venalafaxine hydrochloride with excipients were compared. Disappearance and shifting of peaks were observed.

Angle of repose : Funnel method was used to determine the flow properties of blend where the funnel was adjusted just above the heap approximately above 2cm. Powders mixtures were allowed to pass through it followed bydiameter of powder cone was measured through which angle of repose was calculated.^10,11

Bulk density: Loose bulk density (LBD)and tapped bulk density (TBD) of Venlafaxine HCl and formulation mixtures were determined using bulk density apparatus (ETD 1020, Electrolab, India).¹² Initially powder blend was passed through #18 sieve to break clumps which were in the mixture. Accurately weighed amount of drug 5gm was placed in 100 mL graduated measuring cylinder. The cylinder was tapped initially 200 times from a distance of 15±2 mm. The tapped volume (Va) was measured to the nearest graduated unit. The tapping was repeated and measure was noted down. Similar procedure was followed for the powder mixture. The LBD and TBD were calculated in g per mL using following formulae, LBD = weight of the powder / volume of the packing, TBD = weight of the powder / tapped volume of the packing.

Compressibility index (Carr’s index): Carr’s index of powder blends were determined by using the formula,12 Carr’s index (%) = [(TBD – LBD) x 100] /TBD

Hausner’s ratio: The equation used to determine the Hausner’s ratio was, Hausner’s ratio = TBD / LBD

Post compression studies

Appearance : Formulated tablets were tested for their texture, mottling, cracks, etc. if any, uniform distribution of color and elegance of the tablet.

Dimensions: Digimaticmicrometer (Coolant proof IP 65, Mitutuyo, Japan)was used to determine the thickness and diameter of the formulated tablets. At initial stages, values of thickness were taken consideration to adjust during compression for punching.

Weight uniformity test: Twenty formulated tablets were weighed individually and all put together and average weight was calculated. Then weights of tablets were compared with average weight of twenty tablets for the study.Permissible difference in weights variation is±7.5% as the formulated rapimelts weigh 150mg. Difference in the weight variation was calculated by using the formula,Percentage deviation = {(Individual weight – Average weight) X 100} /Average weight.

Weight variation in the formulated rapimeltsmay lead to under or over medication of the dosage. Hence it was very important to preparerapimeltsof uniform weight. Necessary actions were taken during compression in order to get uniformity.

Hardness test: Monsanto tester was used to determine the hardness of the rapimelts. Six determinations were considered for the calculation of average. Degree of hardness varies from each different manufacturer.^13,14 The rapimelts should have sufficient mechanical strength to withhold the mechanical stress during handling and transportation. Unit used to measure the hardness is kilograms per centimetre square.

Friability test : Rapimelts loose its weight, due to removal of fine particles from the surface. An evaluation test was performed for the formulated rapimelts to check the ability to withstand during manufacturing process, during freight, handling and shipment. Friability of rapimeltswas determined by Roche friabilator (Electrolab, India). Permissible limit for friability is 0.8%.

Ten rapimelts were introduced in the friability chamber and weighed before and after the exposing them in rolling i.e, free fall from 6 inches with in the chamber. Rotations per min 25 was maintained throughout the process (100 rotations for 4 min).

The percentage friability was calculated using the formula; Friability = [(W1 – W2)x100]/W1 where, W1 = Initial weight of the rapimelts before test, W2= Weight of the rapimelts after test.

Content uniformity test : Average weight of randomly selected 3 uncoated rapimeltswas taken. The tablets were crushed in the mortar and pestle. The rapimelts powder mixture was transferred to three 100 mLvolumetric flasks and were filled with phosphate buffer (pH 6.8) solution.The contents of the flaskswere shaken occasionally and kept aside for 24 h to dissolve drug completely. Then, solutions were filtered and absorbances were measured at 224.8 nm using phosphate buffer solution (pH 6.8) solutionas blank. Drug content of rapimelts were estimated.

In Vitro Dispersion Time: Phosphate buffer solution of pH 6.8was used as simulated saliva in petri plate into which the randomly selected rapimelts were dropped. The time required for in-vitro dispersion was noted in seconds.¹⁵

Wetting time and water absorption ratio : Petri plate containing ten mL of phosphate buffer solution(pH 6.8) was taken into which a drop of Eosin (water soluble dye) was added.Tissue papers of same size as that of petri plate was placed by considering inner diameter. With most care rapimelts were placed on the surface of the tissue paper and it should not be dipped in the solution. The time required to reach phosphate buffer solution to upper surface of the rapimeltswas noted as wetting time.¹⁶ Water absorption ratio (R) wascalculated using the formula R = 100 x [Wa – Wb] / Wb ; where, Wa = Initial weight of rapimelt after absorption, Wb = weight of rapimelt before absorption.

In Vitro Drug Release : USP – type IIdissolution apparatus (paddle type)was used to analyse the release patterns of the rapimelts. In vitro conditions were maintained by using 900 mL of phosphate buffer solution (pH 6.8) temperature at 37±0.5 ^o C, and rpm of 50. One rapimelt was placed in each flask of dissolution apparatusto study drug release pattern. The apparatus was allowed to run for 30 min. Samples (5 mL) were withdrawn at 1, 2, 3, 4, 5, 10, 15, 20, 25, and 30 min. Samples were filtered through 10 µm filter. The fresh dissolution medium was replaced every time with the same quantity of the sample. The collected samples were analysed at 224.8nm using the dissolution medium as blank. The cumulative percentage drug release was calculated.

Reproducibility

Reproducibility was verified by manufacturing the selected rapimeltstwo more times. The batch size was increased to 50 rapimelts from 30. The prepared rapimelts were analysed for release pattern and other parameters. The results were compared with earlier batch for reproducibility.

Accelerated stability study

ICH guidelines were followed for the accelerated stability studies by storing the samples at 40 ± 2o C and 75 ± 5% RH for 180 days. The rapimelts were studied for drug release patternson 0th day, 30th day, 90th day and 180th day fordrug content, hardness, and dissolution. The results were compared with rapimelts which were evaluated immediately after manufacturing.

Similarity and dissimilarity factors^17,18

The various factors influence the dissolution profile of any formulations which may include from instrumental factors (temperature, speed, and pH), physicochemical properties (particle size, shape, crystalline or amorphous form, polymorphism), and excipient related factors (diluent, disintegrant, lubricant and surfactants).

In recent days, independent model method gained popularity to compare the dissolution results of test and reference. It is mandate to submit the details for the approval for US FDA for generic drugs.

Mathematical approach was adopted to know about similarity (f2) and dissimilarity factors (f1) of dissolution profile of optimised batch along with the batch which is used in stability studies as per ICH guidelines.

A simple model independent approach uses a difference factor (f1) and a similarity factor(f2) to compare dissolution profiles. The difference factor (f1) calculates the percent (%) difference between the two curves at each time point and is a measurement of the relative error between the two curves

f1 = {[Σt=1n(Rt - Tt) ]/[Σt=1nRt ]} x 100

where n is the number of time points, Rt is the dissolution value of the reference (prechange) batch at time t, and Tt is the dissolution value of the test (postchange) batch at time t. The similarity factor (f2 ) is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) dissolution between the two curves.

f = 50 x log {[1+(1/n)Σt=1n ( Rt - Tt )2 ]-0.5 X 100}

RESULTS AND DISCUSSIONS

Pre-compression study

FT-IR : The pure drug and excipients were analysed via FT-IR. The FTIR spectra of venlafaxine HCl and mixture of venlafaxine HCl and excipients are shown in the Fig. 1 to 5. The FTIR of venlafaxine HCl (drug) showed intense bands at 1613.36 cm-1, 1515.59 cm-1 and 1052.22 cm-1 corresponding to the functional groups C=O, NH, and OH bending, respectively. The FTIR of drug + CP showed intense bands at 1614.13 cm-1,1513.85 cm-1 and 1042.37 cm-1 indicates no change in the functional groups. Similar observation was noticed with SSG, MCC, and CCS. From the above elucidation, it was comprehended that there wasno significant changes in the frequencies of the above said functional groups. Thus the drug and excipients were compatible with one another.

Micromeretic evaluation :

Angle of repose was done in order to know the flow properties of the blend. Its value will be high if the powder is cohesive and low if the powder is noncohesive. All the formulations showed good to acceptable flow properties as indicated by the values of angle of repose (28.1 to 30.1). Carr’s index showed values up to 18.3 denoting that these formulations have acceptable to good flowability. Hausner’sratio showed that powders with low interparticle friction, had ratios of approximately 1.17, indicating good flow properties. All formulations had Hausner’s ratio values within the stated limit (Table 2).

Post-compression evaluation

All the formulated tablets of Venlafaxine HCl were evaluated for hardness, friability, content uniformity, % drug content, wetting time, water absorption ratio, and in vitro dispersion time. The results of all evaluation parameters were within the limits and the data of all the parameters evaluated for the formulated tablets were depicted in the Table 3.

All the formulated tablets were found to be round, white, and flat. Hardness of the tablets ranges from 2.6 to 3.4 kg/cm2. Friability of all the formulations were found to be less than 0.8% shows good mechanical strength. Uniformity of weight was within the limits as per Indian Pharmacopoeia. Drug content (%) in all the formulations ranges from 99.2±0.87 to 99.8±1.33 also falls in the limits of Indian Pharmacopoeia. Wetting time and in-vitro dispersion time (seconds)of formulations were decreasing as the concentration of the super disintegrants was increased. The formulation of R-IX has shown 34.3 ± 2.8 sec, and 26.65 ± 0.82 sec, respectively. Similarly water absorption ratio (%)was increasing with the increase in concentration of super disintegrants, formulation R-IX had shown 99.31 ± 2.32 (Table 3).

Dissolution Profile

After all the physical properties found satisfactory for batches R-I to R-IX, the dissolution of these batches were tested. R-I to R-III formulations of sodium starch glycolatehave shown 58.40, 86.54, and 90.53% of drug release in 30 min, respectively. As the formulations did not meet the expectation, these batches were rejected. R-IV to R-VI formulations of croscarmellose sodium showed 70.98, 73.82, and 76.64 % of drug release in 30 min, respectively. As these formulations also did not meet the expectation, these batches were rejected.

R-VII to R-IX formulations of crospovidone showed the dissolution of 91.8, 96.31, and 100.24 %, respectively in 30,30, and 20 min.(Fig. 6). Thus R-IX formulation was optimised as this formulation showed 100.24% dissolution in 20 min having super disintegrant concentration of 5%. CP acts by both swelling and wicking actions which helped release of drug.

Reproducibility of the Batch F-IX

Batch to batch uniformity is very much essential for obtaining reproducible results. In order to verify this, the tablets of the batch F-IX were manufactured two more times. For this, the batch size was increased from 30 to 50 tablets. Release studies were conducted as specified for in-vitro study. The results were compared with earlier batch for reproducibility.

The release patterns of the first and reproducibility batches are shown in the Fig.7. The perusal to the Fig.7 indicates that, the release patternsare overlapping proving the reproducibility. Further calculated similarity index and dissimilarity index values also supported the results.

Accelerated stability study

Dissolution studies were carried out for the formulations R IX kept for accelerated study in the same way as discussed earlier. Drug release patterns were studied after 30 days, 60 days, 90 days, and 180 days and are shown in Fig. 8. 

Similarity and dissimilarity factors (f₁ and f₂ )

The formulated optimised batch of rapimelts have shown acceptable results when applied with mathematical approach such as similarity factor (f2) = 73.42 (standard range =50 to 100), and dissimilarity factor (f1) = 4.15 (standard range = 0 to 10). Hence the manufacturing procedure is consistent in manufacturing the rapimelts with reproducible results.

CONCLUSIONS

Direct compaction method was found to be effective in the formulation of rapimelts of venlafaxine hydrochloride. Preformulation studies of venlafaxine were performed; the FTIR analysis revealed that the superdisintegrants and excipients used were compatible with venlafaxine. Post compression parameters like friability, hardness, weight variation, and drug content indicate that the values were within permissible limits for all the formulations. The order of in-vitro dispersion time and wetting time for super disintegrants is CP > SSG > CCS. The in-vitro release studies showed 100% drug release within 20 min from the formulations prepared by crosspovidone.

Conflicts of Interest

The authors declare no conflicts of interests.