INTRODUCTION:

A cardiovascular disease is mainlyreason and also responsible for one third of global deaths and which is aleading and also increasing cause contributor to the global disease burden¹. Cardiovascular diseasessuch as cardiac stroke,coronary heart disease, congenital heart disease, peripheral vascular disease, endocarditis. Hypertension is another risk factor for heart disease and is thesingle most risk factor for stroke. Patients with diabetes are 2-4 times morelikely suffering and /or die of coronary heart disease².

Ultra-careful control of blood pressure is neededto monitor in patients suffering with hypertension toprovide the maximum decrease in clinical cardiovascular disease end points, particularly inpatients with coexisting conditions like hypercholesterolemia anddiabetes mellitus. Current clinical trials advised that the single or monotherapy is not successful inmost of the patients. For that purpose, combination therapy may theoretically be favoredfor treatment of multiple diseases. Combination therapy has an edge over monotherapy it minimizesthe dose dependent side effects and increases the overall clinical performance of thedrugs³. Combination drug products also called as fixed dose drug combinations. These are the combination of two or more active pharmaceutical ingredient in a single dosage form. According to the Food and Drug Administration, the United States of America the combination product was defines as a product composed of either combination of a drug with a device or a device with a biological product or a drug along with a biological product or with a drug, drug with device and along with biological product. Where as in case of a fixed ratio combination products the dosage of each ingredients meets the requirements of the individual ingredients separately at a defined population group and it should prove the advantage over the individual or single compound dosage administered separately^4,5. Bilayer tablet can be a main option to avoid or overcome the chemical incompatibilities within or between active ingredients and excipients by material separation. Bilayer tablet is suitable for sequential release of two incompatible components, in which first part is immediate release layer acts as initial dose and maintenance dose as second layer with sustained action. Bilayer tablets are formulations prepared by compressing two different layer granulations fed into a die one on top of another, in layers and compressed by double compression technique. They have the sandwich appearance because the each layer edges are visible⁶. Hence, the present research work is design to prepare bilayer tablets for bimodal drug release. Valsartan is selected as a model drug for preparation of immediate release (IR) layer and metformin HCl as a model drug for preparation of sustained release (SR) layer.

MATERIALS AND METHODS:

Materials:

Valsartan, Metformin HCl, Hydroxy propyl methyl cellulose (HPMC) K100, Poloxamer 188, Sodium starch glycolate (SSG) and lactose were obtained from Yarrow Chem Products., Mumbai. MCC, Magnesium stearate, Talc was obtained from Otto Chemica Biochemical Reagents.

Preparation of solid dispersion:

Valsartan solid dispersion mixtures were prepared by using three different carriers (β-cyclodextrin, PVP K30, Poloxamer 188) with three different ratios (1:3, 1:4, 1:5) using physical mixing (PM) technique^7,8PM1 to PM9.In this technique drug and carrier aremixed gently until uniform or homogenous mixture obtained in mortar and pestle. The prepared homogenous mixture was passed through sieve No. #44 and then it was packed and stored in desiccators for further use. Formulation table for solubility enhancement of valsartan.

Preparation of valsartan IR tablets:

Based on physicochemical characterization, formulation PM8 containing drug: Poloxamer 188 in 1:4 ratio (40 mg of drug: 160 mg of Poloxamer 188) was selected to formulate into IR tablets^8-11. Valsartan PM, SSG, magnesium stearate, talc was added in a mortar and pestle, gently mix for few minutes. The prepared powder blend was evaluated for precompression parameters and the blend was compressed into IR layer by direct compression technique using 8 mm punch. IR formulation ingredients are given in Table 1.

Table 1: Formulation of valsartan IR layer.

Formulation code	Valsartan physical mixture	SSG (mg)	Lactose (mg)	Magnesium Steartae (mg)	Total (mg)
IF1	200	8	10	2	220
IF2	200	10	8	2	220
IF3	200	12	6	2	220

Where each batch contains 60 tablets

Preparation of metformin HCl SR tablets:

All the ingredients of SR layer (metformin HCl, HPMC K100, HPMC K15, xanthan gum, guar gum)¹⁰ were weighed separately and passed through sieve No. #44. All these substances were taken in mortar and pestle and mixed for few minutes using pestle^9-13. The prepared powder blend of SR layer was evaluated separately for precompression parameters. These powder blends were used in the preparation of SR tablets by direct compression technique using 12 mm punch. SR formulation ingredients are given in Table 2.

Preparation of bilayer tablets:

Based on the release profiles of both IR and SR formulations, the formulations IF2 (IR) and SF3 (SR) were selected for the preparation of bilayer tablet^12-15. Steps involved in the manufacturing of bilayer tablets.

Step 1: Ingredients of IR layer (220 mg) and SR layer (600 mg) with different concentration of drug to polymer were accurately weighed.

Step 2: Both powders werepassed through sieve No. #44.

Step 3: Both powders was blended in a mortar and pestle separately.

Step 4: Accurately weighed SR powder of 600mg was fed into the die cavity and compressed at 3kg/cm² with 12 mm flat punch.

Step 5: Similarly, IR powder of 220mg was fed into the die cavity containing SR layer (600mg). So, to maintain the final hardness of a bilayer tablet in between 5 to 6 kg/cm².

EVALUATION:

Compatibility studies:

These studies were performed to know drug-polymer compatibility in the preparation by using differential scanning calorimetric studies (DSC), scanning electron microscope (SEM), fourier transform infrared spectroscopy (FTIR), and X-ray diffraction studies (XRD).

Pre-compressed parameters evaluation:

The prepared physical mixture formulationsphysical properties were performed such as bulk density and tap density, angle of repose, Hausner‘s ratio and Carr‘s compressibility index^16,17.

Post-compression parameters evaluation:

Some of the post-compression parameters such as weight variation, thickness, hardness, friability, content uniformity, disintegration test, and in vitro dissolution test were determined¹⁸.

RESULTSAND DISCUSSION:

Organoleptic properties:

Organoleptic properties¹⁸of two drugs were studied. Valsartan is white crystalline powder with no odor and metformin HCl is white to off white crystalline powder with no odor.

Melting point:

Melting point determines the purity of the compound. If any changes in the melting point indicates the presence of impurities in compound. Melting point of valsartan and metformin HCl was determined by capillary melting method¹⁹. The sharp endothermic peaks are obtained at 114ºC and 220ºC respectively that will be complies with the standard values. This shows that the drugs used are pure without any contamination. DSC also shows the melting point of valsartan and metformin HCl at 117.5 ºC, 226.83 ºC respectively.

Determination of λ_maxof valsartan and metformin HCl by UV-Visible spectroscopy:

Diluted samples of valsartan and metformin HCl were placed in UV-Visible spectrophotometer^19-22.

The peaks show the sharp absorption maxima at 205 nm and 235nm respectively forvalsartan and metformin HCl and absorption maxima are shown in the Figure 1.

Figure 1: UV spectrum of a) Valsartan and b) Metformin HCl.

Identification of drugs:

The absorbance values of valsartan and metformin HCl concentrations 2, 4, 6, 8, 10, 12 µg/mL were determined by using UV-Visible spectrophotometer and the results were given in Table 3 and shown in Figure 2. A graph is plotted between concentration versus absorbance values, known as calibration curve. A Linear equation was obtained from the calibration plot. This procedure was repeated for three times. Out of these three trails straight line equation whose intercept (c) values nearer to zero and coefficient of determination (r) values nearer to 1 was selected.

Table 3: Concentration versus absorbance values of valsartan in 0.1N HCl and metformin HCl in 6.8 pH phosphate buffer.

S. No.	Valsartan		Metformin HCl
S. No.	Concentration (µg/mL)	Absorbance (205 nm)	Concentration (µg/mL)	Absorbance (235 nm)
1	2	0.2227	2	0.1569
2	4	0.402	4	0.2870
3	6	0.5431	6	0.4191
4	8	0.7072	8	0.5684
5	10	0.8620	10	0.7175
6	12	1.009	12	0.8585

Fig. 2: Calibration curve of valsartan in 0.1N HCl and metformin HCl in 6.8 pH phosphate buffer.

FTIR Spectrophoscopy (Shimadzu, FTIR 8700):

The FTIR spectra of pure valsartan, IR formulation, metformin HCl, metformin HCl SR formulation, bilayer formulation was presented in Figure 3.The valsartan FTIR spectrum shows two carbonyl absorption bands at 1710 and 1600 cm^-1, assigned to the amide carbonyl and carboxyl carbonyl stretching respectively^{7, 23}. In the valsartan IR formulation, same characteristic carbonxyl carbonyl and amide carbonyl stretching was recorded at 1700 and 1598 cm^-1. This shows that there was no major shift in the peak values of IR formulation mixtures when compared with the pure drug^24,25. A C-O-C group asymmetric and symmetrical stretching bands were seen at 1590-1000 cm^{-1 23}. The metformin HCl FTIR spectrum showed two bands, N-H primary stretching vibration at 3280 cm^-1 and a N-H secondary stretching band at 3120 cm^-1and a C-H stretching characteristic bands at 1560 cm^-1and 1605 cm^{-1
24, 25}. There is no major shift in the peak values of both SR formulation mixtures and valsartan²⁵. Bilayer formulation has shows two carbonyl absorption streching bands at 1550 cm^-1, 1610 cm^-1 same as valsartan and also it shows two typical bands at 3120 cm^-1, 1540 cm^-1same as metformin HCl. This indicates there is no major interactions, hence the excipients can be used safely to formulate bilayer tablets.

Figure 3: FTIR spectra of A) Valsartan, B) Valsartan IR formulation, C) Metformin HCl, D) Metformin HCl SR formulation and E) Bilayer formulation.

DSC studies (Mettler DSC 821):

DSC qualify the quantitative detection of all process where energy is produced. The thermograms of pure valsartan, Poloxamer 188, SSG, IR formulation, metformin HCl, HPMC K100, metformin HCl SR formulation, bilayer formulations are shown in Figure 4. The valsartan exhibited a melting endotherm at 117.5ºC^{23, 24}, whereas pure Poloxamer 188 showed a melting endotherm at 60.80 ºC^25,26. SSG shows the peak at 204.8ºC. IR formulation shows endotherm at 116.3ºC, indicating that formulation containing valsartan, Poloxamer 188, SSG derived peak shows reduces intensity suggests decreased crystallinity and the drug might have got converted into amorphous form in IR formulation with Poloxamer 188 and SSG compare to pure drug. For metformin HCl a sharp endothermic peak was observed which begins 226.83 ºC and ends at 268.21 ºC and exact peak occurs at 231.03 ºC indicative of anhydrous crystalline state of drug^{27, 28}. HPMC K100 being an amorphous carrier did not show any endothermic events²³. For metformin HCl SR formulation shows a sharp endothermic peak was observed begins at 226.83ºC and ends at 268.21ºC and exact peak occurs at 231.03ºC. The pure drug and the SR formulation shows no shift in the peak which usually signify that there is no drug polymer or excipient interaction. This suggests that SR formulation containing the drug remained in the crystalline state and dispersed in the form of molecular dispersion.For bilayer formulation (ISF) slight change in the endothermic peaks of pure drugs were observed at 117.8ºC, 230.9ºC respectively. These values are in the vicinity of standard melting point range indicating absence of any drug polymer interactions.

Figure 4: DSC thermograms for A) Valsartan, B) Valsartan IR formulation, C) Metformin HCl, D) Metformin HCl SR formulation and E) Bilayer formulation.

Scanning electron microscopy (Zeiss Evo MA15):

SEM of valsartan, SSG, valsartan IR formulation was showed in the Figure 5. Valsartan appeared to be made of irregular crystalline structures^{25, 29-32}. SSG appeared as globular to irregular in shape with varying sizes. In IR formulation the structure of valsartan crystal or mixture are completely different. Which indicates that a formation of new structure in IR formulation containing with Poloxamer 188 and SSG. These findings demonstrated that the drug was changed into amorphous form. Metformin HCl appears as large molecular adducts. HPMC K100 observes as a clear irregular crystal. SR formulation containing HPMC K100 shows increased particle size compare to pure drug²⁶. SEM results shows that the bilayer formulation shows completely different structure compare IR and SR formulation. A new structure is formed for bilayer formulation.

Figure 5: SEM images for A) Valsartan B) SSG C) IR formulation D) Metformin HCl E) HPMC K100, F) Metformin HCl SR formulation and G) Bilayer formulation.

X-ray Diffraction analysis (PW 1729, Philips):

The X-ray diffractograms of valsartan, Poloxamer 188, SSG, IR formulation, metformin HCl, HPMC K100, SR formulation, bilayer formulation is shown in Figure 6. The diffraction spectrum of valsartan showed that the drug was crystalline in nature which was demonstrated by distinct values at 2θ of 19.24º, 23.78º, 38.50º. The diffractogram of IR formulation containing Poloxmer 188 and SSG showed at 38.51º, that some peaks of pure valsartan, SSG, Poloxamer 188 were absent and intensity of peaks was reduced³³. Obtained results indicates that the drug in IR formulation is converted into amorphous. The characteristic peaks of the metformin HCl can be observed around 2θ values 17.90º, 23.57º, 24.87º, 26.76º, 27.52º, 31.58º, 32.87º, 35.75º. Metformin HCl SR formulation showed 2θ values same as pure drug but with the less intensity. This may be due to less concentration of drug in the SR formulation compare with pure drug. For bilayer formulation drugs peaks were observed at 2θ values of 17.85º, 22.54º, 27.32º, 29.69º, 31.42º with varying intensity. This suggests that bilayer formulation containing drug remains in the crystalline form it does not transform into amorphous form.

Figure 6: XRD pattern of A) Valsartan, B) Valsartan IR formulation, C) Metformin HCl, D) Metformin HCl SR formulation and E) Bilayer formulation.

In vitro dissolution studies of solid dispersions:

The results of dissolution studies of all the prepared solid dispersion formulations PM1 to PM9 by using β-cyclodextrin, PVP K30 and Poloxamer 188 in 1:3, 1:4 and 1:5 ratio respectively was shown in Figure 7A. The release is very low for β-cyclodextrin as 39.8 to 58.3 % at the end of 60 mins was seen as the concentration of the polymer increased but where as in case of PVP K30 and Poloxamer 188 as the concentration increased the increase in dissolution rate was seen from 75.7 to 100.2 % for PVP K30 and 91.4 to 99.9 % for Poloxamer 188 with increase in carrier proportion. The SD prepared with Poloxamer 188 showed almost 51.9 % drug release within 10 min, whereas SD prepared with PVP K 30 showed 25.8 % drug release with same concentration, indicating that SD with Poloxamer 188 showed better dissolution profile than PVP K30. This might be due to misceller solubilization effect of Poloxamer 188 whereas PVP K30 is a hydrophilic carrier it increases dissolution only by formation of diffusion layer.

Micromeritic properties:

Flow properties of the formulated valsartan IR formulation IF1 to IF3 and simvastatin SR formulation SF1 to SF6 were evaluated for the parameters such as Bulk density, tapped density, angle of repose, Hausner ratio and Compressibility index for their suitability for direct compression^34-38. The results are given in Table 4. The angle of repose values observed with lowest values for IF2 as 22.92 and highest for IF3 as 28.88. Similarly, lowest value observed for SF5 as 30.96 and highest value observed for SF2 as 35.67. The angle of repose observed values are lower than 40° which indicates good to moderate flowing characteristics of the formulated granules. The compressibility index values of all the formulations are in between the range of 1.42 to 14.66. All the observed values are less than 15% indicating good flow characteristics of the formulated granules., The values of Hausner ratio were observed between 1.01 and 1.13, which was below 1.18 indicating good flow characteristics as per standard values.

Post compression parameters:

The hardness of all the prepared tablet batches were in the range of 4–6 Kg/cm², friability value of the all the formulations were noted to be <1% and the % drug content was in the range of 92.66–106.5%. Disintegration time of IR formulations IF1 to IF3 are 0.07 to 0.1 hrs and SR formulations SF1 to SF6 are 4-8 hrs. From the above post compression parameters results, it indicates that all the preparations formulated by using different concentrations of polymers were of better quality and are within the official specifications towards the hardness, friability, weight variation, disintegration, thickness and % drug content^38-42. The observed data of the all the post compression parameters were given in Table 5.

Table 4: Flow properties of valsartan IR and metformin HCl SR formulations

Formulation code	Angle of repose (º)	Compressibility index (%)	Hausner’s ratio
Valsartan	42.54±0.2	27.38±1.1	1.37±2.0
IF1	28.36±0.3	9.99±1.2	1.11±1.3
IF2	22.92±0.6	14.66±2.0	1.2±0.6
IF3	28.88±0.5	6.154±2.5	1.06±3.2
Metformin HCl	41.98±0.2	24.12±0.2	1.32±0.2
SF1	34.99±0.1	1.66±2.1	1.01±2.3
SF2	35.67±1.2	7.46±3.0	1.08±3.5
SF3	35.52±1.3	11.59±1.2	1.13±2.2
SF4	34.99±1.5	5.79±0.3	1.06±0.3
SF5	30.96±1.8	4.28±2.0	1.04±2.0
SF6	35.52±1.0	1.42±3.2	1.01±3.2

Where all the values are done in mean±SD, (n=3).

Table 5: Post compression parameters of all formulations

Formulation Code	Weight variation^a(mg)	Hardness^b (kg/cm²)	Thickness^b (mm)	Friability^c (%)	Drug content^d (%)	Disintegration^e (hrs)
IF1	215.3±2.5	4.17±0.3	3.03±0.5	0.23±0.3	92.66±3.5	0.08±0.2
IF2	212.3±2.5	4.25±0.3	3.12±0.1	0.46±0.9	97.15±1.4	0.10±0.4
IF3	218.3±1.5	4.50±0.3	3.09±0.4	0.23±2.1	100.3±0.8	0.07±2.1
SF1	598.6±1.5	4.85±0.4	5.15±0.5	0.83±3.2	99.54±0.1	4-8
SF2	609.6±1.5	5.15±0.2	5.14±0.1	0.50±1.9	99.61±3.1	4-8
SF3	608.3±2.8	4.80±0.4	5.18±0.1	0.49±2.4	97.74±2.4	4-8
SF4	629.1±1.0	4.01±0.7	5.28±1.0	0.33±0.2	100.3±0.4	4-8
SF5	631.6±2.0	4.90±0.5	5.12±0.9	0.16±3.2	106.5±6.7	4-8
SF6	628.3±1.7	4.55±0.7	5.14±0.7	0.16±1.1	97.65±2.7	4-8

Where all the values are expressed in mean±SD, (a: n=20, b: n=3, c: n=30, d: n=10, e:n=6).

In vitro dissolution studies:

In vitro dissolution studies IR tablet:

The dissolution studies results of all the prepared valsartan IR tablets formulations IF1 to IF3 by using valsartan physical mixture with 4, 5 and 6 % of SSG was shown in Figure 7B. From the results of dissolution studies of tablets IF1 to IF3, it was observed that the drug release depended on the concentration of superdisintegrant used in the formulation. Formulation prepared with SSG 4, 5 and 6 % showed 88 to 99% of drug release for 60 min, respectively. Hence, the formulation with 5 % SSG was considered as optimum concentration as perthe goal. Complete drug release was observed for IF2 formulation with 5% SSG released 99.69% of drug in 60 min and increase in the concentration of SSG further showed the same release which may be due to increase in viscosity of SSG. Hence, the optimum SSG concentration was fixed as 5 % to the tablet weight.

In vitro dissolution studies of SR tablet:

The results of dissolution studies of all the prepared metformin SR tablet formulations SF1 to SF3 with xanthan gum, HPMC K15M and HPMC K100M with 15 % concentration released 101.29 % in 6 hrs, 100.09 % in 8 hrs and 99.76 % in 12 hrs. Formulation prepared with combination of HPMC K100 M and Xanthan gum in different mixture concentration SF4 to SF6 with total 15 % concentration of polymer mixture released 101.27 % in 9 hrs, 99.14 % in 7 hrs and 98.35 % in 5 hrs and shown in Figure 7C. Formulation SF3 prepared with 15 % HPMC K100M has showed better release in the required time period, which may be due to high molecular weight and high swelling nature of HPMC K100M in appropriate concentration can make the formulation sustain for long period with proper drug release pattern and hence, it has been used further for the preparation of bilayer tablets.

Invitro drug release studies of bilayer tablets:

The results of dissolution studies of the prepared bilayer tablet formulation ISF prepared by using HPMC K100M with 15 % concentration released 98.1 % of valsartan from IR layer in 1hr and 90.11 % metformin HCl from SR layer in 12hrs, % cumulative drug release profiles were shown in Figure 7D.

Comparison of dissolution profile of formulated tablet and marketed tablet of valsartan:

The prepared IR tablet containing 1:4 ratio of drug and Poloxamer 188 and 4 % w/w SSG is compared with the marketed tablet. The drug release profile was shown in Figure 7D. At the same time prepared SR tablet containing HPMC K100 is compared with the marketed tablet. Comparison of dissolution profile of formulated bilayer tablet with marketed SR metformin HCl tablet was shown in Figure 7D.

CONCLUSION:

The present investigation produces a detailed describes about the good formulation and characterization of an antihypertensive and antidiabetic both combination in a one dosage form as bilayer tablet, which contain IR layer of valsartan prepared by adopting direct compression method using various solubility enhancing polymers and super disintegrant in which optimized formula IF2 contains 1:4, drug: polaxomer 188 and 4 % SR layer of metformin HCl was prepared by direct compression method using various release retarding agents in which optimized formulation SF3 was prepared by using 15 % of HPMC K100 M as release retardants. The compatibility studies of drug: excipient were carried out using FTIR showed that there was no interaction in between drugs and excipients. All the pre compression and post compression studies showed that the results were observed to be within the standard official limits. The in vitro drug release studies of valsartan IR layer was found to be 84.46 % within 30 mins and metformin HCl SR layer was found to be 99.69 % at the end of 12 hrs from the bilayer tablet. The release kinetics of the all the formulations showed good linearity with best fitting in to Higuchi model for valsartan IR layer and zero order kinetics for metformin HCl SR layer from in vitro drug release studies. From all the above study, the present research work can be concluded that the prepared bilayer tablets formulation achieved the aimed objective of the research work in treating both diabetes and hypertension with the help of sequential release of two drugs. Which helps in reducing the dosing frequency as these tablets are supposed to be given twice a day and cost effective to the patients, it can also be best alternative for conventional dosage forms which are having more frequency of administration. After conducting the preformulation studies optimized formulations are selected from all formulations. These optimized formulations are used for the preparation of bilayer tablets by direct compression technique. Then these prepared bilayer tablets are evaluated for post compression parameters. Firstly, solubility of valsartan was improved by using various carriers (β-cyclodextrin, PVP K30, Poloxamer 188) at various ratios (1:3, 1:4, 1:5) by using SSG super disintegrant at various concentrations (3 %, 4 %, 5 %). Among all the formulations Poloxamer 188 shows better release. For that purpose, Poloxamer 188 were selected as an IR layer and prepared 3 formulations (IF1, IF2, IF3) by direct compression technique using 8 mm punch. Among the three IF2 containing 4% SSG shows 84.46 % drug release in 30 mins and 99.69 % drug release in 1 hr was further used for preparation of bilayer tablets. Later SR layer is prepared by using individual (15 %) and combination (15 %) of synthetic and natural polymers at various ratios by direct compression technique using 12 mm punch. Among all the formulations SF3 shows 98.76±0.9 % drug release for a prolong period of 12 hrs. Both optimized layers were considered to formulate bilayer tablets by direct compression technique using 12 mm punch. Release kinetics of optimized formulation shows Erosion model with bimodal drug release.From the results it was concluded that combination dosage form can be achieved by bilayer tablet, the prepared bilayer tablet containing 4 % SSG shows immediate action with improved oral BA from IR layer and 16 % HPMC K100 shows drug release for prolonged period of time (12 hrs) with improved BA.

ACKNOWLEDGEMENT:

This research was supported by faculty of Pharmaceutics Department, Maharajah’s College of Pharmacy, Vizianagaram, Andhra Pradesh, India. The authors would like to thank Mr. Satyan Narayanaand Mr. Madhu for supporting the process of Compatibility analysis.

CONFLICT OF INTEREST:

All authors declared that there is no conflict of interest.

AUTHORS CONTRIBUTION:

Dr. Saripilli Rajeswari the main author and guarantor of the present study has designed andguided the experimental process study. Mrs. Prasanthi Teella has carried out the experimental part and analyzed the results using various techniques. Mr. Nataraj KS and Mrs. Prasanthi Teella both have equally contributed inpreparation as well as revision of the research manuscript.

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Received on 05.11.2023 Modified on 01.05.2024

Research J. Pharm. and Tech 2024; 17(11):5575-5583.

DOI: 10.52711/0974-360X.2024.00851

Formulation code	Drug (mg)	Xanthan gum (mg)	HPMC K15 (mg)	HPMC K100 (mg)	MCC (mg)	Magnesium Stearate	Talc	Total weight (mg)
SF1	500	90	-	-	5	3	2	600
SF2	500	-	90	-	5	3	2	600
SF3	500	-	-	90	5	3	2	600
SF4	500	22.5	-	67.5	5	3	2	600
SF5	500	45	-	45	5	3	2	600
SF6	500	67.5	-	22.5	5	3	2	600