INTRODUCTION:

In recent years, sophisticated drug delivery systems have been devised and developed to release the drug substance into the body at a controlled and predetermined rate. Through these controlled release devices, the drug is administered at a specific rate that maintains its concentration within optimum limit and directs the active ingredient to the target area.

Controlled release dosage forms (CRDF) have been developed for over three decades. They have increasingly gained popularity over other dosage forms in treating disease.

Controlled release systems¹provide numerous benefits over conventional dosage forms. Conventional dosage forms, which are still predominant for the pharmaceutical products, are not able to control either the rate of drug delivery or the target area of drug administration and provide an immediate or rapid drug release. This necessitates frequent administration in order to maintain therapeutic level. As a result, drug concentration in the blood and tissues fluctuate widely. The concentration of drugs may be initially high, that can cause toxic/and or side effects, then quickly fall down below the minimum therapeutic level with time elapse. The duration of therapeutic efficacy is dependent on the frequency of administration, the half-life of drug and release rate of dosage form. In contrast, controlled release dosage forms are not only able to maintain therapeutic levels of drug with narrow fluctuations, but they also make it possible to reduce frequency of drug administration. The serum concentration of drug released from controlled release dosage forms fluctuates within the therapeutic range over a long period of time.

The serum concentration profile depends on the preparation technology, which may generate different release kinetics, resulting in different pharmacological and pharmacokinetic responses in the blood or tissues.

These days considerable attention is focused on the development of Novel drug delivery system (NDDS). The reason for this paradigm shift is the low development cost and time required for introducing a NDDS, as compared to new chemical entity. There are various NDDS available in the market but the oral controlled release system hold a major because of their ease of administration and better patient compliance.

NEED FOR THE STUDY:

Pellets are multiparticulates of varying diameter depending on their application. When multiparticulate systems were compared to single unit dosage forms, they⁴ showed low intra and inter subject variability in gastric emptying times and better homogeneous distribution within the contents of gastrointestinal tract. The risk of dose dumping can be significantly reduced with multiparticulates compared to single unit dosage forms. Multiparticulate controlled release dosage forms showed better patient compliance and ease of administration. Many polymers are used as matrix forming agents which includes ethyl cellulose, polyvinyl acetate etc. But lipid offers great potential as matrix formers in loading the drug into matrix pellets, such as the combination of waxes; starches and maltodextrins were successfully used in controlling the drug release. A Combination of Glycerol monostearate and microcrystalline wax could effectively prolong drug release. The addition of glycerolmonostearate to microcrystalline cellulose (MCC) based pellets prepared by Extrusion – Spheronization did not result in the retardation of drug release, it was only controlled by the solubility of drug. Gelucires are successfully used to prepare controlled release matrix pellets. Recently studies⁵ showed that increase in the gelucire content leads a decrease in the drug release rates. So, the present study is carried out to investigate the effects of gelucire blends in formulations and processing parameters on the drug release patterns, which help to understand the drug release kinetics. Nifedipine⁶ is a dihydropyridine derivative and has a narrow margin of safety. It is a calcium antagonist, which is widely used as a coronary dilator in hypertension. Clinical studies⁷have shown that the hypotensive effect of this drug could be correlated with the plasma Nifedipine. It is therefore important to prolong the plasma concentrations so as to control and regulate the therapeutic effects of Nifedipine over a longer duration. Nifedipine is a poorly soluble drug, and its absorption in GIT is rate limited. It has a short biological half-life of about 2-5 hours.

Materials and methods:

Materials

Materials		Source
Nifedipine IP	:	Cadila Ahemdabad
Gelucire 50/02	:	Gattefosse SAS,Chemin De Genas,France
Gelucire 50/13	:	Gattefosse SAS,Chemin De Genas,France
Microcrystalline Cellulose IP	:	Loba Chemie, Mumbai
Lactose IP	:	Loba Chemie, Mumbai
Polyvinylpyrolidone IP	:	Loba Chemie, Mumbai
Sodium lauryl sulphate IP	:	Loba Chemie, Mumbai
Isopropyl alcohol	:	Ranbaxy fine chemicals, Mumbai
Methanol	:	Loba Chemie, Mumbai
Acetone	:	Loba Chemie, Mumbai

Methods:

Preparation

Preparation of Gelucire based matrix pellets by Extrusion / Spheronization

Drug, Gelucire 50/02, Gelucire 50/13, Avicel and aqueous SDS solution (0.5% w/w) were manually mixed in a mortar. Drug, Gelucire 50/02 and 50/13, Avicel was used to make Matrix pellets. 8% PVP solution in IPA: Distilled water combination (20: 80) was used as binder. The quantity of the binder solution used was sufficient to maintain loss on drying.

Procedure

The powders – Nifedipine, Gelucire 50/02, Gelucire 50/13 and Avicel PH 101 were passed through a 40-mesh sieve. PVP was dissolved in a IPA water mixture and stirred to get a clear solution. The powders were granulated with the PVP solution to get a good dough mass of extrudable consistency. The volume of the binder solution required was noted and the quantity of the binder used was calculated from the percentage of binder used was calculated from the percentage of binder solution.

The wet mass was extruded into short cylinders using a cylinder roll type gravity feed extruder with a roller speed setting of 100 rpm. A granulating cylinder with 1.0 mm pore size was used and extrudates were obtained. Spheronization of the extrudates was carried out in the spheronizer using a serrated plate. The Spheronization speed was varied to get pellets of good sphericity. The air velocity was maintained at 1 Kg/ Cm². Drying of the pellets was carried out in a tray drier.

Melt-solidification method

Nifedipine (1 g) was dispersed into a Gelucire melt (4 g). Using a pipette this dispersion was dropped into water (ambient temperature under stirring at 750 rpm), resulting in pellet solidification upon cooling. The beads were separated by sieving, washed with demineralized water, divided into different size fractions (by sieving) and dried at 40 ^oC for 24 hours.

Table 6. Formulation chart (melt solidification method)

Formulation code	Nifedipine (grams)	Gelucire 50/13(g)	Gelucire 50/02(g)
E1	1	2	2
E2	1	1.5	2.5
E3	1	1	3
E4	1	0.5	3.5

CHARACTERIZATION OF MATRIX PELLETS

1. Yield of pellets

2. Particle size distribution

3. Density

3.1 Bulk density

3.2 Tapped density

3.3 Granule density

4. Flow properties

4.1 Carr s index

4.2 Hausner’s ratio

4.3 Angle of repose

5. Mechanical strength / Friability

6. Shape analysis

7. Compatibility studies by FT-IR and DSC

8. Surface Morphology by SEM

Evaluation parameters

1. Drug loading and %encapsulation efficiency

2. In vitro release studies and comparison with marketed product

3. Stability studies

Characterization of matrix pellets

1. Yield of the Process

Weighing the pellets and then finding out the percentage yield with respect to the weight of the input materials that is weight of drug, MCC and lactose used determined the yield.

2. Particle size distribution

Particle size distribution of Nifedipine containing pellets was done by sieve analysis method using a set of US standard sieves. US standard Sieves of the size # 14, #16, #18 and #20 were taken with pellet load of 10 g. Sieve nest was hand shaken for 10 minutes. The arithmetic mean diameter of Nifedipine pellets was determined from sieve analysis. The net weight retained on each sieve was determined and recorded. Average values were used for the calculation of particle size distribution.

3. Density

The bulk and tap densities of pellets are determined to gain an idea of the homogeneity of particle size distribution. The density of pellets can be affected by changes in the formulation and/or process, which may affects other processes or factors, such as capsule filling, coating, and mixing. Variation of density from batch to batch affects the potency of the finished capsule, causes problems in batch size determination during coating and produces segregation during mixing.

3.1 Bulk Density

6 batches of 16g pellets in each batch were taken in a graduated cylinder and volume occupied was found out. Bulk Density is calculated using the formula.

3.2 Tapped Density

About 15 gm of Nifedipine pellets were taken in the measuring cylinder and the initial volume (V_i) was noted. Sample was tapped on tap density tester USP-I mode for the pre-set 500 taps. The volume after tapping (V_f) was noted. Volume were recorded only when the difference of V_i – V_f was less than 2%. If the difference of V_i – V_fwas more than 2%, the tapping was continued for another 750 or 1250 taps till the difference between V_i and V_fwas less than 2%.

The tapped density (g/ml) was calculated by

Where, M = Weight of sample powder taken (gm)

V_f = Final tapped volume (ml)

3.3 Granule density

For the determination of granule density, exactly 1 g of the pellets were poured into 5 ml of petroleum ether taken in a 5 ml volumetric flask. The volume of the ether displaced was measured. The quotient of the weight of pellets and the volume of petroleum ether displaced was taken as the granule density (rg). All the determinations were done in triplicate and the average ± S.D^* was calculated

Where, W is quotient of weight of Pellets

Vp is volume of petroleum ether displaced

4. Flow properties

4.1 Compressibility Index

Carr’s index is a dimensionless quantity, which proved to be useful to a certain degree, as the angle of repose values for predicting the flow behaviour.

The Compressibility index (CI) was calculated using the following formula.

100

Compressibility index and its relationship between flow properties are shown in Table 7.

Table 7. Relationship between CI of powder and its flow properties

Compressibility Index (CI) (%)	Flow Property
1-10	Excellent
11-15	Good
16-20	Fair to passable
21-25	Passable
26-31	Poor flow
32-37	Very poor

4.2 Hausner’s Ratio

The Hausner ratio of the Nifedipine pellets was determined by dividing the tapped density by bulk density. Hausner ratio and its relationship between flow properties are shown in Table 8.

Table 8. Relationship between Hausner ratio of powder and type of flow

Hausner Ratio	Type of Flow
Less than 1.25	Good flow
1.25 – 1.5	Moderate
More than 1.5	Poor flow

4.3 Angle of Repose

Angle of repose is an indicative of the frictional forces exhibited between the particles. The angle of repose is defined as the maximum angle between the surface of the pile and the horizontal plane. The flow properties of the drugs and the excipients are critical for efficient tableting. These properties are necessary to assure efficient mixing, content uniformity and weight uniformity of the tablets. Fixed funnel method was employed. A funnel that was secured with its tip at a given height above the graph paper was placed on a flat horizontal surface. 30 g of pellets were carefully poured through the funnel until the apex of the conical pile just touches the tip of the funnel. The radius and height of the pile were then determined. The angle of repose (θ) for samples were calculated using the formula, the flow rate was calculated as the time taken for 10 g of Pellets to flow through a funnel of 5 mm internal diameter. All the determinations were repeated in triplicate and the average ± S.D was calculated.

q = tan^–1(h/r)

Where, q = Angle of repose

h = Maximum cone height

r = Radius of the base of the pad

Influence of angle of repose on flow properties is given in Table 9

Table 9. Relationship between Angle of repose of powder and its flow characteristics

Angle of Repose () (Degree)	Flow Property
25- 30	Excellent
31 –35	Good
36 –40	Fair
41-45	Passable
46-55	Poor
56-65	Very poor

5. Mechanical strength/Friability

Matrix pellets having size between 1410-1000 µm and a known mass were placed in the Roche friability tester and subjected to impact test at 25 rpm for 5 minutes. After passing the load through the sieve of mesh size (840 µ), the weight of material which do not pass through the sieve was determined and % friability was calculated using the equation.

Where Wo is the initial weight

W is the weight retained

Table 10. Overview of friability testing methods for pellets

Method	Description
Erweka friabilator Roche friabilator Pharma Test friabilator	Rotating drum like friability testing apparatus for tablets.
Turbula	Turbula blender (closed test system)
Born Friabimat Retsch ball mill	Horizontal shaker (closed system)
Laboratory coating apparatus	Fluid bed device

6. Shape analysis

Pellets of the optimum size were taken and stained by Amaranth dye solution in a petridish. After staining they were dried in hot air oven. Tracings of each pellet were taken using camera Lucida fixed to optical microscope (magnification 10x) and were used to calculate the area of the images (A) and the maximum and minimum radii were calculated from which the various shape factors were calculated

Where A is area (cm²)

P is the perimeter of the circular tracing

Min. Radius

7. Compatibility studies by FT-IR and DSC

v Fourier Transformed Infra Red spectroscopy (FTIR)

The prepared and optimized tablets formulations were characterized by Fourier transform infrared spectroscopic analysis, using FT-IR 8400S(Shimadzu, Japan). Spectral measurements of the pure drug and optimized formulation were carried out by dispersing pure drug and formulations in dried KBr powder and the pellets were made by applying 6000 kg/cm² pressure. FT-IR spectra were obtained by powder diffuse reflectance on FT-IR spectrophotometer. FT-IR spectrum of drugs was compared with FT-IR spectra of formulations. Disappearance of peaks or shifting of peak in any of the spectra was studied.

v Differential Scanning Calorimetric Studies

DSC analysis was carried out to ascertain the compatibility of drug with the excipients. Study was performed on a Mettler Toledo, DSC822Japan. About 3 mg to 8 mg of the powered sample was placed in a sealed aluminium pan, heated under nitrogen flow (10 ml/min) at a scanning rate of 10^oC min^-1, from 40^oC to 250^oC. An empty aluminum pan was used as reference.

8. Surface morphology by SEM

v Scanning electron microscopy

The scanning electron microscope Joel, LV-5600, USA was employed to identify and confirm the dimension of pellets, study of surface topography, smooth and optimal spherical shape, at the range of magnification 25X – 100X.

Evaluation parameters:

1. Drug loading and Encapsulation efficiency

Pellets containing drug equivalent to 20 mg was dissolved in 5 ml of methanol and volume was made with 7.4pH phosphate buffer in a 100ml volumetric flask. It was further kept overnight and then filtered using whartmann filter paper. From this, 1 ml of solution is transferred to 10ml volumetric flask. Absorbance was measured at 338 nm; the drug content was calculated from standard plot. Amount of drug is found out by using the formula, Drug loading capacity is found out by calculating the amount of drug present in 100 mg of pellets. It is further calculated by using formula

Amount of drug =

Concentration from standard graph x bath volume x dilution factor

1000

10. In vitro release studies and comparison with marketed product

In vitro drug release from the pellets was carried out 37 ± 0.1^o C in U.S.P automated dissolution tester (Type XXII-paddle apparatus). Dissolution was carried out for 24 hrs at 100 rpm. Pellets were studied both in 900 ml of pH 1.2 HCL buffer for initial two hours and then at pH 7.4 phosphate buffer for 22 hours. At regular time interval, samples were withdrawn and analyzed for the drug using a U.V visible spectrophotometer. In vitro release studies were carried out for matrix pellets prepared by extrusion spheronization as well as by melt-solidification method.

The release data obtained were fitted into Higuchi and Peppas models to understand the release mechanism. Drug release was estimated by UV-Spectroscopy at 338 nm.

The comparative dissolution release study was carried out for optimized formulation F-6 with marketed product Adalat (OROS).

The similarity factor (f 2) was employed to compare the release profiles

A differential and similarity factor was calculated from the mean dissolution data according to the following equations.

Where,

f ₁ Differential factor

f ₂ Similarity factor

n Number of time point

R_t Dissolution value of the reference at‘t’ time

T_t Dissolution value of test formulation at‘t’ time

Differential factor f₁ was calculated by the percentage difference between the two curves at each time point and was a measure of the relative error between the two curves. The acceptable value for f ₁ is 0-15.

The Similarity factor f₂ was logarithmic reciprocal square root transformation of the sum-squared error and is a measure of the similarity in the percentage dissolution between the reference and test products. For a dissolution profile to be considered similar, the value for f₂should be in the range of 50-100. An f₂value of 100 suggests that the test and reference profiles are identical and as the value becomes smaller, the dissimilarity between release profiles increases.

9. Stability studies

Stability is defined as the ability of a particular drug or dosage form in a specific container to remain within its physical, chemical, therapeutical and toxicological specifications. The optimized formulation F-6 was selected for the stability study. Stability study of accelerated conditions was carried out on pellets. Pellets weight equivalent to 10 capsule were packed and sealed in polybags and were placed in glass bottles and subjected to following protocol

Ø 25 ± 2^oC and 60 ± 5% RH

Ø 30 ± 2^oC and 65 ± 5% RH

Ø 40 ± 2^oC and 75 ± 5% RH

The appearance and drug content was evaluated for a time period of 3 months.

Results and discussion:

1. Yield of the process

Percentage yield of matrix pellets prepared by extrusion spheronization were calculated for the six replicate batches. The % yield was found in the range of 86 – 95% summarized in Table 11. Similarly % yield of the pellets prepared by melt solidification method was calculated for four batches and was found in the range of 75% - 79%.

2. Particle size Distribution

Particle size distribution for 6 replicate batches was performed and the data is given in Table 12. The corresponding graph is shown in Figure 12.

Particle size analysis was done by sieving method shows that the process of extrusion Spheronization to prepare Gelucire pellets was successful as 79% of the finished pellets were found on a 14/16 mesh cut. Only 21% of pellets were found in 16/18-mesh cut. Average pellets diameters ranged from 1235 – 1250 microns. Overall 99% of total pellets obtained in desired range proving that the process is very reproducible for preparing the matrix pellets. The moisture content of wet mass was precisely controlled within the limits to obtain Nifedipine pellets of appropriate size and size distribution. The amount of water used during the wetting phase causes an increase in the median pellet size, whatever the following conditions of extrusion or drying process.

Table12: Particle size distribution data of 6 batches of Matrix Pellets of Nifedipine

Particle Size Distribution
Batch No.	14/16 mesh	16/18 mesh	18/20 mesh	Mean Particle Diameter (m)
1.	74.9	24.5	0.6	1239
2.	73.7	25.1	1.2	1235
3.	80.5	19.0	0.5	1250
4.	80.8	18.3	0.9	1250
5.	78.1	21.0	0.9	1240
6.	77.5	22.7	0.8	1245

3.1 Bulk Density

Six batches of 15 g of pellets in each batch were taken in a graduated cylinder and average density with SD was found out. Results are shown in the Table 13 and Table 14. The density data of the pellets shows uniform attributes in whole of the gross batches of The Nifedipine matrix pellets. Though some variation in results of Formulation F-2 and F-5 was observed which could be due to effect of variations in concentrations of moistening liquids IPA, water and PVP, which are used as a binder. The dispersible property of Gelucire enhanced the binding properties of moistening liquid thereby producing greater densification. Pellets containing Gelucire with Avicel PH 101 showed higher bulk densities i.e. prepared by Extrusion, which may be due to the particle size and higher density of Avicel and Gelucire blend.

3.2 Tapped Density and Granule density

Tapped density of the matrix pellets was found out for six batches and the difference between the initial and final volume of the matrix pellets was found to be less than 2%. The tapped densities reported in Table 13 and 14, which indicate that a difference in densities is possible even with the related pairs of drugs. A linear relationship exists between tapped density and equivalent diameter of the dry beads, confirming that a larger equivalent diameter results in less dense packing. Little difference in density (tapped or granule) was found among the pellets obtained by Spheronization and melt solidification method perhaps because, due to similar particle size and size distribution and also the packing properties of pellets did not change.

Table 13. Densities of pellets prepared by Extrusion spheronization method

Formulation Code	F-1	F-2	F-3	F-4	F-5	F-6
Bulk density	0.8265 ± 0.04	0.8303 ±0.81	0.8200 ±0.93	0.8485 ±0.02	0.7548 ±0.03	0.8280 ±0.12
Tapped density	0.9 ±0.48	0.910 ±0.74	0.890 ±0.41	0.923 ±-.05	0.834 ±0.01	0.932 ±0.17
Granule density	1.356 ± 0.74	1.28 ±0.52	1.34 ±0.05	1.58 ±0.03	1.62 ±0.06	1.67 ±0.14

*Standard deviation n=3

Table 14. Densities of pellets prepared by Melt solidification method

Formulation code	E-1	E-2	E-3	E-4
Bulk density	0.776±0.05	0.770±0.34	0.774±0.95	0.793±0.045
Tapped density	0.881±0.06	0.891±0.15	0.852±0.17	0.862±0.053
Granule density	1.17±0.03	1.140±0.04	1.196±0.023	1.096±0.064

*Standard deviation n=3

4. Flow Properties

4.1 Compressibility index

Compressibility index was found for matrix pellets prepared by extrusion spheronization and melt-solidification method and the data is reported in Table 15and16. CI% was found to be in the range of 8 – 12. Hence it can be concluded that the prepared matrix pellets had good flow properties.

4.2 Hausner’s ratio

The Hausner’s ratio and Carr index were more or less the same in all the batches, which might have been due to a similar size distribution. Hausner ratio values showed good flowability. High Hausner ratio of pellets containing Avicel PH 101 may be attributed to a higher span value of the size distribution.

4.3 Angle of repose

An angle of repose < 30^o can also be regarded as an indicator of good flowability of materials. Table 15 and 16 shows the angle of repose and flow rates of the different formulations of pellets prepared by extrusion spheronization and melt solidification method respectively. It was observed that among the pellets containing Avicel PH 101 in higher proportion had the minimum angle of repose. Pellets containing higher proportion of Gelucire had both good circularity as well as high density and as a result they showed very low angle of repose and good flow rate (Table 15 and 16). The flow properties were less satisfactory when the pellets were dried in a tray dryer. An increase in the drying temperature in the tray dryer improved the flow properties, but the flow properties of the pellets depended on the spheronization time. An increase in spheronization time increased the circularity of the pellets. As expected, increased circularity rendered the pellets more flowable. When the spheronization speed was varied, the results were similar to those obtained with changes in spheronization time. An increased speed of spheronization improved the flow properties of the pellets; mainly by increasing the circularities this improvement was very slight.

Table 16. Flow properties of pellets prepared by melt fusion method

Formulation	Cl %	q ^o	Hausner’s ratio	Flow rate g /sec
E-1	11.9	26.45	1.135	1.43
E-2	13.58	27.87	1.157	1.57
E-3	9.15	25.14	1.100	1.356
E-4	8.0	28.54	1.087	1.324

Mechanical strength / Friability

The percent friabilities of all the formulations containing higher proportion of Avicel PH 101 were below 1%. With increase in the concentration of Gelucire percent friability increased, but still the presence of even 25% Avicel PH 101 reduced the friability of the pellets. Higher the proportion of MCC in the pellets, the greater was the mechanical strength of the pellets. The friability of all the batches was below 1%. As the drying temperature increased, the percent friability decreased. At the higher temperatures, the pellets might have become more hardened and less friable because of reductions in porosities and shrinkage. The spheronization time seems to have affected the percent friability of the pellets, even though the change in pellet friability was less pronounced with small increases in spheronization time.

This lack of compaction resulted in light masses, but when the duration of spheronization was increased; hard masses were formed, which led to a reduction in pellet friability. Also, at short spheronization times, the pellets were dumbbell shaped with protruding surfaces, which became more prone to forces during friability testing. % Friability is shown in Table 17 for six batches of matrix pellets prepared by extrusion spheronization. Percent friability values of pellets prepared by melt fusion method were found to be higher when compared to pellets prepared by melt fusion method shown in Table 18.

Table 17. Friability test data of six formulations (Extrusion spheronization)

Formulation code	Weight taken (grams)	Friability
F-1	25	0.43%
F-2	25	0.45%
F-3	25	0.47%
F-4	25	0.50%
F-5	25	0.52%
F-6	25	0.53%

Table 18. Friability test data of four formulations (Melt solidification method)

Formulation code	Weight taken (grams)	Friability
E-1	25	0.67%
E-2	25	0.78%
E-3	25	0.69%
E-4	25	0.86%

Shape analysis

From the results it was observed that sphericity (circulatory factor) was near to one.

The shape analysis of the pellets obtained at different drying conditions is shown in Table 19 and 20. The different shape parameters circularity, elongation, and rectangularity did not change much for pellets. Pellets shrink on drying at a higher temperature. The pellet shrinking might have occurred uniformly throughout the pellets, thus leaving the shape unaffected by the drying conditions. The pellet shapes were, however, highly affected by their retention time in the spheronizer during manufacture. The pellets became rounder with an increase in spheronization time. At 1 and 2 minutes of spheronization the pellets were dumbbell shaped and the pellets became rounder when spheronized for 3 and 5 minutes. However, a further increase in spheronization time did not considerably affect the pellet shapes. At 5 minutes of spheronization, the circularity of the pellets was 0.925, after an optimum time of spheronization; the pellets became compact enough so that no attrition forces could act upon them anymore.

Table 19. Shape analysis of pellets obtained by different drying conditions, spheronization times and spheronization speeds

Formulation code	Circularity	Elongation	Rectangularity
F-1	0.853 ± 0.076	1.242 ± 0.101	0.826 ± 0.069
F-2	0.823 ± 0.056	1.250 ± 0.089	0.831 ± 0.074
F-3	0.890 ± 0.069	1. 244 ± 0.096	0.830 ± 0.063
F-4	0.901 ± 0.060	1.128 ± 0.078	0.827 ± 0.080
F-5	0.913 ± 0.078	1.41 ± 0.068	0.788 ± 0.094
F-6	0.925 ± 0.086	1.149 ± 0.096	0.836 ± 0.077

*Standard deviation n=3

Table 20. Shape analysis of pellets obtained by melt solidification method

Formulation code	Circularity	Elongation	Rectangularity
E-1	0.767 ± 0.065	1.406 ± 0.023	0.836±0.029
E-2	0.732± 0.041	1.543±0.045	0.825±0.082
E-3	0.698±0.087	1.483±0.049	0.815±0.038
E-4	0.773±0.0921	1.734±0.032	0.894±0.043

*Standard deviation n=3

Compatibility studies

FT-IR analysis

Compatibility between the drugs, polymers and other excipients used were studied by using FT-IR spectroscopy, to ascertain whether there was any interaction between the drug and polymers used. The FT-IR spectra obtained are given in Figures 13,14,15 and 16 .The characteristic peaks of the pure drug were compared with the peaks obtained from their respective formulation and are given in Table21. From the data it was observed that similar characteristic peaks appears with identical or with minor differences, at frequencies 3329.0 cm^-1 (N-H stretch), 3101.3 cm^-1 (aromatic C-H stretch), 2961cm^-1(C-H stretch for CH3), 1683.8 cm^-1 (C=O stretch), 1226.9 cm^-1 (C-O stretch), 1433.9 cm^-1 (aromatic N-O stretch) and 825.5 cm^-1 (aromatic C-N stretch) for Nifedipine and F- 6 formulation, it appears that there was no chemical interaction between the drug and the polymer. Also the characteristic peaks of the pure drug were compared with the peaks obtained from their formulation and are given in Table 22. From the data it was observed that similar peaks appears with identical or with minor differences, Hence it appears there is no chemical interaction between drug and polymer and it can be concluded that the characteristics bands of pure drugs were not affected after successful loading. There was no any change in their peak position, indicating that there was no chemical interaction between drug and the polymer used.

Table21. F T –IR Spectra data of pure drug (Nifedipine) alone and Formulation containing Nifedipine prepared by Extrusion spheronization method.

Group absorption	Frequency of Pure Drug (in cm^-1)	Frequency of Formulation (in cm^-1)
N-H stretch	3329.8	3329.2
C-H stretch	3101.6	3101.3
C-H stretch	2961.7	2954.7
C=O stretch	1683.8	1681.8
C-O stretch	1226.9	1226.9
N-O stretch	1433.9	1434.9
C-N stretch	825.5	833.2

Table 22. FT-IR Spectra of pure drug (Nifedipine) alone and Formulation containing Nifedipine prepared by Melt solidification method

Group absorption	Frequency of Pure Drug (in cm^-1)	Frequency of Formulation (in cm^-1)
N-H stretch	3329.8	3339.8
C-H stretch	3101.6	3101.3
C-H stretch	2961.7	2954.7
C=O stretch	1683.8	1681.8
C-O stretch	1226.9	1226.9
N-O stretch	1433.9	1434.9

Differential Scanning Calorimetry

Differential scanning Calorimetry was carried out in order to investigate the possible interaction between the drug and polymers, differential scanning Calorimetry studies were carried out. DSC thermogram of the formulation was compared with the DSC thermogram of pure drug sample. About 70 mg of powdered sample was placed in a platinum crucible and the DSC thermograms were recorded at a heating rate of 5^oC/min from 25^oC to 300^oC.

The DSC thermograms obtained are reported in Figure 17. The pure Nifedipine displayed a sharp endothermic peak at 175.20^oC corresponding to the melting point of the drug, and a similar peak was also observed in the formulation F-6 at 174.57^oC confirming the stability of the drug in the formulation also a similar peak was observed at 174.68^oC for E-3 formulation prepared by Melt solidification method.

8. Surface Morphology

Scanning electron microscopy

Scanning electron microscopy (SEM) is one of the most commonly used method for characterizing drug delivery systems, owing in large part of simplicity of samples preparation and ease of operation. Scanning electron microscopy was carried out in order to characterize surface morphology, texture and porosity of the prepared matrix pellets.

Independent from the used extrusion liquid and extrusion force, all pellets show nearly the same surface texture. Accordingly, the quantity of liquid also has an effect on the roundness of the spheres. Figure18 and 19 shows the surface topography of pellets, where a smooth surface can be observed with its optimal, spherical shape. It also shows approximate diameter of pellets ranging from 1.2 – 1.5 mm. SEM picture of pellets prepared by melt fusion method were scanned at 15 kV. Pellets prepared by melt fusion method were irregular as shown in Figure 20. The shape of pellets can be attributed to lack of plasticity in mass.

Drug loading and Encapsulation efficiency

The test for drug content uniformity was carried out to ascertain that the drug is uniformly distributed in the formulation. Here the drug equivalent to 20 mg was dissolved in 5 ml of methanol and volume was made with 7.4pH phosphate buffer in a 100ml volumetric flask. It was further kept overnight and then filtered using whartmann filter paper. From this, 1 ml of solution was transferred to 10ml volumetric flask. Absorbance was measured at 338 nm. The results obtained are reported in Table22 and 23 for the pellets prepared by spheronization and melt solidification method. From the results obtained, it can be inferred that there is proper distribution of Nifedipine in the matrix pellets and the deviation was within the limits.

Table 23. Drug loading and Encapsulation efficiency of formulations prepared by Extrusion spheronization

Formulation code	Drug loading (mg)	Encapsulation efficiency (%)
F-1	16.5	82.5
F-2	17.8	89.0
F-3	16.9	84.5
F-4	18.9	94.5
F-5	17.65	88.25
F-6	19.2	96.0

Table 24. Drug loading and Encapsulation efficiency of formulations prepared by Melt fusion method.

Formulation code	Drug loading (mg)	Encapsulation efficiency(%)
E-1	16.5	82.5
E-2	15.5	77.5
E-3	14.6	73
E-4	15.8	79

In vitro release studies

In vitro release studies were carried out for all the formulations in both acidic and basic media. The release studies were carried out in 1.2 pH HCl buffer i.e., in SGF for the first two hours to mimic the acidic conditions prevailing in the stomach. For the next 22 hours the release was carried out in basic pH i.e., 7.4 pH buffer to mimic basic condition prevailing in the intestine. The in vitro release data is given in Table 25 for formulations prepared by extrusion spheronization. In contrast to the pellets prepared by the melt solidification method, the observed drug release rates were about constant during significant time periods, irrespective of the type of medium. It was found that Avicel PH101 and different molecular weight blends of Gelucire have proved useful for modulating the release of active agents in controlled release devices for drug release. The addition of the microcrystalline cellulose filler to both matrices has a marked effect on the dissolution rate. In case of formulation (Formulation) F-4, (Formulation) F-5 and (Formulation) F-6 the microcrystalline cellulose is seen to decrease the release rate. This effect becomes more pronounced as the percentage of Gelucire 50/13 in the formulation increases in formulation (F-6). The main characteristic of the use of microcrystalline cellulose as a filler material is the lack of disintegration which results in a prolonged diffusion controlled drug release.

The effect of pellet curing at different temperatures on Nifedipine release in phosphate buffer pH 7.4 was seen for the pellets cured at 40 ^oC and 45^oC for 24 hours. Curing for 24 hours at 40^oC led to an increase in the release rate, whereas curing for 24 hours at 45^oC led to a decrease in the release rates. The acceleration of drug release upon curing at 40^oC can be attributed to decrease in the residual moisture content of pellets. In contrast, curing at 45^oC improved the mechanical stability of the lipid matrices as a result lipid matrices were softened and coalesce with each other resulting in a denser structure and decrease in the drug release rates. In case of pellets prepared by melt solidification method; irrespective of the type of medium Nifedipine release was relatively rapid i.e. within approximately 8 hours the entire drug was released. Interestingly, the release rate was high at early time points, which declined with time. This is a typical behaviour of diffusion-controlled drug delivery systems. At early time points, the diffusion pathways are short, resulting in steep concentration gradients (being the driving forces for diffusion) and, thus, high drug release rates. With increasing time, the length of the diffusion pathways increases, resulting in decreased drug concentration gradients, and thus decreased drug release rates. In- vitro release profile of pellets prepared by Melt solidification method is reported in Table 26.

Table 25 In-vitro release data of Nifedipine from Gelucire based matrix pellets prepared by Extrusion spheronization.

Time in hrs	Cumulative percentage release Mean ± S.D*
	Formulation code
	F-1	F-2	F-3	F-4	F-5	F-6
0	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
1	5.3 ± 0.05	7.6 ± 0.09	7.9 ± 0.029	8.6 ±0.083	9.15±0.021	10.3±0.066
2	16.7 ± 0.07	20.9 ± 0.02	22.6 ±0.037	23.7±0.027	25.1±0.056	28.6±0.022
4	26.9 ± 0.06	31.8 ± 0.08	42.1 ±0.029	46.8±0.080	49.1±0.075	51.3±0.087
6	49.8 ± 0.02	56.1 ± 0.028	59.8 ±0.081	60.5±0.034	63.5±0.019	65.6±0.076
12	65.7 ± 0.01	71.9 ± 0.026	75.6 ±0.019	77.6±0.015	79.5±0.045	82.5±0.018
16	73.2 ± 0.03	79.6 ± 0.039	83.5 ±0.030	85.9±0.018	88.6±0.017	90.1±0.087
18	79.9 ± 0.04	84.7 ± 0.037	86.9 ±0.028	89.8±0.072	93.8±0.076	95.3±0.063
20	82.0 ± 0.06	86.6 ± 0.087	90.2 ±0.076	92.1±0.038	95.9±0.016	96.9±0.074
24	84.1 ± 0.05	88.9 ± 0.038	92.5 ±0.091	94.9±0.011	96.5±0.065	98.9±0.022

*Standard deviation n=3

Table 26 In-vitro release data of Nifedipine from pellets prepared by Melt solidification method.

Time in hrs	Cumulative percentage release Mean ± S.D*
	Formulation code
	E-1	E-2	E-3	E-4
0	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00
1	25.6 ±0.04	27.2±0.09	27.9±0.04	28.6±0.13
2	46.7±0.012	51.9±0.037	52.6±0.06	53.7±0.07
4	76.9±0.05	77.8±0.026	79.1±0.06	81.8±0.018
6	99.8±0.05	-	-	-
12	-	-	-	-
16	-	-	-	-
18	-	-	-	-
20	-	-	-	-
24	-	-	-	-

*Standard deviation n=3

Fig 21: In-vitro release profile of Nifedipine from matrix pellets prepared by Extrusion spheronization

Fig22: In-vitro release profile of matrix pellets prepared by Melt solidification method

Comparison with a marketed product

Formulation F-6 was compared with a marketed product Adalat CR OROS capsule (20mg) to be given once in 24 hours. In the Figure 23 the percentage of drug released from formulation F-6 and marketed controlled release Nifedipine capsule is plotted as a function of time. The dissolution data is tabulated in Table 27. It is evident that prepared matrix pellets by extrusion spheronization have similarity in release when compared to the marketed product.

Formulation Adalat OROS (20mg)

Dissolution of drug from the F-6 formulations was compared with marketed product OROS (20mg) using f ₁ (differential) and f ₂ (similarity) factor. The values of 0-15 for the f₁ and the values of 50-100 for f₂ are acceptable. The values of f₁and f₂ of formulation F-6 and OROS were found to be 5.98 and 93.6 respectively. The values showed the similarity in release profiles

Table 27.Drug release data of formulation n F6 and OROS Adalat

(20 mg)

S.No.	Time (hr)	% Drug Release ± S.D^*
S.No.	Time (hr)	F-6	OROS
1	1	8.9 ± 0.7	10.3 ± 1.2
2	2	26.34 ± 0.9	28.06± 2.1
3	4	48.23 ± 1.6	51.3± 0.8
4	6	65.6 ± 0.4	67.21 ± 2.8
5	12	84.34± 1.4	82.5 ± 1.6
6	16	88.65± 1.6	90.1 ± 1.7
7	18	92.38 ± 0.2	95.3 ± 2.4
8	20	94.45±0.5	96.9 ± 1.7
9	24	96.01±0.1	98.3 ± 2.4

Table- 28. Release kinetic data of formulations F-1, F-2 and F-3

Time in Hrs	Formulation Code
	F-1		F-2		F-3		Log t
	Log % Cum. Rel	Log % Cum. Ret	Log % Cum. Rel	Log % Cum. Ret	Log % Cum. Rel	Log % Cum. Ret	Log t
1	0.7242	1.976	0.88	1.965	0.897	1.964	0
2	1.222	1.92	1.32	1.898	1.354	1.888	0.301
4	1.429	1.863	1.5	1.833	1.624	1.762	0.602
6	1.6972	1.7	1.748	1.642	1.776	1.604	0.778
12	1.817	1.535	1.856	1.448	1.878	1.387	1.079
16	1.864	1.428	1.9	1.309	1.921	1.217	1.204
18	1.902	1.303	1.927	1.184	1.939	1.11	1.255
20	1.913	1.255	1.937	1.127	1.955	0.991	1.301
24	1.924	1.201	1.948	1.045	1.966	0.875	1.38

Table 29. Release kinetic data of formulations F-4, F-5 and F-6

Time in hrs	Formulation Code
	F-4		F-5		F-6		Log t
	Log %	Log %	Log %	Log %	Log %	Log %
	Cum. Rel	Cum. Ret	Cum. Rel	Cum. Ret	Cum. Rel	Cum. Ret
1	0.934	1.96	0.961	1.958	1.1	1.952	0
2	1.374	1.882	1.398	1.875	1.448	1.856	0.301
4	1.67	1.725	1.691	1.706	1.71	1.687	0.602
6	1.781	1.596	1.802	1.562	1.816	1.536	0.778
12	1.889	1.35	1.9	1.311	1.916	1.243	1.079
16	1.933	1.149	1.947	1.056	1.954	0.995	1.204
18	1.953	1.008	1.972	0.792	1.979	0.672	1.255
20	1.964	0.897	1.981	0.612	1.986	0.491	1.301
24	1.977	0.707	1.984	0.544	1.995	0.041	1.38

Table 30. Data of various parameters of model fitting of formulations F-1, F-2 and F-3

Model Fitting	Formulation Code
	F-1		F-2		F-3
	R	K	R	K	R	K
Zero	0.9604	3.0480	0.9550	3.2781	0.9479	3.4929
First	0.9196	-0.0484	0.9200	-0.0545	0.9123	-0.0616
Matrix	0.9176	12.4575	0.9308	13.4813	0.9337	14.4069
Peppas	0.9434	9.7133	0.9407	12.5832	0.9334	14.7250
Hixson	0.9402	-0.0136	0.9411	-0.0151	0.9361	-0.0166

Fig.25: Comparison studies of optimized F-6 (Formulation) and Marketed

Fig 26: Release mechanism of formulations F-1 to F-6

Fig 27: Release kinetic profile of formulations F-1 to F-6

Table 31. Data of various parameters of model fitting of formulations F-4, F-5 and F-6

Model Fitting	Formulation Code
	F-4		F-5		F-6
	R	K	R	K	R	K
Zero	0.9517	3.6822	0.9291	3.8597	0.8682	4.0003
First	0.9135	-0.0684	0.9027	-0.0758	0.8944	-0.0795
Matrix	0.9497	15.2374	0.9536	16.0709	0.9635	16.8635
Peppas	0.9510	15.9603	0.9466	19.1864	0.9567	24.4529
Hixson	0.9442	-0.0180	0.9371	-0.0195	0.9274	-0.0203

Table 32. Release kinetic data of formulations (F-1-F-6) Higuchi plot

Time in hrs	√ time	Cumulative release in mg
Time in hrs	√ time	F-1	F-2	F-3	F-4	F-5	F-6
1	1	1.06	1.52	1.58	1.72	1.83	2.06
2	1.41	3.34	4.18	4.52	4.74	5.00	5.162
4	2	5.38	6.36	8.42	9.36	9.82	10.26
6	2.44	9.96	11.22	11.96	12.1	12.7	13.12
12	3.464	13.14	14.38	15.12	15.52	15.9	16.5
16	4	14.64	15.92	16.7	17.18	17.72	18.02
18	4.242	15.98	16.94	17.38	17.96	18.76	19.06
20	4.472	16.40	17.32	18.04	18.42	19.18	19.38
24	4.898	16.82	17.78	18.5	18.98	19.3	19.78

Fig. 28: Higuchi plot of formulations (F-1 – F-6)

Stability studies

Stability studies of the F-6 formulations of Nifedipine pellets were carried out to determine the effect of formulation additives on the stability of the drug and also to determine the physical stability of the formulation. The stability studies were carried out at 25ºC/60% RH, 30 ºC/65% RH and 40ºC/75% RH for 90 days. There was no significant change in the drug content and appearance of pellets.

Table 34: Stability studies of formulation F-6

Sampling Interval	% Drug loading
Sampling Interval	25 ºC/60% RH	30 ºC/65% RH	40 ºC/75% RH
15 Days	96.802 ± 0.25	96.786 ± 0.89	96.784 ± 0.56
45 Days	96.754± 0.55	96.743 ± 0.56	96.741 ± 0.88
60 Days	96.702 ± 0.23	96.709 ± 0.25	96.690 ± 0.92
90 Days	96.690 ± 0.89	96.668 ± 0.98	96.663 ± 0.37

*Standard deviation n=3

SUMMARY AND CONCLUSION:

The objective of the study was to prepare Gelucire based matrix pellets loaded with Nifedipine by the process of extrusion and spheronization and Melt solidification method. Blend of Gelucire were successfully used to prepare controlled release matrix pellets. The following conclusion were drawn from the results obtained

1) Good yellow coloured spherical pellets with smooth surface were obtained with a yield of 94.5% proving overall superior of this method. The pellets gave good appearance, sphericity and had a suitable density for filling in capsules.

2) The scanning electron micrograph clearly shows that pellets showed nearly the same surface texture i.e. pellets obtained by Extrusion spheronization were smooth with optimal and spherical shape. In contrast pellets obtained by Melt solidification method were irregular.

3) From the FTIR spectra, it was observed that similar characteristic peaks appear with minor differences for the drug and its formulation hence it appears that there was no chemical interaction between the drug and polymers for the pellets prepared by Extrusion spheronization and Melt solidification method.

4) The DSC thermogram obtained for the pure drug and for the formulation shows no significant shift in the endothermic peaks confirming the stability of the drug in the formulation for the pellets prepared by Extrusion and Melt solidification method.

5) From the results of flow properties of pellets it can be concluded that the prepared matrix pellets had good flow properties within the limits and had adequate mechanical strength/friability. From the results of shape analysis it can be confirmed that pellets were nearly spherical with sphericity values near to one.

6) From the results of drug content uniformity it can be confirmed that there was a proper and uniform distribution of drug in the pellets prepared by process of Extrusion/spheronization. The drug loading capacity also showed that the drug loading is optimum.

7) Particle size analysis results showed that all the process variables were within the limits and process is reproducible.

8) The in vitro drug release profiles for all the formulations F-1 to F-6 were not similar and only F-6 showed the release profile as per USP specifications. In case of E-1 to E-1 to E-4 release was relatively rapid i.e. within approximately 8 hours the entire drug was released.

9) The results of mathematical model fitting of data obtained indicate that the drug release through matrix pellets is occurring through Non fickian diffusion or by super case II transport respectively.

10) Formulation F-6 showed similarity release profile with OROS a marketed product when compared in dissolution studies.

11) The results of stability studies carried out on optimized formulation indicate that after 90 days, at25 ºC/60% RH, 30 ºC/65% RH and at 40 ºC/75% RH there was no significant change in drug loading and appearance of pellets.

It can be concluded that the formulation F-6 corresponding to trial 6 of drug release studies would be an ideal formulation to prescribe for once a day administration.

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Received on 18.04.2014 Modified on 29.05.2014

Research J. Science and Tech. 6(3): July- Sept., 2014; Page 156-172

Formul-ation	Cl %	q ^o	Hausner’s ratio	Flow rate g /sec
F-1	8.1± 0.054	25.30±0.021	1.083±0.014	1.623± 0.028
F-2	8.7± 0.038	28.40±0.053	1.090±0.086	1.634±0.056
F-3	7.8 ±0.021	24.11±0.038	1.085±0.076	1.653±0.067
F-4	7.7±0.016	27.56±0.051	1.087±0.064	1.689±0.028
F-5	9.5±0.050	23.19±0.032	1.100 ±0.082	1.70 ±0.081
F-6	11.5±0.080	22.38±0.012	1.120 ±0.056	1.72 ±0.023

Parameter	F-1	F-2	F-3	F-4	F-5	F-6
K	-0.0003	-0.0003	-0.0003	-0.0004	-0.0004	-0.0003
A	0.5910	0.5853	0.5794	0.6140	0.6033	0.5926
R²	0.9673	0.9545	0.9454	0.9686	0.9617	0.9519

Formulation Code	Nifedipine (% w/w)	Gelucire 50/13 (% w/w)	Gelucire 50/02 (% w/w)	Avicel Ph 101 (% w/w)	SLS (%w/w)
F1	20	5	10	65	0.5
F2	20	10	10	60	0.5
F3	20	15	10	55	0.5
F4	20	20	10	50	0.5
F5	20	25	10	45	0.5
F6	20	30	10	40	0.5

Gelucire 50/02

Gelucire 50/13

Microcrystalline Cellulose IP

Lactose IP

Polyvinylpyrolidone IP

Sodium lauryl sulphate IP

Isopropyl alcohol

Methanol

Acetone

Methods:

Characterization of matrix pellets

1. Yield of the Process

v Differential Scanning Calorimetric Studies

v Scanning electron microscopy

Evaluation parameters:

1. Drug loading and Encapsulation efficiency

Comparison with a marketed product

Table 30. Data of various parameters of model fitting of formulations F-1, F-2 and F-3

Fig 26: Release mechanism of formulations F-1 to F-6

Fig 27: Release kinetic profile of formulations F-1 to F-6

F-1

F-2

F-3

F-4

F-5

F-6